This transcript has been edited for clarity.
Sumanta Pal, MD: Hi. My name's Dr Monty Pal, and I am a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles. Welcome to Medscape's InDiscussion series on renal cell carcinoma. Today we're going to be discussing adjuvant treatment with immunotherapy.
First, let me introduce my guest and dear friend Dr Tian Zhang, who's an outstanding medical oncologist who just joined the UT Southwestern Medical Center Cancer Center. She's got tons of experience in the area of renal cell carcinoma, and I'm very excited today to discuss with her how she goes about treating patients in the adjuvant setting. Tian, welcome to the program.
Tian Zhang, MD: Thanks so much for having me, Monty. It's truly a pleasure to be here.
Pal: I wanted to first introduce you to our guests and audience and give them a sense of how your interest in kidney cancer and other genitourinary malignancies came about. Can you shed some light on your career path so far?
Zhang: Sure, Monty. You know, it's hard to say that I was a 5-year-old saying I wanted to study kidney cancer, but a lot of things along the way, life events, and wonderful mentors along the way really piqued my interest in kidney cancer. And when I was graduating fellowship at Duke, 7 years ago, at this point, I imagined myself as a gastrointestinal (GI) oncologist. But the clinical need at Duke was in genitourinary (GU) cancers. And so, with career guidance from Dan George and others at Duke, I established more of a renal cell track record. As you know, we designed and opened a phase 3 trial in kidney cancer in the Alliance Cooperative Group and launched my career as a more of a GU medical oncologist. Along the way, I found the people to be wonderful in this GU field. I found wonderful mentors, role models, and colleagues all across the country. You were and are continuously one of these role models and supporters, Monty, as are people who are close to us — Tony Choueiri, Brian Rini, Moshe Orenstein, and my colleagues now at UT Southwestern, like Hans Hammers, James Brugarolas, and Kevin Courtney. I think the GU medical oncology space is truly young and growing, and I've really enjoyed forming all of these connections throughout the country.
Pal: It's so funny. We've chatted so many times, and I had no idea that your career started in the area of GI oncology. I started in breast oncology when I was at UCLA doing my training, and when I moved over to City of Hope, I had some great mentorship opportunities in kidney cancer, and that's what pushed me down that path. It really is all about those people you surround yourself with, isn't it?
Zhang: Absolutely, Monty. I think that people who support and guide young oncologists and trainees are really critical in shaping a career. I hope that I can also start to build other's careers around me and pay it forward.
Pal: That's awesome. Let's jump right into the subject matter of the day, and that's adjuvant therapy for kidney cancer. There's so much that's being done in this space. But I would say it's been a little bit of a murky area in the era of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). Can you walk us through what yesteryear looked like in adjuvant therapy for kidney cancer, with a focus on targeted therapies?
Zhang: To set the background, we have had multiple VEGF-targeted therapies tested in this adjuvant space. It's a post-nephrectomy space to try to prevent disease recurrence, to extend time until disease recurrence, and ultimately to improve overall survival. In the adjuvant space, we initially did have sunitinib approved based on results from the phase 3 trial called S-TRAC, and that was approved back in 2017. But to me and I think many others practicing in this space, we were looking at the balance between benefits of extending disease-free survival compared with the risks for toxicity from treatment with sunitinib for a year. Often, that encompassed hypertension, hand-foot syndrome, and mucositis — the list goes on with toxicities. Also, of course, there was the inconvenience and costs of treatments. Often when we were recommending sunitinib — and it was very few patients for whom we were recommending adjuvant sunitinib — they were more likely to be younger patients, with probably more anxiety levels about disease recurrence and a high threshold for allowing themselves to undergo the side effects of treatment. I think in your practice probably too, we all went through these conversations about whether or not giving sunitinib for a year meant enough to put our patients through the side effects.
Pal: Very well said. It's interesting — ever since the label came out for sunitinib in the adjuvant setting, I don't think I've actually prescribed it myself. I've had a couple of individuals filter through the clinic who had been started on it elsewhere. It creates a little bit of a quandary, too. This is a bit of a hypothetical situation, but I always struggled to know what I would do if I had a patient who progressed after an adjuvant VEGF-TKI. Do you have any sort of standard practice in that setting? I know these patients don't come that often.
Zhang: I'm right there with you. I think there's probably a handful of patients since 2017 to now to whom we actually gave adjuvant sunitinib. They took it for a year, and it depended on the timing of recurrence or progression after their sunitinib. And if that was during the year, we would try to alter the mechanisms of action use things like immunotherapies or mTOR-targeted treatments, or even MET and Axl, broadening out the TKI repertoire. In contrast, if it's a patient who has done the year of sunitinib and now having recurrence 2 or 3 years later, what does rechallenge look like? I think this will impact our discussion of progression after adjuvant immunotherapies, too. I think timing plays a role in how patients are thought of in terms of how refractory their disease is to the adjuvant treatment.
Pal: I couldn't agree with you more. These discussions inform some of the current dialogues that we're having around adjuvant treatment with immunotherapy, no doubt. I think some of those thresholds we drew for ourselves; we talked a lot about what would and wouldn't be acceptable in terms of endpoints. I think there was a strong desire to at least see consistency among trials — you know, seeing a disease-free survival benefit across multiple trials in the TKI space would be nice. We also thought that trends toward overall survival, even if not an absolute overall survival benefit, would be helpful. You didn't really see any of those things, so that's a good pivot to discuss the landscape of adjuvant treatment now, with immunotherapy for kidney cancer. I know it's still sort of an evolution. Lots of studies still to be reported out. But can you give us sort of a sense of what the current landscape looks like?
Zhang: You know, Monty we've had, I think, up to five adjuvant immunotherapy trials (trial 1, trial 2, trial 3, trial 4), if we're adding in the perioperative PROSPER trial. These are all studies comparing checkpoint inhibitor, which we've seen to be effective in the metastatic space, but in this adjuvant space, to see whether comparing these checkpoint inhibitors with placebo or with observation will delay disease recurrence. We talk a lot about disease recurrence and disease-free survival as an endpoint and how that can translate as a surrogate for overall survival. But to be honest, it is an endpoint that the FDA will approve treatments around in multiple disease types, and so it's not surprising that, when we saw the results of KEYNOTE-564 of pembrolizumab vs placebo, we gained approval for pembrolizumab.
Pal: Absolutely. In case our readers aren't fully aware, can you give us a flavor for what that trial looked like in broad strokes?
Zhang: This was a study of high-risk kidney cancer after nephrectomy. These patients all had T2, T3, or T4 disease or node-positive disease, or they were within a year of their nephrectomy when they had oligometastatic disease and underwent metastasectomy. These patients all had clear cell kidney cancer, too. That is a node that we made sure we had when we enrolled patients to the trial — that everyone had clear cell disease.
They were all randomly assigned to receive either pembrolizumab at 200 mg every 3 weeks dose or placebo. As investigators on the study — and I would note that we did enroll patients at Duke while I was there — we did not know which cohort our patients were assigned to. So, it was double-blinded and patients were randomized to either pembrolizumab or placebo. They enrolled a good number of patients overall — I believe slightly over 900 patients. All of these patients were treated with either pembrolizumab or placebo for a year before looking for disease-free survival and overall survival endpoints.
Pal: I was struck by the data for disease-free survival. I thought they were pretty compelling. Toni Choueiri has given us some updates since then at ASCO GU recently. I guess there's no mature overall survival data yet, but it seems like it's moving in the right direction. I'm sure you'd probably agree. Any thoughts? Or maybe you can distill for the listenership what the data are looking like today.
Zhang: We had an update at GU ASCO 2022 in February of this year with a 30-month follow up, and the primary endpoint of disease-free survival for this trial was met, with an ongoing disease-free survival benefit. As you are well aware, the hazard ratio was right around 0.6 and was statistically significant. So I do think there is quite a bit of difference between patients who were treated with pembrolizumab vs those who weren't, who received placebo, but there weren't enough overall survival (OS) events. This was a secondary endpoint and not enough of the OS events had occurred. We're starting to see a little bit of daylight between the curves, but certainly much more follow-up will be needed before we see that that difference pan out.
Pal: You know, it's interesting, Tian, I've heard all sorts of perspectives since the data were presented. I tend to fall in the camp where, if I saw a patient for whom the dataset was relevant — T3, T4, especially node-positive disease for sure — post-metastasectomy, I'd probably feel pretty comfortable adding adjuvant pembrolizumab to the patient's regimen. I've heard others say that they're holding out for the overall survival data. I've heard some suggest that they would probably not utilize this strategy in the lower-risk patients among those that were included. Where do you sit within that spectrum of opinions?
Zhang: It's certainly impacting all of our practices, right, Monty? We're seeing these patients, and to your point, we did see a couple of subsets of patients at higher risk that were presented at GU ASCO — so, any T4 disease or any node-positive disease that the hazard ratio seemed to favor pembrolizumab more in terms of disease-free survival.
And then the population (and I will counter that it is a slightly controversial population) of M1 NED — the patients who have been rendered no evidence of disease (NED) by metastasectomy — those patients also seemed to do better with having adjuvant pembrolizumab vs placebo. But there are naysayers and people who are in the camp of saying, this is a little controversial because this population shouldn't exist, right? If they've had oligometastases resected, they also potentially had micrometastatic disease. And indeed, the majority of those patients had recurrence within 2 years. So does that population truly exist if we're looking across the population?
Finally, [there were patients with] sarcomatoid features at the time of nephrectomy. This was a smaller group overall, but it seemed that if sarcomatoid features were present, those patients benefited a little bit more.
So those, in my current practice, are the takeaways: If they had T4 disease, if they had node-positive disease, or if they fit in that camp of people who had oligomets rendered NED, those would be the patients who would benefit from adjuvant pembrolizumab.
Pal: That makes perfect sense. I think the only thing that would give me some pause is if this particular study stood out among all others as being positive. You know, I've put a lot of my eggs in the IMmotion010 trial basket that I've been working on for a while with adjuvant atezolizumab. But as you so appropriately point out, there is adjuvant nivo, nivo-ipilimumab, perioperative nivo, adjuvant durvalumab, tremelimumab, et cetera. There's so many potential regimens out there, and I'm hoping that this go-around, as opposed to with TKIs, there's some consistency across the trials.
So I completely agree with you on points around KEYNOTE-564. I'm really hoping that in this area, we see some consistency among all the adjuvant immunotherapy trials. As you so appropriately point out, we've got adjuvant atezolizumab, nivolumab, nivo-ipi, perioperative nivo, adjuvant durva, treme. I'm hoping that there's a good consistent signal as opposed to what we saw among the TKIs.
Some of the things that I've gotten questions about in the community so far are, what would you do for those non–clear cell subtypes? We do come across that in practice. Every now and then, the surgeon will send to me — in fact, I got this the other day — a patient who had pathologic T3 N1 disease after nephrectomy, and it was papillary histology. What would you do in a scenario like that? Would you offer adjuvant pembro, or just observe?
Zhang: To be honest, I've been seeing these patients as well. I had a patient last week with a 30-cm tumor resected, and if ever there was a T4 tumor, that was it. But it turned out to be FH-deficient type, right? Papillary type. Are we giving adjuvant pembrolizumab? If you're a true reader of the data for KEYNOTE-564 then, you know that we should probably not offer adjuvant pembrolizumab because the study only enrolled persons with clear-cell disease. But when you're reading the approval label carefully, it doesn't actually specify clear-cell disease.
So could you do it? Probably. Is that beneficial? I think it depends a bit on the histology. In papillary disease in particular, we've seen more benefit. I would say as the other trials are enrolling that in your trial, cabozantinib seems to have a better effect than immunotherapies, but we haven't proven that for sure. And you know, if it's chromophobe [renal cell carcinoma], then my goodness, I don't think immunotherapy is as beneficial. But these histologies matter, and what we consistently hear from the kidney cancer patient communities and advocates is that we really need more trials specifically to study those subpopulations of non–clear cell disease.
Pal: I couldn't agree more. I love the idea of sort of parsing out clear-cell and non–clear cell kidney cancers into all the various subcategories and really looking at the effects of strategies like adjuvant immunotherapy separately. I think that makes a lot of sense.
The other subset of patients that's drawing a lot of attention — and you did a great job highlighting this already — is the N1 population that's been resected. They draw that fine line at patients who have had metastasectomy within a year of their original surgery for kidney cancer. Nowadays, I've seen a lot of patients — and this may just be coming to front of mind because of the recent approval — who have had metastasectomy come to me after 5 years, 6 years, et cetera. Would you consider offering adjuvant pembro in those scenarios, or are you sticking to the eligibility in the trial?
Zhang: After 2 or 3 years, they're at higher risk for sure. After 5 or 6 years, their disease may have proven itself and it might be more indolent. So let them have some time, some more time, right? Another 3 or 5 years off of systemic treatment and delay that.
I also like to point some of my patients to this recurrence prediction nomogram that the Fox Chase and ECOG investigators put together. It's online, with easy access. It's a nomogram to predict disease recurrence as well as for overall survival for patients. It was built off of the ASSURE data, which was one of the ECOG trials. What I like about it is that it puts into numbers the recurrence risk without treatment. Then we can extrapolate for that recurrence risk with treatment. I think that sometimes will help the discussions. it obviously depends on the patient and how much data they want to hear, but that has been a tool in the toolbox to help make these decisions.
Pal: Great. I think we'll wrap up with one last question around the adjuvant space. We talked about the context of TKIs. What are your thoughts on patients who get adjuvant pembrolizumab and their disease progresses on that? Are you approaching them as you would a standard frontline patient? Are your considerations a little different there?
Zhang: This is a quandary that we all will face as more patients receive adjuvant pembrolizumab. I think my comment earlier about timing of when they are recurring or progressing makes a lot of difference in terms of what mechanisms we might want to use in their now first-line metastatic setting. But truthfully, this population did not exist in the first-line metastatic trials that we've enrolled and completed, looking at all the immunotherapy combinations. So it is an opportunity, in some ways, to study this patient population more. If they've been off of adjuvant pembrolizumab for 2 or 3 years and now they're having recurrence, I definitely think rechallenge should be given with any of our immunotherapy combinations that make sense in the first-line metastatic space. Those still have activity for those patients.
Pal: Speaking of first-line therapy, I'd love for you to give a little plug for PDIGREE, which is a brilliant trial that's still enrolling now, if I understand correctly, and it could certainly use the support of our listenership.
Zhang: Thank you for giving me the opportunity, Monty. We've been running PDIGREE in the Alliance Cooperative Group now for almost two and a half years, and it's still ongoing in terms of enrollment. It's a phase 3 adaptive trial design where everyone with intermediate core risk, clear-cell disease are all enrolled and treated with upfront ipilimumab and nivolumab. So they get the dual checkpoint inhibition up front. Then we adapt treatment for the 3-month responses: Patients who have complete responses receive nivolumab alone, patients who have progressive disease receive cabozantinib alone, and everyone in between are randomized to either nivolumab or nivolumab with cabozantinib. When we started the trial, nivolumab with cabozantinib was not approved as a combination. It's now gained its approval.
We think this will have a lot of interesting data for us in terms of sequencing. And also, it is the first trial to prospectively discontinue treatment for patients with complete responses at 1 year. So I think there's some relevance there too, for when can we stop immunotherapies for patients who achieve good responses.
Pal: So many great things to come out of the PDIGREE trial, I'm sure — a rich repository of biomarkers, and clearly this is the sort of cooperative group study that takes years to generate but is going to garner multiple results that inform kidney cancer practice in years to come. Question for you, Tian, and we'll close with this: For junior faculty folks who are getting into the field, what's your advice to them as they're trying to establish themselves in kidney cancer or other specialties?
Zhang: I think overall, the road in academic medicine is truly a marathon and finding the right mentors and collaborators along the way is really important. I think it's also really important to have early-career faculty that have a compass, with some overarching themes that motivate them, that drive their work. One thing that I tell our fellows and early-career faculty a lot is that rejection is not indicative of their value and their worth as a clinician or researcher. I don't know who needs to hear this, but so many of us have had manuscripts rejected, grants rejected, and those with the persistent nature of picking themselves up after the rejections will ultimately win the longer race in the marathon.
And finally, [my advice is] just to make the most of all the opportunity shared with them. I think successfully completing their projects will gain further opportunities down the road.
Those are the three pearls that I share with our early-career faculty, and I appreciate being able to share that with our audience today.
Pal: That's terrific, Tian. Thank you so much. I think that's a great way to close the program. Thank you, Tian, for joining us today. And listeners, thanks for tuning in to Medscape's InDiscussion.
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Cite this: Adjuvant Treatment With Immunotherapy - Medscape - Sep 01, 2022.