In this JCO Article Insights episode, Lauren Shih summaries "Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs" by  Jessica L. Burris, et al published November 19, 2024.

Come back for the next episode where JCO After Hours host, Dr. Davide Soldato interviews the author of the JCO article discussed, Dr. Jessica Burris.

TRANSCRIPT

Lauren Shih: Hello and welcome to JCO Article Insights. I'm your host Lauren Shih, and today we will be discussing the article, “Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs” by Dr. Jessica Burris and colleagues published in the March issue of JCO. This study reports the finding of the Just ASK Initiative, an effort aimed at improving universal smoking assessment in cancer programs nationwide.

We know that smoking after a cancer diagnosis is associated with numerous negative outcomes including worse survival, increased treatment related complications, poorer quality of life and higher healthcare costs. Patients who smoke are also at increased risk for cancer recurrence and second primary malignancies. Despite these risks, data show that a significant number of patients with newly diagnosed cancer still smoke and around 15% of cancer survivors continue smoking. Recognizing this discrepancy, national oncology organizations strongly recommend routine smoking assessment and cessation support as part of standard cancer care. However, despite these guidelines, smoking assessment and cessation assistance remain inconsistent across oncology practices.

Surveys show that most National Cancer Institute designated cancer centers have insufficient resources to effectively support smoking cessation efforts. To address this gap, several large scale initiatives have been launched, including efforts by the National Cancer Institute, the Canadian Partnership Against Cancer, and the American College of Surgeons. The largest of these initiatives, through the American College of Surgeons, is the subject of our report today.

In 2022, the American College of Surgeons introduced the Just ASK Quality Improvement Program with the goal of increasing routine smoking assessment. As member institutions, accredited programs are required to complete at least one quality improvement program annually. And in 2022, 40% of programs chose to participate in Just ASK. The primary goal of this quality improvement program was to ask at least 90% of newly diagnosed cancer patients about their smoking status. Offering smoking cessation support was encouraged, but not a mandatory component or primary endpoint for the initiative. To implement Just ASK, participating programs used a well-established Plan-Do-Study-Act methodology which is a structured, iterative approach for improving healthcare processes. Programs used local quality improvement teams and resources for implementation and had access to online training, educational webinars, and technical resources to help integrate smoking assessment into routine care.

Programs completed three surveys: a baseline survey reflecting smoking assessment practices in the year before Just ASK; a midpoint survey after six months of participation; and a final survey after one year in the program. The surveys assess program characteristics, barriers to smoking assessment, readiness to change, and the frequency of smoking related clinical practices such as asking about smoking, documenting smoking status, and advising smoking cessation. Programs reported on implementation strategies they adopted to improve smoking assessment. Finally, programs reported the number of newly diagnosed cancer patients they saw, how many were asked about their smoking status and how many were identified as current smokers during each reporting period. Results from 762 participating cancer center programs were analyzed. The programs represented a diverse mix of practice sites with over 50% identified as community based. Retention in the program was high, with nearly 90% of programs completing the final survey. Most programs reported moderate organizational readiness at baseline along with an average of 4.6 implementation barriers to conducting routine smoking assessment. Barriers included factors such as lack of time, competing clinical priorities, and lack of designated tobacco treatment specialists. At baseline, the ask rate was 87.8% and this increased to 91.9% at the final survey, meeting the previously identified goal for the initiative.

Throughout the initiative, programs reported increases over time in assessing smoking status, in advising patients who smoked and quit, and in documenting these assessments and recommendations in the medical record. Importantly, the smoking rate among patients asked ranged from 18.5% to 19.8% across the three surveys, demonstrating a high rate of current smoking among newly diagnosed cancer patients. The most common implementation strategies adopted by programs to promote change included gaining leadership support, improving documentation on the electronic health record, and training staff and providers. There were no major differences in implementation strategies based on program type. Organizational readiness was positively associated with better smoking assessment practices, and implementation barriers had a negative impact, although not always statistically significant. The number of implementation strategies used by programs showed a positive, significant association with smoking assessment practices at the final survey. Exploratory analyses did not suggest that program type or patient volume had a consistent relationship with the outcomes.

Although the primary goal of Just ASK was smoking assessment and not cessation assistance or intervention, programs did report on cessation related practices. For example, programs reported providing education or self-help materials increased from 26% to 48%, referrals to tobacco treatment specialists increased from 25% to 35%, and referrals to quit lines increased from 27% to 45%. Prescribing or recommending FDA approved cessation medications increased from 17% to 21%.

In conclusion, Just ASK is the largest nationwide initiative to standardize and improve smoking assessment in cancer care. It successfully improves smoking assessment across a diverse range of cancer practices, ensuring that hundreds of thousands of newly diagnosed cancer patients were asked about their smoking status. As nearly 20% of the cohort reported smoking, this represents a critical first step in helping patients access smoking cessation resources. Participating programs demonstrated small but sustained practice changes in smoking assessment, meeting the a priori determined goal of a 90% ask rate. However, as a quality improvement initiative, Just ASK was not designed as a clinical trial, so conclusions regarding the efficacy of the program as an intervention are limited. Selection bias may have also played a role in the findings as program participation was voluntary. Additionally, the initiative lasted just one year and while the initial improvements were steady during that time, the long term impacts of Just ASK on smoking assessment remain uncertain.

Looking ahead, the American College of Surgeons recently completed the Beyond ASK initiative. This initiative is designed to go a step further and focuses on improving smoking cessation assistance and we await the results. The Just ASK initiative demonstrates the routine smoking assessment is feasible to complete as routine cancer care. This assessment is essential as identifying patients that smoke is the first and critical step towards offering smoking cessation support, which in turn can improve health outcomes and reduce cancer treatment costs. While Just ASK was a success in increasing assessment, the challenge now is ensuring that smoking cessation support is readily available for all patients who need it.

Thank you for listening to JCO Article Insights. Please give us a rating or review and subscribe so you never miss a JCO episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, "“Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas."

TRANSCRIPT 

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center.

Welcome.

Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here.

Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.” And this was published in the JCO on January 27, 2025.

And please note, our participants do not have any conflicts of interest.

So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting?

Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases.

Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together.

Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas?

Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old ‘red devil’, like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation.

Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for.

Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study?

Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas.

And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help.

But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints.

Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that.

Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors.

The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously.

Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect?

Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is “Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses.” So that's the first point.

The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage.

Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?” Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination?

Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients.

But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things.

There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors.

Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting.

I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered?

Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge.

So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy.

The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study.

So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that.

And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents.

Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting.

And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas?

Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients.

Shannon Westin: Well, I support that and my vote is on your side.

So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data.

And thank you to all of our listeners. This has been JCO After Hours’ discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript.

And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or wherever you get your podcasts.

Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Wilky Disclosures 

Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus

In this JCO Article Insights episode, Peter Li summarizes “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al. published on December 13, 2024.

TRANSCRIPT

Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, “Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years,” by Dr. Jianwei Zhang et al. 

For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy. 

They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver.  

Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm.  

Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials. 

The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach. 

In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone.  

This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats.

TRANSCRIPT 

Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles.

Welcome, Dr. Aronson.

Dr. William Aronson: Thank you, Shannon, and delighted to be here.

Dr. Shannon Westin: We are so excited to have you discussing your manuscript, “High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial,” which was published in the Journal of Clinical Oncology on December 13, 2024.

So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help.

Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer.

Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population?

Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems.

Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population.

Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease.

For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available.

Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations?

Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive.

Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial?

Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer.

Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint.

Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks.

Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention?

Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group.

Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners?

Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called ‘macrophage colony stimulating factor’. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed.

Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get.

It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial?

Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study.

Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps?

Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer.

Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon.

Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in.

Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that.

And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Aronson Disclosures:

Stock and Other Ownership Interests Johnson and Johnson

Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas

Research Funding: Lantheus Medical Imaging

UCLA Health Article Video

In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study."

TRANSCRIPT

Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the “Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.” 

Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.  

In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The D\docetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial. 

When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel. 

Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65. 

Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial. 

In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs. 

Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.  

This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Host Dr. Davide Soldato and his guests Dr. Ann Wu and Dr. Alexa White discuss the article "Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study" and the editorial "Growing Evidence for the Role of Air Pollution in Breast Cancer Development" 

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.

 Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. 

Today, we are joined by JCO authors Dr. Anna Wu and Dr. Alexander White. Dr. Wu is a professor of Population and Public Health Sciences at the Keck School of Medicine of UCS, while Dr. White is an investigator in the Epidemiology branch of the Environment and Cancer Epidemiology Group at the National Institute of Health. 

Today, we will be discussing the article titled, “Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study,” and the accompanying editorial. 

So, thank you for speaking with us, Dr. Wu, Dr. White.

Dr. Anna Wu: Thank you for having us.

Dr. Alexandra White: Yes, thank you so much for the invitation to be here.

Dr. Davide Soldato: So before going in depth about the results of the study that was published in the JCO, I was wondering if you could give us like a brief introduction and a little bit of background about what was known about air pollution as a risk factor for breast cancer and what was the evidence before this study was conducted.

Dr. Alexandra White: Okay. I can start with that question. So, there's been research for decades looking at the relationship between air pollution and breast cancer. And it's been a really challenging question to address for a number of reasons. One being that it can be really difficult to assess exposure to air pollution and many previous studies have had really limited information on people's residences over time. But in general, what we thought leading up to this study was that evidence was most consistent that exposure to traffic related pollutants such as nitrogen dioxide was more consistently related to a higher risk of breast cancer. The evidence for fine particulate matter or PM2.5 was less consistent. More recently, there have been a few large, well conducted studies that have supported a positive association. This new study in the multiethnic cohort led by Dr. Wu is really important because it really demonstrated that, in this large study of over 50,000 women in California, that they also do see an association with PM2.5. 

Dr. Davide Soldato: Thank you very much for the introduction. So, Dr. Wu, we just want to hear a little bit more about the results. So, what was the association that was observed for PM2.5? And specifically, the study that you ran was focused on a very diverse population, a multiethnic cohort, and so I was wondering if you observed any type of differences when you consider the different populations that were included in your study. And if you could also give us a little bit of what was the composition of the women that were enrolled in this cohort.

Dr. Anna Wu: Thank you for the question. So, the multiethnic cohort study is a cohort of over 200,000 individuals who were enrolled when they lived in Hawaii or California. For the air pollution studies that we've been conducting, we have focused on primarily the California participants. And in this instance for the breast cancer study, it was based on roughly 56,000 individuals out of- there were about 100,000 because half of them were men and they were not included. Of the California participants, 75% of them were African Americans or Latinos and they were self-identified as these racial ethnic groups when they enrolled in the study. And this was a particularly important consideration for us because in most of the studies that have been published so far on-air pollution and breast cancer, as well as other cancer sites, most of those studies were conducted among whites in the US or whites in Europe. And even if they included non-white populations, the numbers tend to be small so that they were not able to conduct racial ethnic specific analysis. So, we were particularly interested in examining these other racial ethnic groups because we know from other studies that racial ethnic minority groups tend to live in communities of low socioeconomic status and those communities also tend to have higher levels of various types of environmental pollutants. And so, it was important for us to actually try to tease apart these various interrelated factors. 

So, what we found was that per 10 micrograms per cubic meter, we had a 28% increased risk overall in all participants combined that meet across the racial ethnic groups. We actually did not see any differences or significant differences in the hazard ratios by race ethnicity and they were in general quite compatible with each other. But we did see a stronger finding among the white participants in our study.

Dr. Davide Soldato: Thank you, a lot, Dr. Wu. So, I think it's very interesting the fact that in the end you observed that air pollution is a significant risk factor across all the ethnicities that were included in the study. But I think that one very strong point of the manuscript and one very strong point of the analysis was that in the end you also corrected for a series of different factors because we know that the incidence of breast cancer can be modified, for example, by familial history or BMI or smoking habits or also alcohol consumption. And a lot of these risk factors were included in your analysis. And so, I was wondering if you could tell us a little bit whether you observed any significant differences when you observed or included also these risk factors in your analysis, or whether the association for air pollution as a risk factor stands even when we consider all of these other elements.

Dr. Anna Wu: Yes. So, we considered all the well-established breast cancer risk factors. And in this situation, we were particularly interested in considering smoking, alcohol intake, use of menopausal hormones, history of diabetes, body mass index, family history, as well as physical activity, because many of these risk factors, such as, for example, diabetes and body mass index, they are risk factors for breast cancer, and air pollution, have also been found to increase risk of these factors. 

So, in our analysis, we first adjusted for all of these potential confounders in a mutually adjusted manner, so all of them were considered. In addition, we also conducted stratify analysis. So as an example, we stratified the analysis to examine whether the hazard ratio associated with PM2.5 provided comparable risk estimate or hazard ratio estimates for never smokers, former smokers, and current smokers. Although we did not see significant heterogeneity by these various subgroups, we did see a significantly stronger effect of PM2.5 among individuals who did not have a family history of breast cancer. 

Interestingly, our finding was also stronger among individuals who were never smokers and light alcohol drinkers, even though the results were not significantly different. So, we surmised that maybe individuals who already had a high risk because of other established risk factors for breast cancer, we were less likely to be able to observe the effect of air pollution. But it's important to note that other studies, such as the ones that Dr. White has conducted, have also looked at various subgroups, and I think part of the limitation that all of us have is that once you subdivide the study population, even if you start out with a large sample size, often the sample size gets cut in half or a third. And so, we still lack the statistical power to be able to observe significant differences. But I think it is important to note that, in fact, the hazard ratio estimates are actually quite comparable, but we did see a hint of stronger effects among never smokers, and people who were light alcohol drinkers. So, I think this is an area that we certainly need to continue to investigate since there are other subgroups, such as menopausal status, such as hormone receptor status of breast cancer, that we need to consider in future studies. There's still a lot of work we need to do to sort this out, to actually figure out who are the women who are the most susceptible to the exposures.

Dr. Davide Soldato: Dr. White, I would really love a comment from you on this specific area and specifically on what still needs to be done. And related to this, a question actually, for both of you, because I think that from a methodological point of view, there is a lot of work that goes into deciding how we are going to assess the exposure to air pollution. So which type of data are we going to use? Which type of data are we currently using in the epidemiological studies that have been conducted and in the one that we are discussing right now in JCO? And what are the caveats for this data that we are using? Meaning, I think that we use mostly residential addresses, which means that we are looking at the exposure where people actually live, which might not be the place where they spend most of their time. For example, if someone is working, maybe they could be more exposed and have higher exposure when they are at work compared to when they are at home. So, I was wondering if you could give us a little bit of an overview as to what is the methodological standard of care right now in terms of this analysis and what can we do better to refine and understand this specific factor as Dr. Wu was mentioning?

Dr. Alexandra White: Yeah, so I'm happy to take a first stab at that question. So, I think it's important to note just how far we've come. I think even a few years ago, air pollution was really not considered a risk factor for breast cancer. And a lot of the work that we've been doing and others have really moved this forward in terms of understanding this as a risk factor. And as I mentioned earlier, there have been a lot of challenges in exposure assessment. And to get to your question, I think that our studies in general are doing better at looking at exposure over more years, residences, more time. We know that cancer takes time to develop, and we can't rely on just a single snapshot of exposure. But as you mentioned, almost all of the studies published have really exclusively focused on residential estimates of exposure. And so, there's a real need to understand the exposures that people are experiencing in other aspects of their life, from their commute to their jobs, to really capture that totality of exposure. 

And then I think one of the points that Dr. Wu was alluding to as well as we know that breast cancer is a very heterogeneous disease, so risk factors for breast cancer vary by tumor subtypes, by menopausal status at diagnosis. And a lot of studies have really focused on considering breast cancer as a combined outcome, and that might be missing some really important signals where we might have a stronger effect for certain subtypes due to the fact that there's different biologic pathways that are underlying these subtypes or by menopausal status. And so having large study populations where, as we discussed earlier, would really give us the power to look among these smaller groups of women who might be more susceptible and those with younger women, we know that incidence of cancer is rising in young people, and we need to understand the risk factors for that. And most of our studies are really focused on older individuals, so I think that's one important gap, as well as having the power to really look at different differences by tumor subtypes.

Dr. Davide Soldato: I think it's very interesting, and I think one point both of you made in the original article and in the accompanying editorial is also the fact that we tend to look at these risk factors in people who are actually aged, while we maybe should be looking at this in an earlier phase of development and potentially during puberty. Do you think that we should design studies that are more focused on this population even though I think that they will take a lot of time to produce significant results? 

Dr. Alexandra White: Yeah. I think that it is really important to consider how exposure during early life is related to breast cancer risk. We know that exposures during pregnancy or even as early as during puberty might be particularly relevant for breast cancer. And I think a lot of our studies have really been up against the challenge of the fact that exposure monitoring for air pollution really didn't start until the 1990s. And so, it's challenging, especially for these older cohorts, to get back at that time period that might be relevant. But I think that's something that definitely newer cohorts are going to be able to address, and I think it's going to be really important, and also will give us some clues to better understand the important windows of exposure, but also that might provide clues for the biologic pathways as well that are relevant.

Dr. Davide Soldato: And just a related question, because I'm not aware of this, but are there right now cohorts that are specifically looking at this in the US or in other parts of the world? If you are aware of that, of course. 

Dr. Alexandra White: There have been some cohorts that have focused on exposure during these hypothesized windows of susceptibility, but I don't think they've been able to follow those women long enough to develop breast cancer. One of the things that we're working on in the sister study is trying to expand our assessment of air pollution exposure back in time to try to get at these earlier windows of exposure. So, I'm hoping that it's something we'll be able to comment on and at least for some of the women in our cohort who are younger. But I don't know, Dr. Wu, if you're familiar with any other populations that are doing this now? 

Dr. Anna Wu: Well, NCI funded several new cohorts in the last couple years that are really focused on trying to get a much more refined exposure assessment. So, I know colleagues at University of Michigan that are peers and also Dr. Wei Zheng at Vanderbilt, they are putting together newer cohorts that are younger and also trying to include a range of exposure, not just air pollution, but really environmental exposures. Those cohorts I think have the potential in the future to try to address some of these questions, but again, it will take at least another number of years before there are a sufficient number of endpoints so that they can actually do these types of studies. 

Another possibility is that there are a number of big cohort studies in Asia. The age of diagnosis tends to be earlier in Asia. I know that investigators in China are very interested and concerned with the air pollution effects in China. I think there are potentials that in other countries where the age of breast cancer diagnosis is actually younger than in the US and if they establish in a manner that allows them to assess air pollution that they may have opportunities. 

And I think the other way to try to address this question, whether there are studies where you can actually tap into either biomarkers or pathology samples so you won't be actually studying air pollution in a large population, but you're actually narrowing it down to try to see if you see any signals in a way that would give you some additional clues and insights as to the mechanism. So I think we're going to have to piece together various types of study to try to answer the questions because one type of study like these observational air pollution studies, will allow us to address one slice of the questions that we have and then we need to put together other studies so that we can address other aspects that we're interested in to put it together.

Dr. Davide Soldato: Thank you very much both of you. That was very interesting. 

Coming back to the results of the manuscript, we really focused up until now on PM2.5. But it's true that inside of the study you evaluated different pollutants. So, I was wondering whether you saw a similar association for other pollutants that were included in the study or whether the association for higher risk was observed only for PM2.5.

Dr. Anna Wu: The results for NO2, NOx, PM10, and carbon monoxide were actually very compatible with the risk estimates that other studies have published as well as from the meta-analysis. So, I would say that our results from the other pollutants are actually very consistent with other results. I think one difference is that our PM2.5 estimates were based on the satellite-based PM2.5 estimates, whereas all the other pollutants were based on monitoring station estimates from EPA sponsored air monitoring stations. So, they are not measured in the same way. And I think different studies over time have used either monitoring station type measures for other pollutants. And I think we were particularly interested in PM2.5 because the measurement of PM2.5 in the monitoring world didn't start until around 2000. So, studies up until that time were less able to actually provide the assessment of PM2.5 as good as we can for air pollution. There's always misclassification. So, I think it's a matter of how much misclassification in the assessment. But, again, we are really limited in really just having exposure over one part of adult life. 

Dr. Davide Soldato: Thank you very much. And one potentially related question. We are speaking in general about air pollution, but I think that since we are considering residential addresses, probably we are capturing more either traffic pollution or pollution that comes from probably industries or stuff like that, which is mostly related to residential areas or the place where people live. But I think that in the end we also think about air pollution as something that can come from different forms. And one very interesting point, Dr. White, that you made in your editorial is also that there is a global change also in the way we are faced with air pollution. For example, you made the example of wildfires in your editorial and how this might potentially change exposure to air pollution, maybe for limited times, but with concentrations that are fairly higher compared to what we generally observed. So, I was wondering if you could comment a little bit on that and also, if there is potentially a way to also consider this in future epidemiological studies.

Dr. Alexandra White: Yeah, so when we talk about exposure to fine particulate matter, PM2.5, we're assessing exposure to particles that are based on the size of the particle, and we're really not evaluating the types of particles that people are experiencing exposure to. And we know that, in general, that PM2.5 composition really varies geographically due to differing sources of exposure. So, like you were saying, there might be a stronger contribution to industry or from agriculture or from traffic. And so that could really change the PM2.5 exposure profile that individuals experience. And so it could be that this is another really important area that this research needs to consider, which could really help us identify what sources of exposure are most relevant.  

Wildfires are a really important growing concern. We know that wildfires are increasing in both intensity and duration and frequency, and we really don't understand the long-term health impacts of wildfires. But we know that wildfire associated PM2.5 might be one of the most dominant contributors to PM2.5 moving forward. And although we've seen historic declines in PM2.5 in the US after the Clean Air Act, those declines have really stalled. PM2.5 itself is projected to increase over the next few decades, so understanding different PM2.5 composition profiles and the sources that drive them can really help us identify the most important targets for any potential interventions. And wildfire PM2.5 in particular may be of concern because it's a combustion byproduct, and so it's thought to have more of the components that might, we hypothesize, are most relevant for breast cancer, such as PAHs or polycyclic aromatic hydrocarbons or metals. And so, these components are thought to act as endocrine disruptors, which may be particularly relevant for breast cancer. So, I think understanding this changing landscape of PM2.5 moving forward is going to be really important in understanding how PM2.5 contributes to cancers beyond just breast, but as well as other female hormone driven cancers and all of the cancers really. 

Dr. Davide Soldato: Thank you very much. So, one closing remark, because I think that in general, we have been really in a field of primary prevention for breast cancer where we were focusing on individual behaviors, for example, smoking cessation, reduction in alcohol intake, reduction of BMI, increase of physical activity. But I think that the evidence that is accumulating in the last three years or so is telling us more and more that we also need to shift the perspective on prevention going not only on individuals, but also as including environmental risk. So, I was wondering, how can we include this new evidence in the policies that we implement and how policymakers should act on the data that we have available right now?

Dr. Anna Wu: I think it's really important that this new information is communicated to all the stakeholders, including our policymakers, so that they are, first of all, really aware that any changes and not actually adhering to current guidelines can have long lasting consequences, deleterious consequences. And I think it's important to also note that over 90% of the world actually live in areas where PM2.5 exceeds the limit. We have observed increases in breast cancer in many middle- and low-income countries, so I think it's particularly important to emphasize that this is really not just a western country issue, it is really a global issue.

Dr. Alexandra White: I agree. And I would just add to that that air pollution is not something that an individual can really change on their own. There are things you can do, you can monitor air quality, you can try to live in a home that's far away from traffic. But really these are large scale problems that really require large scale solutions. And we know that policy changes can be effective here and that this is something that, in my opinion, is not something that we leave to the individual to change. This is something that we as a society should encourage change for the health of everyone.

Dr. Davide Soldato: So, thank you very much again, Dr. Wu, Dr. White, for joining us today on the podcast.

Dr. Anna Wu: Thank you.

Dr. Alexandra White: Thank you so much for having us. 

Dr. Davide Soldato: So we appreciate you sharing more on your JCO article and accompanying editorial titled, “Air Pollution and Breast Cancer Incidents in the Multiethnic Cohort Study.” 

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on  "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies" by Bhardwarj, et al and "US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations" by Dilawari et al published in the Journal of Clinical Oncology. 

TRANSCRIPT

Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is “Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies,” and the second one is the “US FDA Approval Summary on Capivasertib with Fulvestrant  for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration.” 

As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further. 

In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option. 

Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis. 

By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib. 

In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor. 

Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Host Dr. Davide Soldato and guests Dr. Suzanne George and Liz Salmi discuss their JCO article "Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality"

TRANSCRIPT TO COME

Dr. Davide Soldato: Hello and welcome to JCO’s After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy.

Today, we are joined by JCO authors Liz Salmi, Researcher and Patient Advocate, and by Dr. Suzanne George, who works as a Medical Oncologist at the Dana-Farber Cancer Institute where she acts as the Chief of the Division of Sarcoma. She is also Associate Professor of Medicine at Harvard Medical School. Today, we are going to discuss with Suzanne and with Liz the article titled, “Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality.”

So thank you for speaking with us, Suzanne, Liz.

Liz Salmi: Thanks for having us.

Dr. Suzanne George: Yes, thanks.

Dr. Davide Soldato: I just want to make a brief introduction because I think that the concept of patient partner research is very wide and I'm not sure that all of the readers of JCO really have a deep understanding because I imagine that there are a lot of ways we can involve patient and patient advocates in the research process. And so I was wondering if you could give us a little bit of an introduction about the concept.

Dr. Suzanne George: Sure. I think the point that you raise is really important because there are many terms that are used, patient-partnered research, patient advocacy, but I don't think that there's a single definition as to what that actually means. In the context of our work, we’ve sort of summarized our experience through something called the PE-CGS or the Participant Engagement and Cancer Genome Sequencing network. And in that project, which is a Moonshot funded network, the intention is to have participants in research be true partners working with traditional academic research teams in order to develop networks specifically focused on cancer genomics. So what we've done, every center is a little bit different in the network, but we're really having research participants not just act, but really work on the research team from the beginning of the project inception all the way through the research project.

Liz Salmi: What brings me to the PE-CGS network is my 17 years experience as a person living with a low grade glioma, brain tumor or brain cancer and involving patients in the co-design of research is super critical because patients bring unique lived experiences that can shape research questions, study designs and outcome measures in ways researchers might not anticipate. And we're finding this through our network. So through my work, including my patient experience and brain tumor focused study designs, I've seen firsthand that patient insights can drive more practical implementations that ultimately benefit both patients and the researchers. And so the particular project I work on in the network, we've got like five different arms and different groups of cancer types that are being represented, so I'm basically focusing on the OPTIMUM study around how brain tumor patients can help in this study design. So in this project I serve as not just a participant in the research, but also as a patient co-investigator.

Dr. Davide Soldato: That is very interesting. And I think that we really captured the essence of patient-partnered research by having both of you here talking with us about the PE-CGS. And the second question that I wanted to ask is: I really think that the network focuses on something that is quite important right now and currently in medical oncology - so cancer genome sequencing, access to novel therapies - and I think that it's really challenging to imagine a way in which we can really get our patient and get patient advocates to help us designing new trials who are looking into this. And I just wanted to know, do you think that there is something that is particularly challenging when we are speaking specifically about cancer genomics and access to this type of drugs that are targeting specific molecular alteration? Because I think that in general it might be a little bit easier, maybe I'm biased on this, so you can also tell me if I'm wrong, but I think that it's a little bit easier when we are trying to design, for example, behavioral intervention or things that are more commonly found in oncology and a little bit more complicated when we are speaking about genomics.

Dr. Suzanne George: So I think that's part of what this network is trying to address, which is really what are the barriers and the opportunities around cancer genomics from the patient perspective and how do we make sure that that perspective is included as we're thinking about study design and inclusion? As Liz mentioned, this network has five different networks within the network, five different centers, and each center is slightly different with the population that it engages with. And so there's diversity there in terms of reaching out to different patient communities and partner communities around potential barriers for genomics research. I think one of the things though that we're finding across the network is that people want to be part of this work. People that have a lived experience of cancer want to help move the field forward. And what we ended up writing about was some of the barriers that get in the way of that. It's awesome to have people like Liz that are like all in and then there's people who are on the other end of the spectrum that want to share their information to help move the field forward around genomics, but then there's all these barriers at the systems level that get in the way of that. So I think that that's one of the challenges we're trying to overcome and learn about across the network.

Liz Salmi: Yeah, I think I bring this really interesting, I can't say I'm really interesting, but I think I bring this really niche perspective. Not only am I a person living with a brain tumor and I'm a co-investigator but also like a participant in this study. I also, in my day job, I'm an investigator as part of the director of communications and patient initiatives on the OpenNotes lab at Beth Israel Deaconess Medical Center. And our lab really focuses on how open, transparent communication between doctors and patients improves care. And that's been going on for longer than I've been around on our team. But what I bring to that lab is I focus on engaging both patients and clinicians in spreading the awareness about the power of how easy access and transparent communication, access to information across healthcare settings helps patients feel more involved and informed in their care.

And I work specifically, it's a really niche area. I work on projects that aim to expand access to notes and test results in diverse care settings, really helping tailoring initiatives so that various patient communities can understand how they can be involved in these types of research projects. Ultimately that's what brought me into this space. I might be one of the first generation of patients that actually starts helping co-design studies on things like this. And I think that across a lot of healthcare settings cancer is really what we're focused on. But patients are now increasingly being involved as research collaborators. And there's many different funding institutions such as the NCI but also PCORI they now mandate that funders reflect a shift towards more patient centered research frameworks. So it's like the PE-CGS network isn't the only group that's being funded to do research in this way. And I think other investigators, even outside of the cancer space, but specifically in cancer, need to learn how to do research in this way.

Dr. Suzanne George: Yeah, I agree. And I think the other thing that we need to do is if people want to participate and that participation in many of these networks has to do with record sharing and data sharing, the system needs to accommodate that. If people want to share their information in order to allow research to be performed, then we need to make sure that that can happen, and that it's not that the institution systems don't connect with someone else's systems or that you to pay X, Y and Z dollars for the data to go A, B and C, or that some places are on this EHR and some places are on that EHR and so, sure, you can share it, but you have to go through all of these hurdles in order to make it happen. When a patient signs a consent form that says, “I want my data to be used,” we as an investigator community, we owe it to that patient to make sure that their information is being part of the data set that will be used for learnings. And that's part of what we wrote about, is the lots of behind the scenes things that just get in the way and that we need to work towards improving.

Liz Salmi: Both Suzanne and I are really passionate about this stuff. And as a person living with a brain tumor for the last 17 years, I'm a chronic research participant. I always, always, am really curious. I'm like, “Yes, let me contribute my data. Whether that's electronic health record data or maybe I'm being interviewed about certain aspects of the cancer care experience.” And the one thing that bummed me out for like the first 10 years of being this chronic research participant is I would enroll in things, I'd be interviewed for things, I'd fill out these surveys and then I never heard anything about what happened with that information and that time I spent. And people would send me like a $10 gift card to Amazon, like, “Thanks for participating,” but really what I wanted to know is like, did you do anything with that? How did that inform things? So that really annoyed me to the point where I was like, I'm just going to be part of the research process and really figure out how we share that information back to everybody who had spent so much time. And so my participation in this space is like, “Let's change it. Let's give people information back.” And now I know it takes a really long time to have a finding that could be published somewhere that we then get it back. But closing the loop on the communications gap is something I'm really passionate about.

Dr. Davide Soldato: Do you think that we are changing a little bit this perspective? I feel like we are getting a little bit better in creating patient communities of patients who are included in specific clinical trials. And then we do the effort of creating a community, of keeping people really involved with the research that they are participating in. I think that we are not quite there yet, but I think that we are making some kind of steps in that direction. For example, trying also to inform patients to participate in the study when the publication that is related to that specific study comes out. What is the benefit? What have we discovered? I think that we are not quite there yet. There is a lot of room for improvement, particularly in the way I think we communicate these to patients who participated in research. But I have the impression that we are making some steps forward. So I don't know. Do you share the same thoughts?

Liz Salmi: So Dr. George talked about the PE-CGS network and then there's five different cancer types being studied. So the thing I can reflect on is what we've done in the, this is a really long acronym but, Optimizing Molecular Characterization of Low Grade Glioma. Say that 10 times fast. So our particular group is people who donate tissues about their brain tumors. We're really collecting data from people with multiple brain surgeries over time, which is really complicated and to make that process easier. And then once those tissue samples are stored somewhere, studying that information about what changes in the brain tumors over time and then also giving those results back to people so they can take that research level data and bring it back to their neuro oncology team and say, “Hey. Here's what I found out, “and having a conversation.

So, this is a long multi touch point study and in order to do that, to even make that possible is the individual patients need to understand what's in it for them. They're donating precious tissue in order to make the research process work. And so in order to do that, it's not just the investigators saying, “Hey. Give us your brain tissue, peace out.” It is we have a whole research advisory council of people living with these particular tumor types who help us co-design how do we do that outreach, how do we explain why this is important, or how do we message the importance of this work so they understand,“Oh, this is what's in it for me and this is what's in it for other people like me.” And from there then with that process, which again I mentioned, all of these multi-step processes, once we're able to understand how patients want to hear that information, what's in it for them, then we bring it back to like those bench scientists, investigators going, “Okay. And here's how this workflow should work for the patients,” and design everything around the patient experience before we even care about what's happening from the scientist researcher perspective.

Dr. Suzanne George: I agree. I think to your point, I think the fact that we're all here today talking about this is just like you said, is that we are making progress, right? Like we're even here having this conversation. Just like you said, I think there's opportunities to improve and further refine the communication and the involvement back in the patient community. When I think- if I put on my clinical investigator hat, I'm very involved in PE-CGS, but my primary research interest historically has been clinical trials and drug development. And I think that our approach in communicating results back has just not been consistent. But I do think that there's opportunities, just like you said, to provide summaries of information to loop back. I don't think that we've completely solved: What do we do? How do we provide information back to loved ones of patients that may no longer be alive that participated? How do we provide information to people who maybe we don't have their contact information? What if we lose track of them? How do we also make sure that we give people the choice to know? Do you want to know about this or would you rather just participate and then give space to that research? Because maybe that's how people's best for them. So I think that you're right, we're making progress, but I think that there's also a lot more that we can do. So I'm glad we're talking about it.

Dr. Davide Soldato: How much do you think that directly involving patients in this process, like asking them directly and co-designing the trial from the very beginning and understanding the level of information? This might also be another question inside of the question. So first, how much co-designing this type of research helps, and then do we also need to further refine at that level of communication, different communication depending on the level of information that different people want to have? Because I think that that's another level of complexity that we need to work towards at a certain point. We need to work on that first level of giving back the information. But then I think that there is also the other point of providing the information and information that should also be probably adapted to the cultural belief of different patients, to the ethnicity or to whatever cultural background or social background or whatever they may place their most interest in.

Dr. Suzanne George: So I think that you're 100% right on all of those points. I think those are all topics that need to be considered. We may be able to get to a certain degree of granularity around those communication points, but on the other hand, we also want to be able to communicate broadly and accessibly as possible.

One of the interesting things about PE-CGS, as Liz was mentioning, is each of the five centers has a slightly different focus. For example, one of the centers is focused on American Indians and Tribal Nations, and the communication practices coming out of that center are really unique and really very special and something that's been really, I think for me, very fascinating to hear about. Because to your point, like, just the strategy and what's considered appropriate is just different. I think if we hope to build a research world where our research participants and research data come from a broad swath of the population that really represents the population, the only way that we're going to be able to do that is find ways that bring meaning across the population as well. And that may be different based on where people are coming from and where people are at in their own journeys and in their own lives. But it's on us to be open to that and like to hear that, so we can do the right thing.

Dr. Davide Soldato: And I think that this is one of the objectives of the PE-CGS, really trying to bring this type of research participation to really diverse and underrepresented populations, not only in terms of cultural background, but I also think about different types of tumors. Like Liz was referring about brain cancer or low grade glioma, which is a very niche population. And I also think about sarcomas, for example, the degree of variability that we have in that specific type of disease is such that we really need to probably find different ways to communicate also inside of this diversity in terms of single patient and experiences, but also in terms of single diseases.

You were speaking a little bit before about the fact that the manuscript is really on the barriers that we would need to identify and then to change to make this system a reality. We were talking a little bit about consenting information and consenting the sharing of information, and I think that you make a very interesting point about the consent process when we are designing research. Could you give a little bit of your impressions about giving informed consent? What we need to change, how can we improve?

Dr. Suzanne George: The bottom line is the consent process needs to be simple, clear, and transparent. And sometimes I feel, because the traditional way that we've always gone about consent is frequently consent is as it should be in many ways. These consent forms are developed from a regulatory framework. What are we required to do to consent and how do we meet those requirements? Sometimes that becomes directly at odds with how do we do this simply, clearly and transparently? And I think as a research community, we have to be able to find a common ground there. That has to include regulatory requirements, that has to include IRBs. When we think about consents and work with our patient communities on this, everybody agrees the consents need to be more simple, except the IRB or maybe the IRB agrees, but it's this tension between how do we make it simple, clear and transparent and not get so bogged down in the regulatory that we lose that intent.

Liz Salmi: It's complicated. As a person, I mentioned, I'm a chronic research participant living with a brain tumor for 17 years. I remember enrolling in studies and seeing things that are just so complicated. I'm like, “Well, I'm just going to sign off.” I imagine somewhere somebody who knew more than me said, “I should just fill out this thing.” And then as I switched to the research world, I spent more time digging into, “Wow, this is a really complicated consent,” versus, “This is a really streamlined consent and I love this.”

And throughout my work with Dr. George and others on the PE-CGS network, an example of a good consent that's easy for people to understand is what the NIH All Of Us research project did, where they're trying to get a million people, more than that, signed up to be in this longitudinal study. And their consent is to go to their website and they have a whole bunch of short YouTube videos. There's a kind of like a quiz involved and they're animated, they have multiple languages involved. And I signed up for that study and I was like, “This is a beautiful consent.” And it's a very plain language. And more consents like that. If you're looking for a good example, go there. I have not been paid by them in any way. I'm a participant in their study.

I'm not sure if you guys and your listeners are aware, but there was I think, October 19th of this year or 2024, there was a special communication published in JAMA on an update on the Helsinki Principles for Medical Research involving human participants. And what they're saying is an ethical update is patient engagement in research, which emphasizes the need for continuous, meaningful engagement with research participants and their communities throughout the research life cycle, before, during and after studies. And so this is what we're talking about here. And it's now been embedded in these updated principles.

Dr. Suzanne George: That's really great and I agree with you. I think the All Of Us consent process is very accessible. It feels like you can understand it. But the other thing is that, again, I also am not directly involved with All Of Us, but the other thing about it is that they also have a high-touch way to consent where they have navigators and people that will go into communities in a very resource intensive way. So there's all different ways to go about it. We need to find a way that we can balance the complexity around regulatory and the simplicity and transparency that we need in cancer research.

Dr. Davide Soldato: Do you think that in terms of patient engagement we are doing better in academic sponsored research compared to sponsored research? A little bit of a provocative question maybe.

Dr. Suzanne George: I think that's a really interesting question. I think this idea of participant engagement and involvement is being infused across the research community. And in part, the FDA has prioritized it as well. I think the industry sees the FDA prioritizing this as well. And I think that there are many companies that are involving participant and advocacy communities in different ways in the study design, in the study process early on. So I think it's happening.

Liz Salmi: I'll be spicy. I've been a participant, I've been an investigator, co-investigator on studies and I have been reached out to often by pharma of, “Hey Liz, brain tumor patient advocate, would you be kind of like the poster child of our study or be involved in that way?” And I personally want to have no work in that space. I have no interest. However, I am approached, and other people living with cancer have been approached, by industry about lending their likeness or being commercials. And I don't think there's enough education to patient advocates of what that necessarily means, pros and cons. But I also can't speak on behalf of all of the patient advocates who might want to see that's a way that they could lend their voice and advance research. I personally think that there needs to be more involvement from the academic side of creating spaces where patients can be involved in the co-design of research and they also get compensated for their time fairly at the same level or some version of it in a way so they don't just jump to the pharma side of things. But that's an opinion that I have. Opinions.

Dr. Suzanne George: I think it's really interesting the point that you make about providing more awareness or information about what it even means to do these things from a patient side. I certainly don't know that side as well, but I do see, often, the term patient advocate used very frequently in many different contexts that mean many different things. And I think that there's an opportunity there for understanding more about what that really means and what it can mean.

Liz Salmi: Yeah. We want to involve patients, we want to do patient engagement. The BMJ or the British Medical Journal, have this new policy in place for patients as reviewers of research. And what I find interesting with the BMJ is they also ask patients to declare their conflicts of interest. So this is kind of a new space. If you're involved in patient research or perhaps working with pharma, patients, if you're involved at that level, should also be declaring their conflicts of interest if they're getting paid by a pharma. Or do I have a conflict now that I'm doing this cool ASCO podcast? Maybe. But do we want to overburden patients with tracking all this information? So it's a new world. The more we have access to information, the more we share information, the more we can read studies and we co-design, there's a new space I think over the next 5 to 10 years where how do we define this in a transparent way.

Dr. Suzanne George: Yeah, I think you're right. I know that we're getting long, but I just want to say one other thing about that, which is that you're right. If we're bringing patients in to be partners, then we have to treat each other that way. We have to acknowledge- I think this issue that you raise about compensation and about paying people for their time or acknowledging people for their time, I think that's really important and very under-discussed. Liz and I were at the annual meeting for the PE-CGS and someone was there giving a talk about- this was a guest speaker that was giving a talk about a very large high impact grant and that included a patient advocacy kind of module, let's say. And they put in a specific funding and budget for that component that included compensation for the people- from the people in the advocacy community that were spending their time. And the PI of this project, again, not to get into the details of it, but they were sharing that they got a fair bit of pushback on that. But the PI pushed back and said, “Listen, we're compensating other people for their time. These guys, we want them to be partners, we need to treat them as such.” And I think that also again, kind of we're in a new space, but if we're going to do it right, then we have to acknowledge that we're partners.

Dr. Davide Soldato: But I think that maybe an experience like the PE-CGS probably can be also a network for expanding awareness for patient advocates and also for creating sort of a new culture about what does that mean and how can we also improve on that part. Because in the end, if we want to engage, we also need to provide patients with the instruments to engage in a way that we think it's both useful for them, that can make research better, but can also make them at the exact same level as everyone who is participating in that research, which I think it's the bottom line of all the concepts that we are discussing right now.

Liz Salmi: Yep.

Dr. Suzanne George: Yes, I agree.

Dr. Davide Soldato: So I think we have covered a lot of things. Just wanted to make one last reference to a point that Suzanne mentioned earlier, which is the interoperability of systems. And I think that when we come to the cancer genome, that is very important, being able to share information, especially for those diverse and less common cancer types that we were discussing earlier. There is a lot of work in gaining all that information and we need to be able to gather all of that information in the same place to advance research. You were mentioning before that the process is actually very complicated and I was wondering if in the network you are already working on some potential ways to address this type of issue.

Dr. Suzanne George: I think our first step is really just calling it out, acknowledging how hard this is and what the barriers are. Oftentimes I think in research, we don't talk enough about what our methodologic barriers are. We talk more about what our results are, but not like how hard it is. But like in our projects, the Count Me In project, my network that I'm involved with, we're doing rare tumors. We can only do the United States and Canada because of privacy issues. And we're doing a completely web based platform. So we have the technology. But the privacy laws are impeding our ability to involve other parts of the world. And even within the United States, it's not as easy as we would like to get records. For example, despite the fact that people are saying, “Yes, use my records.” But then it's like, “Okay. Well, that's not that easy. How are we going to get them?” We had to hire a third party vendor in order to get the records, in order to manage all the different consents and releases that were needed across all these different hospital systems. So I think the first question is just calling it out and then from there working together as a community to try to see what the solutions can be, because we need to come up with those solutions.

Liz Salmi: Yeah, we're in the same camp as Dr. George and the fact that of the five partners, we're not associated with one particular institution. So we can reach out around the country and get access to those records. And we need them at multiple points in time, over time and it takes a lot of effort and work. And it's not like you could just, say, call hospital A and they have all the information. It's like all of the calls to all of the other sites. And it's not just from one surgery, it's from two or more surgeries. But also the way that people stay involved, and, by people, I mean patients and family members, there's this promise that at some point you're going to get some sort of information in response. Like, it's the “what's in it for me?” aspect of it. We do interviews with those who've been enrolled in the study, those who could be potential enrollees in the future because they've only had one surgery. And what we're learning overall is there's this altruistic nature that people have of- they want to participate in the research because they're like, “Here's my horrible cancer experience. I know other people are going to go through this as well.” There's this guiding light of “I want to do something, and I'm not going to be the person that creates the cure, discovers the genome or whatever for this particular cancer type. But my little bit of participation in this multiplied by 20, 30, 100, 1000 people, is what is going to lead us to the next phase in development and is going to move the needle for this particular tumor type or other cancer types.” And so what I think the impact in this space and participant engagement isn't just something we figure out, like a little research method and a little finding for one small tumor type, it's like the methods to do that is the big impact. The method around participant engagement can impact even beyond the cancer community.

Dr. Davide Soldato: Yeah. As Suzanne was saying, we need to be in a system that really helps us and allows us to do that. So I think that you really have a lot of things to work on inside of the network.

Dr. Suzanne George: I think one thing that I would say is I think that this issue of interoperability is acknowledged as a challenge. We refer to several different initiatives across the US where this is supposed to ideally change over time. I think people want it to change over time. I think investigators at the ERTC want it to change over time. I think different countries are working on this. And I think, again, the first step is getting us at the table talking about it, and then figuring out ways to move it forward. And I think it's there. I think that there is the will. We just have to figure out the how and continue to work on that together, because there's just a tremendous opportunity. I live in the rare tumor space, and between the FDA and the EMA and the regulatory, the national and the international research groups, the patient communities, people want this to be solved and I do hope that we will be able to get there.

Dr. Davide Soldato: So I would like to thank Liz and Suzanne for joining us today.

Dr. Suzanne George: Thanks for having us.

Liz Salmi: Thank you.

Dr. Davide Soldato: Suzanne, Liz, we appreciate you sharing more on your JCO article titled, “Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality.”

If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

DISCLOSURES

Liz Salmi

Speaking Honoria: Medscape. Research Funding (Inst): Abridge AI, Inc., Yosemite.

Dr. Suzanne George

Honoraria CStone Pharmaceuticals Consulting or Advisory Role Blueprint Medicines, deciphera, Bayer,  Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, Kayothera, Immunicum, BioAtla   Research Funding Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks Therapeutics, TRACON Pharma, Theseus Pharmaceuticals, BioAtla, IDRx, NewBay Pharma, Acrivon Therapeutics   Patents, Royalties, Other Intellectual Property Company name: UptoDate

Stock and Other Ownership Interests Abbott Laboratories and Pfizer Recipient: An Immediate Family Member

In this JCO Article Insights episode, Rohit Singh provides a summary on "First-Line Nivolumab Plus Relatlimab Versus Nivolumab Plus Ipilimumab in Advanced Melanoma: An Indirect Treatment Comparison Using RELATIVITY-047 and CheckMate 067 Trial Data", by Long et al, published in the November issue of the Journal of Clinical Oncology. The article provides insights into the use of the two dual immune checkpoint inhibitor regimens in patients with untreated advanced melanoma.

TRANSCRIPT

Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host Rohit Singh, Assistant Professor at the University of Vermont Cancer Center and today we'll be discussing the article “First-Line Nivolumab Plus Relatlimab Versus Nivolumab Plus Ipilimumab in Advanced Melanoma: An Indirect Treatment Comparison Using RELATIVITY-047 and CheckMate 067 Trials,” authored by Dr. Georgina Long from the Melanoma Institute of Australia and her colleagues. 

So as we know, nivolumab plus relatlimab and nivo plus ipi, I'm going to refer to as ipi-nivo moving forward, are dual immune checkpoint inhibitors regimens that are approved for treating patients with advanced melanoma based on the phase 2 and 3 RELATIVITY-047 and phase 3 CheckMate 067 trials respectively. Nivo plus relatlimab is the only dual PD-1 and LAG-3 inhibitor regimen approved for treating patients with advanced melanoma and relatlimab is the first in class human IgG4 LAG-3 blocking antibody. Ipi plus nivo is a dual PD-1 and CTLA-4 inhibitor regimen. 

So this paper basically is an indirect treatment comparison using a patient level database from these trials and this pretty much was conducted because of the absence of head to head trials looking at different regimens in advanced melanoma in first line setting. In this trial, the authors tried to compare these two trials. However, it's always hard to compare two different trials and we usually don't do cross trial comparisons. The problem is that the groups might be different to begin with. For example, one group might have younger patients, healthier patients, while the other might have older or sicker. These differences can make it hard to tell if the treatment caused improvement or if the groups were different to begin with. In this trial, researchers use inverse probability of treatment weighting to adjust the baseline differences between the two patient groups or between these two trials. Inverse probability of treatment weighting is a method used in research to help make a fair comparison between two groups when studying how a treatment intervention works. Basically, IPTW helps level the playing field between the two groups or like two trials for this paper. So, it calculates the likelihood of receiving a treatment. For each person, for each patient, researchers estimate the chance they would have gotten the treatment based on their characteristics like age, health, condition, their baseline staging, and based on that they create weights. People who are less likely to get the treatment but did are given more weight, and those who are very likely to get the treatment are given less weight. The same is done for the group that didn't get the treatment, and then they rebalance the groups. By applying these weights the group becomes more similar in their characteristics as if everyone had an equal chance of getting the treatment. This way, IPTW helps researchers focus on the effect of treatment itself and other differences between the groups. It's like adjusting the scales to make sure you are comparing apples to apples. 

The key outcomes the authors are looking at in this one was progression free survivals, overall survival, confirmed objective response rate, melanoma specific survival, and treatment related adverse events. Looking at the results of this cross comparison trial, first looking at the PFS or progression free survival, both regimens ipi plus nivo and nivo plus relatlimab, showed similar PFS. At 36 months, PFS was 36% in nivo-relatlimab versus 39% in the ipi-nivo regimen with a hazard ratio of 1.08 indicating no significant differences. Looking at the overall survival at 36 months, overall survival was 57% in both the treatment regimens with a hazard ratio of 0.14, again, indicating no significant differences. Now looking at another confirmed objective response rate, confirmed objective rates were similar between both treatment regimens after weighting, 48% versus 50% with an odds ratio of 0.91 suggesting comparable response rates between the two regimens. Looking at melanoma specific survival at 36 months it was 65% versus 62%. Both treatments had similar melanoma specific survival with a hazard ratio 0.86. 

An interesting thing in these results was subgroup analysis. Subgroups showed larger numerical differences in efficacy which favored ipi-nivo over nivo-relatlimab that included acral melanoma with a hazard ratio of 1.42 and OS with a hazard ratio of 1.72 in favor of ipi-nivo. Similarly for BRAF mutant melanoma, it showed a confirmed objective response rate with odds ratio 1.54 and same applied to mucosal melanoma with odds ratio of 1.59 and patients who have high LDH more than two times upper level limit. Looking at the safety and adverse side effects, nivolumab plus relatlimab had fewer grade 3 or 4 treatment related adverse effect which is 23% versus 61% and fewer any grade treatment related adverse events leading to discontinuation which was 17% versus 41%, which means 41% of the patients in the ipi-nivo arm lead to discontinuation. However, I would like to add to that that ipi-nivo was conducted much earlier and at that time we were still kind of assessing and trying to understand the immunity adverse effects, how to manage them, which probably could have made discontinuation more common compared to a nivo-relatlimab trial. By that time we definitely had much more experience dealing with immunity adverse effects.A couple of things mentionable in this, notable rates of hepatic and GI grade 3 or 4 treatment adverse events were lower in nivo plus relatlimab than with ipi-nivo, although the onset of any grade endocrine GI hepatic or skin related treatment related adverse events occurred most frequently in both treatment arms and in less than three months from randomization. 

So looking at all this data and looking at all this, it definitely seems like both the trials are very comparable in terms of efficacy, though nivo plus relatlimab seems to have a better safety profile. This trial does have some strengths. It does use the patient level data from two large well conducted trials allowing for a robust comparison and inverse weighting which would definitely better help balance baseline characteristics, enhancing the reliability of the results, and it does lead to comprehensive assessment of both efficacy and safety outcomes, and provides a holistic view of the treatments. Given all this, definitely the fact that it's a cross comparison trial which leads to a big limitation, as I already mentioned, like definitely two trials, it's hard to compare two trials which can have its own inherited biases. So it has some differences in trial design, conduct and follow up times. Small size subgroup analysis definitely limits the ability to draw definite conclusions from those groups. There's definitely some inherent uncertainty with direct head to head cross comparison trials. 

Looking at the future direction I would take from this trial, if we can have a direct head to head trial because both of the treatments are proven first line setting, it will be comparing these two regimen that can definitely provide more definite evidence and further research is needed to explore the efficacy of these regimens in specific subgroups. As I mentioned in this, some subgroups showed increased benefit in the ipi-nivo regimen, however, they were very small sample size so we need more research exploring those subgroups. One other part in both these trials, patients with active brain mets were excluded. However, there's a phase 2 trial looking at ipi-nivo in active brain mets patients. So I think assessing patients with active brain mets moving forward is also a crucial part looking at, because often, patients with advanced melanoma develop brain mets. It does lead to some unanswered questions like long term survival and quality of life. How do these regimens compare in terms of long term survival and quality of life? While the study provides data on PFS and OS, long term survival and quality of life metrics are essential for understanding the full impact of these treatments. Optimal sequencing strategies: what are the optimal sequence strategies for these patients who progress on one regimen? There is data suggesting that patients may respond to alternative regimens after progression, but more research is needed to establish the best treatment sequence. And real world performance: how do these treatments perform in real world settings outside of clinical trials? Real world data can provide insight into the effectiveness and safety of these regimens in a broader patient population. 

So, in summary, nivo plus relatlimab offers similar efficacy to nivolumab plus ipilimumab but a significantly improved safety profile, making it the potentially preferable option for patients with untreated advanced melanoma. However, results should be interpreted with caution due to limitations of cross trial analysis for certain subgroups like acral melanoma, mucosal melanoma, BRAF mutant melanoma, and patients with high LDH more than two times off upper normal limit. The trial showed that there's a trend definitely with ipi-nivo may be more beneficial. Also, today data on the use of nivolumab plus relatlimab in active brain mets has not been reported. Based on these existing data, ipi-nivo remains a standard immunotherapy for patients with active brain mets. Further research, including direct head to head trials is needed to confirm these findings and explore optimal treatment strategies. 

Thank you for tuning into today's episode. We hope this detailed summary of the study comparing Nivolumab Plus Relatlimab and Nivolumab Plus Ipilimumab in advanced melanoma has been informative. This is Rohit Singh. Thank you again for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Host Dr. Davide Soldato and Dr. Aaron Mitchell discuss the JCO article "Quality of Treatment Selection for Medicare Beneficiaries With Cancer"

TRANSCRIPT

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Hospital San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Aaron Mitchell. Dr. Mitchell is a medical oncologist working at Memorial Sloan Kettering Cancer Center where he is also part of the Department of Epidemiology and Biostatistics. Dr. Mitchell specializes in treating genitourinary malignancy and has a research focus on improving how the healthcare system helps people with these and other cancers. So today, Dr. Mitchell will be discussing the article titled, “Quality of Treatment Selection for Medicare Beneficiaries with Cancer.”

Thank you for speaking with us, Dr. Mitchell.

Dr. Aaron Mitchell: Well, thank you for inviting me. I'm very glad to be here.

Dr. Davide Soldato: So I just wanted to introduce the topic by asking a couple of questions, very general, about the background of the article. So basically you reported the data using the SEER-Medicare to assist to assess the determinants of optimal systemic therapies delivery and selection. So, in particular, you focused on individuals that were diagnosed with cancer who were Medicare beneficiaries and in particular were part of the low income subsidy, which is also known as LIS. So I just wanted to ask you if you could briefly explain to our listeners how this program works, and what was the rationale of the study, and if there is any element of novelty in your study compared to what was done before the study was published.

Dr. Aaron Mitchell: Yeah. So that's a lot to cover, but yeah, a lot of opportunity to introduce the low income subsidy program which is a very important part of the Medicare program for prescription drugs, but often one that flies under the radar a little bit in the policy discussion. So this subsidy was created synchronously back with the Medicare Part D Program, which was created in 2006. There was some anticipation that for some high cost drugs, not all patients would be able to afford them even with the Part D program insurance as it was being created. And so they created a pathway to give an additional subsidy to some patients who had low income, who were anticipated to being at need and needing that assistance to afford high cost drugs. As the number of high cost drugs has really risen since 2006, this program has played an important role in helping patients afford drugs, especially those who need very expensive cancer drugs. 

And what this program does is, once you meet the eligibility requirements, which require patients to have both quite a low income. So if you're single, that is at 135% of the federal poverty limit or below, and it also places some restrictions on assets. You also have to have low assets, so low income and low assets in order to qualify for the subsidy. But then once you do, the subsidy is really quite large. Patients who qualify for the LIS at the full subsidy level will pay about $10 per month per drug, even for specialty cancer drugs. So if you think about drugs such as those that we use to treat prostate cancer, my specialty, drugs like enzalutamide or XTANDI that run $15,000 to $20,000 per month, the out of pocket cost for a low income subsidy beneficiary is $10. So that is a huge discount. $10 isn't nothing, but even for someone with a low income, if they've got one or two cancer drugs that are at this rate, it's something that they can often afford. 

This program applies to Part D cancer drugs that are prescription drugs basically. By and large, these are oral pills that patients are taking on a daily basis at home. These are the drugs that the low income subsidy program applies to. So if a patient needs a drug like that to treat their cancer, then they are able to receive it at very low cost. And what you'll see is a patient- in the studies that have been done, when a patient has low income, low enough for them to be able to qualify for this program, they then have better access to these drugs. You see increased adherence rates, you see increased prescription fill rates. And then when someone, when their income is just high enough to no longer qualify for this program, and they go back to regular Medicare Part D coverage, that's when the problems arise. So it's like as your income moves up the scale, you actually get more problems affording your cancer drugs. So that's the state of the literature so far. 

And what we realize though, is that all these studies that have looked at the low income subsidy have really focused on just the Part D drugs themselves, the oral drugs. And that's certainly not all of cancer care. There is a growing number of oral drugs, but for many cancers, especially when you're talking about immunotherapy drugs or new systemic radioligand therapies, these are not Part D drugs, these are Part B drugs. And so even if you are low income and you're qualifying for this subsidy, it's not going to help you if you need a Part B drug. Yes, there are certainly a whole host of other programs and different avenues that we can get patients assistance, but some percentage of them, even though they're low income and high need, would not have assistance with a Part B drug. 

So now, in coming back, the long answer to your question, our rationale was, let's look at these Part D low income subsidy patients and let's see what their access looks like, not just to the oral drugs, but to cancer care writ large. And can we study where they're fitting into the system, not only when they need oral drugs, but when they need any kind of cancer care across the board?

Dr. Davide Soldato: So basically, just to summarize, it was an extension of previous literature, but specifically evaluating whether novel regimens that use, for example intravenous drugs, they were covered at the same level and whether there were any inequities in access to cancer treatment under this specific program, which is the LIS.

Dr. Aaron Mitchell: Yes, I'd say that's a fair summary.

Dr. Davide Soldato: Okay. So more or less, you included 9,000 patients inside of the study and 25% of them were beneficiaries of the LIS program. And you specifically looked at factors that could be associated with not receiving therapies at all, and also whether the quality of care that these patients were receiving were any different compared to those who were not part of the LIS program. So I just wanted to see if you could guide us a little bit in the results, whether you see any kind of differences when we look at access to any type of systemic therapies and whether being a part of the LIS program modified access to the drugs.

Dr. Aaron Mitchell: Let me take this opportunity also to highlight a feature of our study that differentiates us a little bit from previous work that's been done. And this is around the specific definition of quality that we use. I know quality is in the title of the manuscript, but I think it's important to emphasize exactly what we mean in this study when we say quality, and it's something very specific. So our measure of quality references back to the NCCN guidelines, which I don't think our audience needs much of an introduction to that. It's the most worldwide recognized standard of care guidelines for oncology practice. And we specifically looked not only at the NCCN guidelines, but at their evidence block scoring system. So what we did was we looked not only at one set of guidelines, but we looked at guidelines across time. We looked at guidelines across our full study period, which was, give or take, 2015-2018, depending on the cancer. And we looked at each point in time to see what was the treatment regimen that was recommended by the NCCN guidelines as being preferred. Some of them make that designation, some of them don't. If there was not a designation of preferred, then we turned to the evidence blocks. And the evidence blocks, we then apply several different measures to kind of rank treatments from those that get high scores for efficacy and safety to those that get low scores for efficacy, safety and the quality of evidence. So we basically come up with a kind of a rank list of the recommended treatments at each point in time. And then we look at the ones that are the highest, we say which are the most highly recommended treatments at any given point in time. That then becomes our definition of quality treatment. And I'm saying this with air quotes, we use the term “optimal treatment” in the study. Did they get that treatment? If there were ties, you could have gotten either of the two treatments that got the equally good score, did you get that treatment versus did you get anything else? 

So then getting back to our analysis, what we really did was kind of a two-stage study. First, we put all of our patients into our pool, into one big analytic model. And we looked to see what are the factors that predict or are associated with a patient either getting no systemic therapy or any systemic therapy. And then as a second question, we look at the patients who got some form of systemic therapy, and then we ask, again, what percentage of those got the optimal treatment or high quality treatment as opposed to one of the more lowly recommended treatment regimens? So that's how we asked it. We found that patients who were low income subsidy recipients, the low income ones, they were both less likely to receive any systemic therapy. And then even the ones that receive systemic therapy, the ones who made it in the door to see their doctor or their part of the system, they still were less likely to get the optimal treatment that was recommended for their cancer type at the time that they were diagnosed.

Dr. Davide Soldato: So basically, even when you are a part of this subsidiary program, you still have a lower access to any type of treatment. And even if you get treatment, you kind of get the ones that were not the preferred according to the NCCN guidelines, or at least they were not scoring as well as those specific regimens. But I think that what our audience might be wondering about is that frequently there are also some other types of characteristics, for example, age or number of comorbidities, which can be associated with having a low socioeconomic status. So I was wondering whether in the analysis you kind of looked specifically also at patient factors, for example, income rather than age or comorbidities, and whether you found any significant association with those and whether it was something that you planned to do in your study.

Dr. Aaron Mitchell: Yes. So we looked at many patient factors and those included age and they included the degree of comorbidity. And what we saw with respect to those characteristics was not too surprising. We saw that patients who were older were less likely to receive systemic therapy. We saw that patients who had more comorbidities were also less likely to get systemic therapy. And then across our different designations of treatments, we saw that those patients were also less likely to get the optimal treatment for their cancer. This result though, we would say it certainly needs more study in the future, but it's not immediately concerning. And that is because for patients who have more age, more comorbidity, those often correlate with frailty. And so it could be that these patients aren't getting optimally treated or it could be that their oncologists are just making clinically appropriate decisions about patient selection. 

We saw as we were doing this work that the treatment regimens that are often getting the highest recommendations from the NCCN, hence, it would become our definition of high quality optimal treatment, are often ones that are aggressive. They're often ones that are multi-drug combinations. They're often ones that it's not just your old antineoplastics, it's the antineoplastics plus an additional immunotherapy or plus a targeted drug. So it's the ones that are more aggressive by and large, and that might be in some cases more than a patient who is older, more frail, could be able to tolerate. And so the oncologist might be making inappropriate judgment to say I'm going to do something a little bit less aggressive here and make an appropriate trade off between anti cancer efficacy and safety. 

I think we've got kind of a bookmark there and we can look at those trends in the future. So we saw that kind of as expected, and then we turned and looked towards the low income subsidy. And our premise there is, well, your income shouldn't predict what you're getting clinically. In an ideal world, you'd be able to get the appropriate treatment for a patient, and not depend on whether their income is above or below 135% of the poverty limit. So that one seems more like on its face an immediate concern.

Dr. Davide Soldato: Thank you very much for the explanation. I was just wondering, did you make some kind of selection when you were analyzing specific diseases or settings where you included just metastatic patients or you also included patients with early stage neoadjuvant treatments? Because I think that it is also very interesting from the perspective of the objectives that we have as oncologists when we are administering systemic treatments.

Dr. Aaron Mitchell: Yeah, thank you for bringing that up. That was also one of the goals of our study was to be broad. And we wanted to look for factors, whether it be low income subsidy, whether it be age, socioeconomic background, etc., things that would be broad predictors of outcomes, and by which I mean care delivery outcomes across the board. So not just for, let's say, metastatic breast cancer, but also across any cancer that a patient might walk in the door with, what are the systemic predictors. And so when you mentioned before that our overall cohort is approximately 9,000 patients, that's 9,000 patients split over a variety of what we call clinical scenarios or clinical indications. And that includes multiple solid tumor as well as liquid tumor malignancies. It includes both patients who are initiating systemic therapy with palliative intent for metastatic disease. It also includes several groups of patients who are getting adjuvant therapy. So we want it to be as broad as possible. Our selection of those scenarios was really done with the goal of being as broad as possible and really bringing in everything that we could within the constraints of our data source. And that was really the only limitation that we applied in concept was tumor types that are common enough to have a meaningful sample of patients to analyze. So, one, are there enough patients? And then two, are you able to identify this specific group of patients within SEER-Medicare data? Because when the NCCN divides groups of patients by biomarkers that are not available in SEER-Medicare, we can't really say, “Oh, we're going to study this group of patients.” That would then be one that we have to leave on the side and not include. But everything else where one of those things didn't apply, we tried to include it as best we could.

Dr. Davide Soldato: Thank you very much for the explanation. And among the scenarios that you included in the study, were there any striking differences in terms of access to treatment and access to quality treatment the way you define the study?

Dr. Aaron Mitchell: Yes, there were differences between these different cancer types, these different cancer indications, but they're not differences that I want to over interpret or read too much into. Certainly, every cancer indication is going to be different, but when we start getting into the individual cancer types, the sample size does get smaller. And we've not done formal tests of comparison or heterogeneity among cancer types. So I don't want to say that the differences which we certainly do see, like numerically, there are differences in the proportion of patients who are getting optimal treatment versus no treatment. I don't want to say that it's because the low income subsidy status or patient age has a bigger impact, let's say for lung cancer than breast cancer. I want to say that is heterogeneity for potential future study when we are able to do a similar follow up analysis with say a larger sample size. I don't want to over interpret those differences at the moment.

Dr. Davide Soldato: I was just wondering in case there was anything in particular that you wanted to highlight. But in the end, I think that we also have to acknowledge that the data are based on claims data, observational data. So maybe you're right when you say we should not over interpret this type of difference. 

And this is just to speculate a little bit, do you think that if you would look at this same specific question in a more contemporary diagnosis frame, like for example, you refer to the fact that most of the diagnoses were between 2016 and 2018. Now that we have more and more of these drugs that would qualify as Part B in the adjuvant or new adjuvant setting, do you think that you would see more differences compared to what you observed in the current study or do you think that it would be more or less the same? Of course this was not part of the analysis that you did, but it's just to have your opinion on the topic in general.

Dr. Aaron Mitchell: My expectation would be that since not much has changed with respect to the low income subsidy program from the time period of our study until now, my baseline expectation would be that those results would hold. On the other hand, it is the case that there have been improvements to the standard Medicare Part D benefit since the time of our study. So the low income subsidy patients would be paying the same low out of pocket costs that I mentioned before, about $10 a month give or take, for a specialty cancer drug. But what has started to happen is that for everyone else, their coverage has improved. Because in the US we're in the process of closing, or I think now we finally finished, but you know, a few years lag in claims data, we've closed what used to be called the donut hole, where there was this big coverage gap where patients had to pay a large amount out of pocket for drugs. So there might therefore be a narrowing of the difference, let's say between our low income subsidy participants, the lowest income patients, and then everyone else. But not so much because the low income subsidy status improved or changed, but just because the baseline level of coverage for everyone else may have improved, narrowing that gap. So I'd say that would be very possible. 

And if your question is more geared towards not so much policy changes, but treatment landscape changes, I would say the big thing that I would maybe guess, and again, this is very much speculation, but you introduce the speculation in TBD on follow up. I think the big change in the landscape has been the broadening indication and uptake of immunotherapy drugs, our PD-1, PD-L1 inhibitors, for a variety of cancer types. And I think the way that that would manifest in our data, were we to repeat it in a more contemporary data set, would be, I think that the access for, let's say, that any systemic therapy among older patients might change. And that is because rather than just having your cytotoxics in hand, the clinical oncologists now know that for many cases there's if not first line therapy, then second line therapy for patients who don't qualify, you can go straight to it, to someone who's not a chemo candidate, you've got a much more tolerable treatment in your back pocket. And so I think that for patients who are more old or more comorbid, we might start to see that a greater proportion of them receive some systemic therapy, it just might not be the cytotoxic agent that is still most highly recommended. It might be, say a single agent, PD-L1 inhibitor, because their oncologist wants to be able to give them something. So I wouldn't be surprised if that gap starts to narrow as well if you're measuring no systemic therapy versus any systemic therapy.

Dr. Davide Soldato: And going back to the policy part of the study that you did, do you think that the results of the study that you published in the JCO can better inform policy makers on how to make these treatments more available and be sure that the largest possible proportion of patients gets a systemic treatment and gets the optimal systemic treatment?

Dr. Aaron Mitchell: Yes, I do think that this study has some direct and indirect policy implications. I think that our finding is one to highlight the low income subsidy program and maybe help it not to fly under the radar so much anymore. I think all the work that has been done on how much it has helped patients who need oral cancer medications is great, and it shows how beneficial this program can be. We're now shining the light kind of everywhere else and saying, “Okay. That's great. Here's how well it can work when it covers an oral drug, but we've got this group of low income patients who are still at need and they're still very clearly not able to access everything else. When it's not axitinib that they need, it's a pembrolizumab, they're still very much behind the curve and they need some help.” So I think that's one thing just to call attention to this as an ongoing problem. Low income patients, it's not a solved problem yet. It's something that needs further attention. 

And then for direct policy implications that are on the table, I think we're about to see the Medicare program be able to start negotiating not just Part D drugs, but also in future years, Part B covered drugs and try to lower the price for everyone, both for insurance, both for Medicare itself. And then to the extent that that boils over to the patient's out of pocket responsibility, it'll start to reduce the patient out of pocket costs as well. So I think we can look forward to hopefully an aggressive negotiation program by Medicare to start to directly lower the prices of Part B cancer drugs that these patients are unable to afford.

Dr. Davide Soldato: Thank you very much. You did the research you published in the JCO, but you really seem very passionate about the topic of care delivery and quality of care and policy. So I just wanted to ask on a personal note, how did you come to this area of research which is frequently not one that is very cared for by oncologists? It's more frequently something that biostatisticians or public health scientists put their attention to. I just had this curiosity and I wanted to ask you if you could explain a little bit how you came to this area of research.

Dr. Aaron Mitchell: Thank you for asking. That's a great question. I'll tell my favorite story about my journey there. I entered medical school planning to be a clinical investigator or maybe even a basic science researcher, and I had some background in that. I went to medical school at NYU where the teaching hospital is Bellevue, which is a large, well known public hospital within New York City. And my eyes started to open regarding the inequities in the system. You always hear about it, you read about the problems in the US healthcare system, but then when you see it on a day to day basis and you can walk four blocks from a private, very well resourced hospital to see a patient with a similar condition four blocks down the road at a under resourced public hospital getting very different treatments and receiving very different outcomes, the injustice in the system really hits you on a visceral level. And it was really, I would say, as soon as I started my clinical rotations in medical school that I realized maybe that's where I can make the most impact with my career and just really fell into it. By the time I was done with medical school, I then knew that I wanted to do something that was in the health policy space. And then by the time I was done with residency, I was like, “Oh, someone had mentioned the words health services research” and the light went on. It's like, “Oh, that's me. That's what I want to do.”

Dr. Davide Soldato: Thank you very much. That was a nice story. And I really think that we should all work towards trying to make sure that the inequities inside of the system are eliminated as much as possible. 

So I think that this concludes our interview for today. So thank you again, Dr. Mitchell, for joining us.

Dr. Aaron Mitchell: You're very welcome and thank you so much for your interest.

Dr. Davide Soldato: We appreciate you sharing more on your JCO article titled, “Quality of Treatment Selection for Medicare Beneficiaries with Cancer.” 

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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinion, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors" by Schaffer et al published in the Journal of Clinical Oncology July 17th, 2024.

TRANSCRIPT

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the October 1st issue of JCO titled, “Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors,” by Shaffer et al.

The CIBMTR registry study set out to compare outcomes of patients undergoing allogeneic stem cell transplantation hematologic malignancies by HLA antigen matching status as well as by the type of GVHD prophylaxis regimen received either calcineurin inhibitor-based prophylaxis or post-transplant cyclophosphamide or PTCy. This study included patients reported to CIBMTR from January 2017 to June 2021 with AML, ALL or MDS, and required that they have undergone allotransplant with either a calcineurin inhibitor based so tacro or cyclosporine, GVHD prophylaxis, or PTCy, which included a calcineurin inhibitor or sirolimus with or without MMF and ATG. Matched unrelated donors were defined as an 8 out of 8 HLA match. And mismatched unrelated donors were defined as HLA mismatched at any single locus or 7 out of 8. The primary objective of the study aimed to compare overall survival or OS and GVHD and relapse-free survival (GRFS) within and between matched unrelated donors versus mismatched unrelated donors separated by calcineurin inhibitor versus PTCy based GVHD prophylaxis.

GRFS was defined as survival without grade 3 to 4 acute GVHD, moderate to severe chronic GVHD requiring systemic therapy or relapse. 10,025 patients were included from 153 centers, with a median follow up of over 36 months. Mismatched unrelated donor recipients were made up of 22% minority ancestry patients as compared to just 8% of patients receiving a matched unrelated donor allo transplant, showing an enrichment for patients of minority ancestry in the mismatched unrelated donor group. Just under 10% of patients were of minority ancestry in the study overall, reflective of challenges in transplant care for these patients, which may include inferior access to care, fewer available and suitably matched donors, among other factors. 54% of all patients were transplanted for AML and 29% for MDS. 45% of patients received myeloablative conditioning, 25% received regimens containing ATG, and 23% overall received PTCy with either a calcineurin inhibitor or sirolimus as well as MMF.

Among patients receiving PTCy, the authors did not find differences in overall survival by degree of HLA matching, whereas among patients receiving calcineurin inhibitor-based prophylaxis, there remained survival differences by HLA matching status. When comparing matched unrelated donor calcineurin inhibitor patients with PTCy matched unrelated donor patients, the PTCy arm had better OS, and the mismatched unrelated donor group who received PTCy had similar OS as well. For GRFS, matched unrelated donor and mismatched unrelated donor PTCy patients had no difference in GRFS, similar to the trend the authors see with overall survival. But these patients also had better GRFS than matched unrelated donor patients receiving calcineurin inhibitor-based prophylaxis. Within each prophylaxis arm, there was no difference in GRFS by HLA matching status. HLA mismatched patients receiving PTCy were less likely to experience GRFS than HLA mismatched patients receiving calcineurin inhibitor-based prophylaxis.

The authors saw similar differences in comparative trends when subgrouping patients based on conditioning intensity and additionally did not find differences in GRFS and OS by ATG exposure. When looking at patients with minority ancestry, those patients who received a match unrelated donor or mismatched unrelated donor with PTCy had comparable outcomes to non-Hispanic white patients. Additionally, among minority ancestry patients, there was a significant benefit in both GRFS and OS in the PTCy groups as compared to calcineurin inhibitor-based prophylaxis. When examining other specific toxicities included in the composite GRFS endpoint, such as GVHD rates among PTCy patients, the authors note that patients receiving a matched unrelated donor had similar rates of grade 3 to 4 acute GVHD but lower rates of moderate to severe chronic GVHD requiring systemic therapy. There appears to be signal that among PTCy patients, HLA matching reduced rates of moderate to severe chronic GVHD compared to mismatched unrelated donor patients receiving PTCy. These same trends also held when the authors looked at non relapse mortality with no significant differences within the PTCy groups by HLA matching status but reduced non relapse mortality compared to both calcineur and inhibitor-based groups.

However, notably, there was a greater risk of relapse among matched unrelated donor PTCy patients than matched unrelated donor calcineurin inhibitor patients, although this risk was comparable between mismatched unrelated donor patients by type of prophylaxis. The authors note that this has also been observed in other retrospective cohorts and may be confounded by differences in conditioning intensity between these cohorts of matched unrelated donor patients, affecting the risk of relapse. Finally, the authors also evaluate whether expansion of donor search criteria to mismatch donors from full HLA matching would increase availability of young donors from minority ancestry patients, and the study noted striking increases for all subgroups examined.

This study fits nicely with the BMT CTN 1703 trial published in the recent past, which has showed the superiority of PTCy with the calcineurin inhibitor and MMF when compared with conventional calcineurin inhibitor based immune prophylaxis for reduced intensity matched related donor and matched unrelated donor allotransplant. Of note, very few patients with one HLA antigen mismatch were enrolled on that study. However, others have shown the feasibility of PTCy in the mismatched unrelated donor setting, which has led to its adoption in practice. Although less than a quarter of patients included in this current study received PTCy overall, the findings clearly are aligned with the BMT CTN 1703 study, which is likely to change clinical practice in the longer term in this field.

As the accompanying editorial in JCO, written by Dr. Chakravarty nicely lays out, the differences between this study and the EBMT registry study, also published in this issue of JCO are subtle but worthy of note. While both studies show that mismatched unrelated donor patients had worse OS and GRFS than those receiving matched unrelated donor transplants, and then among matched unrelated donor patients the addition of PTCy improved GRFS and OS, there is discordance between the studies whether the addition of PTCy abrogates the effect of HLA mismatching on GRFS and OS. As this editorial points out, there are strikingly different rates of T cell depletion with ATG between the US and Europe, which may account for differences in comparator arms that lead to this discordance. There are several very exciting clinical trials ongoing that will aim to answer some of these outstanding questions regarding comparisons of PTCy and T cell depletion, which the field eagerly looks forward to reviewing.

In summary, this registry study of patients receiving allo transplant with matched unrelated donor or mismatched unrelated donor and calcineurin inhibitor or PTCy based GVHD prophylaxis, most notably shows that for patients who may not have a matched unrelated donor available, the addition of PTCy to a mismatched unrelated donor allo transplant allows for improved outcomes after transplant in toxicities and survival. This is most significant for patients of minority ancestries who usually have fewer matched unrelated donors available in registry searches. Improving the transplant options available to these groups of patients is of critical importance in improving equitable access to care for all of our patients. And this study, although retrospective in nature, provides an important understanding of our progress to date and suggests directions for future investigation may indeed be very feasible to continue to close these gaps in care for patients in need of an allo transplant for hematologic malignancies.

This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.