Emerging Strategies for Renal Cell Carcinoma - Episode 10

Emerging Therapies for Relapsed/Refractory MRCC

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Michael Atkins, MD: Something I’m excited about is the HIF2-alpha inhibitor, particularly the drug that came out of Peloton Therapeutics, now being developed by Merck &Co: the MK-6482 agent. That’s going to have a potential role for some patients as a second-line treatment, particularly patients who clearly have HIF2-alpha–driven cancer because it blocks not only VEGF but also other things that are downstream of HIF2-alpha that may drive tumor progression. It’s an oral agent, it’s reasonably well tolerated, patients may be able to stay on it for a long time, and it may be a new agent that we’ll have to figure out how to use. It may have the potential to be combined with TKIs [tyrosine kinase inhibitors]. There’s a rationale for that, and there is also potential for combination with checkpoint inhibitors where it’s less likely to cause hypoxia in the tumor microenvironment. Therefore, it may be a better drug to combine with an I/O [immuno-oncology] agent than current TKIs.

Robert Alter, MD: That was presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], and there was a buzz that it was worth of having. We’re both involved in second-line therapy using MK-6482, so it’s going to be exciting to finally get to use it. It’s ultimately going to be a real player when it comes down to treating our patients not only in the second-line setting but most probably in the combination therapy setting moving forward as well.

I like what Chung-Han “Joe” Lee presented in regard to using lenvatinib-pembrolizumab as a second-line therapy in patients after failing first-line I/O therapy. It’s using it like how we see things clinically. We are definitely data driven, but after a while, we have to adapt. If we treat someone with ipilimumab-nivolumab as a first-line therapy and with cabozantinib as a second-line therapy, where do these drugs come in as third-line therapy? There are no significant data. There are small data talking about using immunotherapy as a third-line therapy, but we are secretly practicing using it. When you now have data to support it, and it’s coming in real time, we’re offering our patients 4 or 5 lines of active therapies for which we have high hopes. It’s not just palliating our patients. When you look at the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium], they looked at the analysis that less than 50% of patients are receiving second-line therapy, and we’re talking about how we incorporate 5 lines of single and combination therapies. Going back to the days before 1992, it is becoming quite remarkable where the science is taking us.

Michael Atkins, MD: In our hands, very few patients who progress on first-line therapy don’t get a second-line therapy. That may have been the case when you had sunitinib as your first-line treatment, and there were people who had aggressive disease who didn’t respond to sunitinib who weren’t in shape to get a therapy afterward. Now that we’re giving immunotherapy as a frontline therapy, for many patients, their most aggressive disease is being eliminated. And if they do progress, it may be with slower disease. In our hands, one can always get TKIs into those patients and give them a chance if they need it.

I agree that the lenvatinib-pembrolizumab data were interesting, but I have a caveat about that. The fact that lenvatinib-pembrolizumab produced a high response rate after nivolumab-ipilimumab is not surprising because it’s the first time those patients are seeing a VEGF receptor TKI, and the patients who aren’t responding to nivolumab-ipilimumab may be enriched for patients who might respond to a VEGF receptor TKI, so a 55% response rate in that group is not surprising. You might say, “There was another group that got a VEGF receptor inhibitor and an I/O who also had a high response rate.” But those were not patients who got axitinib-pembrolizumab. Those are patients who got sunitinib often for a short period of time or at a lower dose because of toxicity. They may not truly have progressed and went off it early so they could get nivolumab, because that’s what they really wanted, and then they progressed on nivolumab and went to lenvatinib-pembrolizumab. They may not have been truly resistant to the VEGF pathway. It’s not surprising that you could see a response to a better VEGF receptor TKI in a group of patients whose disease was still responsive to VEGF inhibitors. I’m not sure what the contribution of pembrolizumab is to that combination after people have already progressed on the TKI, and that’s a question that is well worth addressing scientifically.

Robert Alter, MD: That’s right. As of now, we’re still using lenvatinib as your second TKI; it should not be used as a first TKI, though we do get excited about not just its science and mechanism but also about its efficacy that we’re seeing.

The last question I have to ask you is a question everyone has: Do we have a predictive biomarker that we are using yet with which we can come to the conclusion that we can predict how to treat our patients? Are we still looking for that?

Michael Atkins, MD: We’re getting close. As was published in Cancer Cell last week, there’s a thorough review of the biology of the tumors from the patients who went on the IMmotion151 study, comparing atezolizumab and bevacizumab to sunitinib. You could see that they divided tumors based on transcriptomics into 7 categories: 2 of which are angiogenesis driven, 3 of which were more proliferative and immunotherapy responsive, and 2 in which patients probably didn’t respond to either of those. That type of data are where we want to get to in order to help us choose treatment options.

There was then another component where they looked at next-generation sequencing, and they saw that those groups tended to divide where there’s a group that’s PBRM1 mutated, which is more the angiogenesis sensitive, and the BAP1 mutated, which is more the immunotherapy sensitive. If we can boil those transcription factors and next-generation sequencing mutations down to a few factors that we can analyze on a histologic specimen, we may be able to be at a place where we can say, “Here’s a group of patients who should get TKI–I/O, and here’s a group of patients who should get I/O–I/O.” We’re probably no more than a couple of years away from being able to do that and to have the data in this manuscript validated in an independent study prospectively so we can use them as biomarkers to help us choose the right treatment.

Robert Alter, MD: As community oncologists in academics, we’re definitely using next-generation sequencing more. We’re putting patients on clinical trials more, which is my approach to community oncologists: If you have an academic institution that has an excellent clinical trial for your patients, it’s worth it to discuss and consider that. The pulse of what we’re trying to think about is not just immunotherapy. Do we have the potential of taking care of the patient and the cancer rather than just taking care of the cancer? Can we offer patients durable remissions and an improved functional quality of life with curability? Ultimately, the way we are looking at our patients is not about what I can do for them in the next 6 months; it’s what I can do for them for a lifetime.

Michael Atkins, MD: I’ve been in this business for a long time, and when I started, the median overall survival for patients with metastatic kidney cancer was 10 months. With interferon, it may have been prolonged to 13 months. With high-dose IL-2 in the patients who went on those studies, it was prolonged to 17 months. With the single-agent first-line TKIs, it may have been 25 to 28 months. We’re now at a point where we can expect a median overall survival to be as long as 5 years, and that’s all because of basic and clinical research studies where we’ve seen that tremendous improvement in overall survival over a 30-year period. That wouldn’t have happened if it wasn’t for basic science and translating that basic science into clinical trials, which led to changes in clinical practice. There are still new drugs out there that could potentially push that survival bar even higher: things like the CAR [chimeric antigen receptor] T cells that are targeting CD70 or CA9 or PSMA. Other targets include glutaminase inhibitors and CXCR4 and CDK4/6 inhibitors, which might be potential opportunities for groups of patients who don’t respond well to the standard TKI checkpoint inhibitor regimens. There is still a need and an opportunity for clinical research to raise the bar higher, and we shouldn’t stop until we’re offering curative therapies for as many patients as possible or until we have a therapy that we think is the best therapy to offer in the first-line setting for each patient we see.

Robert Alter, MD: We’re still very excited about going to work every day.

Michael Atkins, MD: Yes, we are.

Transcript Edited for Clarity