Dr. Rana McKay:
Welcome to The ASCO Post Roundtable Series on Later-Line Considerations in Relapsed/Refractory Renal Cell Carcinoma. I'm Dr. Rana McKay. I'm a GU medical oncologist at the University of California in San Diego. And joining me today are my two colleagues. So awesome to have them here on the program with us today.
Dr. Pal, do you want to introduce yourself?
Dr. Monty Pal:
Thanks a lot. My name is Monty Pal. I'm a medical oncologist at City of Hope in Los Angeles. I focus on kidney cancer primarily.
Dr. Bradley McGregor:
I'm Brad McGregor, also GU medical oncologist, on the other side of the country at Dana-Farber in Boston.
Dr. McKay:
Today we're going to be discussing the treatment and management of relapsed/refractory RCC with three patient case studies. So we're just going to dive right in. Our first installation will focus on the treatment of metastatic favorable-risk RCC after progression on VEGF/IO therapy. So we're going to dive right in.
So our first case, Ms. LB, is a 67-year-old female who presented in May of 2007 with hematuria and had imaging performed to work up the hematuria, given its persistent nature. And she was found to have a large renal mass about 10 cm in size, and ultimately ended up undergoing a radical nephrectomy, removal of the mass, and it showed clear cell RCC measuring 10.5 cm, grade 2, PT2, negative margins. She did have staging scans, a CT of the chest was negative, and no evidence of metastatic disease.
So first, I'll pause. What do you all do in this situation? You've got somebody with localized disease, has some high-risk features. How do you surveil these individuals? What do you currently do?
Dr. McGregor:
Yeah, I think things have changed from 2007 to now, although maybe not for this specific case. So this is a T2 grade 2. And so for these patients, I think the data support that surveillance is really the most appropriate option. I do a scan, CT test on pelvis, every 3-ish months for the first year, then every 4-ish months, and then I space it out to 6 months to 12 months at year 3 and beyond. But I wouldn't offer any adjuvant systemic therapy in this situation.
Dr. Pal:
Yeah, I totally agree with you, Brad, but it is interesting how things have evolved since 2007 for slightly higher stages of disease.
Dr. McKay:
Yeah. This was 2007. It was even before the approval of sunitinib for adjuvant RCC, so this takes us back.
Moving on with the case, she was under surveillance for a long period of time, actually completed her 5 years of surveillance. A couple of years after the 5 years, she even went on to continue imaging and then stopped doing surveillance scans. In April of 2017, almost 10 years from her original diagnosis, she developed night sweats, and in the workup of the night sweats, she ultimately ended up having imaging get performed, and CT of the chest showed that she had pulmonary nodules. Her labs were otherwise within normal limits, and ultimately did undergo a sampling of those pulmonary nodules demonstrating that she had a clear cell RCC.
I guess the first question is, what do you do now? How do you approach these patients that present with metastatic disease? How do you risk stratify them? What's your approach? Maybe Monty, you can start.
Dr. Pal:
Yeah, sure. This is a great case, and it's interesting when you see these patients with this huge latency in the onset of metastatic disease. It's certainly a favorable risk factor, I would say. In a specific scenario like this, I think a lot of it hinges on what that scan looks like, if you're seeing small, scattered pulmonary metastases that she's asymptomatic from. In this case, I guess it's hard to know how the night sweats tie into things. But I would probably propose just observation, in cases like this, for a period of time. I think that's pretty fair. I'm still of the mindset that the typical risk stratification tool that we use, the IMDC criteria, are actually quite helpful in guiding these patients. If I do see that the patient is intermediate or poor risk, I'd probably steer more towards offering systemic therapy. But I will say that I'd still put active surveillance as perhaps top of my list for this patient.
Dr. McKay:
Very good. Brad, what are your thoughts? Are you still using IMDC risk today?
Dr. McGregor:
100%, yeah. I think it's helpful specifically in this very situation. If you think of this as maybe in that very good risk thought process with that over 2 years since nephrectomy to this point here, I 100% agree with everything Monty said. I think one of the key things here is, assess the burden of metastatic disease. One, is there any systemic treatment? And then is it maybe something that's amenable to localized therapy? Is there a cluster of nodules all in the same area that potentially could be treated with some sort of definitive local therapy, is something we always think about in these late relapses. Obviously, in this situation, it seems like there's probably multiple nodules not amenable to local therapy. And I think a surveillance approach would be what I would most likely pursue.
Dr. McKay:
Yeah. Absolutely. Yeah, she definitely had favorable-risk disease with this long latency period from her original diagnosis, no IMDC risk factors. The IMDC risk factors, I agree with you all, they're still highly relevant today, and even have been prognostic in the context of a lot of the phase III studies conducted with IO combination therapy. So they're still, I think, highly relevant, and patients still stratify to favorable, intermediate, and poor based off of the application and the variables.
Initially, that's what happened for this individual. She was monitored for a period of time. She had the dominant lesion that was resected, and didn't really have too much going on on her scans, and was essentially monitored for a period of time, almost a year. Then in April of 2018, she had a CT of the chest that showed continued stable pulmonary nodules, but she ended up having an increase of a small adrenal nodule that ended up growing over time on her serial scans and actually ended up developing a pancreatic mass as well.
Maybe I'll stop there just to think about sites of metastases and this patient's progression. Certainly we're realizing that site of metastasis matters in RCC. It's incredibly prognostic. And the tropism for why a tumor goes to the pancreas vs the liver or the bone, it's certainly been really interesting to see the data about the differential outcomes based off of where a patient's metastases are. Do you take that into consideration when you're strategizing around treatment, where people's metastases are? Or are there top key sites that you definitely integrate into your decision-making?
Dr. Pal:
Yeah, I definitely think that it's wise in a situation like this to, first of all, alleviate the patient's concerns around the pancreatic lesion. I'm sure in all of our mutual experiences, patients see that, and they really freak out, and I completely understand it. But now, we've seen enough series, I think originally from MD Anderson, really documenting very nicely that patients with pancreatic metastases really tend to have an exceptional outcome. I remember an initial series from the MD Anderson group suggesting a threefold higher PFS with VEGF TKI therapy in the context of pancreatic metastases, which was really encouraging. I love sharing that sort of thing with patients.
Dr. McKay:
Yeah, I agree.
Brad, anything to add? I think it definitely factors in, if you saw a liver vs osseous metastases, how you approach knowing pancreas vs some of these other sites.
Dr. McGregor:
Yeah, 100% agree. It really is just taking the big, total picture into account. I think all the progression to pancreas is obviously very different from progression to pancreas and then multiple other sites at the same time. So I think it's all very individualized, but I would agree with everything, that the most important thing in these situations is to reassure the patients. Basically, we see pancreas, and the patient rightfully gets very scared. And as we've heard, it really can be associated with better outcomes and better responses to some therapies.
Dr. McKay:
So this is 2018. It was right at the cusp of the presentation of the CheckMate 214 data coming out. Prior to that time, she actually ended up ultimately initiating therapy, just given the new sites of disease, growth of the adrenal nodule after undergoing a period of surveillance for some time, and did start on treatment with pazopanib. Certainly experienced some side effects related to it, diarrhea, fatigue, that required dose modifications. She stayed on it for almost a year and a half before, in 2019, actually discontinued treatment because of just intolerant toxicities.
Her disease was stable. She did have a response and we were monitoring her initially until she developed some disease progression and then transitioned to therapy with nivolumab at that point in time, because she had seen a VEGF TKI, got into nivolumab based on the old CheckMate 025 data, and did okay for a short period of time. But didn't really have too great of a response with the nivolumab after several months. Continued having growth of the adrenal nodules and continued having growth of her pancreatic metastases, and then nivolumab was discontinued.
In this scenario, what do you all think of as a next-line option? What are the things that you have in the compendia that you think of? She's seen a VEGF TKI, she's seen IO therapy. Didn't have a great response to IO. Wasn't really too tolerant of the VEGF TKI. So what do you think of, and how do you think about the treatment options?
Dr. McGregor:
I think, yeah, this really does come down to the individual case. If you look at the NCCN Guidelines, if you start looking at subsequent-line therapy, there's no preferred regimen, because there's just so much data out there, and there's different options, and you really can have that discussion with the patient. It's based upon what they've had in the front line, second line, how they tolerated that therapy. And so I think, obviously, additional TKI therapy is very appealing. Cabozantinib, we have really probably very strong data in the post-IO setting from the CONTACT-03 study and several phase II in the retrospective analyses. I think tivozanib is an option. I think lenvatanib/everolimus is certainly an option. I guess I probably would maybe worry about that combination just given her poor tolerability of pazopanib. Then now, the FDA approval of belzutifan, I think there's so many options. The one thing I probably would not lean towards is an IO/TKI regimen, just given the CONTACT-03 data that shows that adding atezolizumab to cabozantinib after progression on IO increases toxicity but doesn't improve outcomes.
Dr. Pal:
Yeah, it's comforting to see that the practice on the East Coast so closely mirrors practice on the West Coast. It's pretty much exactly the way that I would frame this scenario. I totally agree with Brad. I think that, as Brad pointed out already, consideration of this patient's prior toxicity profile is really key. So I got the flavor that she had difficulty with the GI toxicity associated with pazopanib. So in that context, I might actually look a little bit more favorably towards a drug like tivozanib for her in this setting, just because I've found that to spare GI toxicity by and large, whereas regimens like cabozantinib and lenvatinib, despite having very reasonable levels of evidence, I think would probably promote those sorts of toxicities.
Dr. McKay:
That's excellent. I completely agree with all of you all. I think understanding these patients and the pace of their disease and the pancreatic metastases that tend to be very responsive to actually VEGF-based therapies. We always promote clinical trials. I think it's important for our patients to participate in clinical trials. It's really, I think that's the way we move the needle forward. And I think for patients, it has the potential to provide the treatments of tomorrow today. She actually did enroll on a clinical trial and actually was randomized to receive everolimus back in 2020 and was on therapy for a long time, the everolimus actually. She did quite well for some time on the everolimus and then ultimately ended up developing progression of her pancreatic metastases after a several-year period on the everolimus.
That brings us more into the modern day of treatment options. She's still doing well. Her main site of disease is the pancreas, the adrenal gland, and some scattered pulmonary nodules. So what would you all lean for now for this individual? So she's had pazopanib, she's had nivolumab, she's seen everolimus. Thinking about next options for her.
Dr. Pal:
Perhaps the conversation doesn't change too much from what we've described previously, since she's still just been exposed at this point to a single line of TKI, and probably still focus on that as my prevailing option. And I'd probably go with something like tivozanib, although it's hard to pick a wrong answer here amongst cabozantinib and perhaps belzutifan.
Dr. McGregor:
Yeah, 100% agree with Monty. I think she's done exceptionally well on everolimus for a prolonged period of time. I think any of the options that are available... She went on the trial comparing belzutifan vs everolimus, and now she needs belzutifan as a standard of care given the recent FDA approval, given that improved objective response rate, and PFS vs everolimus in the phase III trial. So I think it just, again, it's coming from that discussion with the patient. Overall, I am optimistic that she will respond well to any of these potential options.
Dr. McKay:
That's great. Well, that's exactly what happened. She ended up transitioning to belzutifan, which was now FDA-approved, and she's just starting on therapy.
Dr. Pal:
I really like the fact that you highlighted this extreme responder to everolimus, because I have a handful of those patients in my practice, and remember a couple of years ago, and the three of us, we contributed to that series that Toni Choueiri and others had led looking at the profile of these exceptional responders. And I think we did find a preponderance of mTOR, TSC1, TSC2 alterations. I think cases like this underscore perhaps, and I'm just looking to say something controversial since we've agreed on everything so far, we probably will agree on this, that there may be a role for somatic genomic profiling in patients with advanced disease. Because every now and then, you get an alteration that might steer you in the direction of a TOR inhibitor, or maybe you'll find a needle in a haystack that drives you towards ALK-directed therapy. These are exceptionally rare cases, but I think there's some justification in doing it, especially as patients progress in lines of therapy.
Dr. McKay:
Yeah, I completely agree. I definitely get genetic testing in later line just to strategize options, clinical trials, and other things like that. And I think it's particularly important for non–clear cell patients where there's a paucity of data of what to actually do. And many of the non–clear cells may have VHL alterations. Now we've got belzutifan available. So I think there's a lot that we can learn. So I'm really glad that you brought that point up, Monty.
Dr. McGregor:
And I would 100% agree. I think it's helpful in the later lines. I would caution these early on, and don't overinterpret the data in these situations. So we know if someone has a low TMB, it doesn't mean you shouldn't get immunotherapy. We know that TMB is not something that is predictive of benefit of immunotherapy. Immuno cell carcinoma, we know PD-L1 doesn’t necessarily there. So I think we have very good front-line options that have made a huge difference, and I think we should go for those. And then I agree, use that somatic analysis potentially later on down the line, when you're trying to get into the third- and fourth-line therapies.
Dr. McKay:
I think the key takeaway here is there's really a lot of options for patients that have relapsed/refractory disease. I think it's critically important for us to take into account patients' clinical parameters, their clinical variables, their risk factors, their sites of metastatic disease, the pace of their progression, how they're progressing. I think these are all the factors that come into play when we're deciding on what's the next best regimen for them.
Just a word on belzutifan. It's a recently approved HIF-2-alpha inhibitor approved predominantly for patients with clear cell RCC post immunotherapy and post a VEGF TKI. It's got a very unique mechanism of action still targeting the VEGF HIF pathway, but in a different way than our tyrosine kinase inhibitors traditionally do.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in RCC, or visit ASCOpost.com.
