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Key Issues Impacting RCC and Urothelial Cancer: A Review of Recent Trials

Interview with Guru Sonpavde MD

‘Filmed by PracticeUpdate with permission for inclusion on Uro Onco. More information and additional ASCO coverage can be found at www.practiceupdate.com

‘Interview transcript’

Dr. Haffizulla: Welcome to this PracticeUpdate. I’m Dr. Farzanna Haffizulla. Joining me today is Dr. Guru Sonpavde. Dr. Sonpavde is an Associate Professor of Medicine and Director of Urologic Oncology at UAB Comprehensive Cancer Center, but I know that you are on your way to Dana Farber as well. Great to have you here.

Dr. Sonpavde: That’s right. Thank you.

Dr. Haffizulla: Excellent. Now, I wanted to talk about TKI therapy in renal cancer. What sort of impact do you think combination therapy with TKIs with newer immunotherapy will have in renal cell carcinoma?

Dr. Sonpavde: I think that is a question that still awaits an answer. We’re waiting for a number of randomized trials going on that are combining VEGF-inhibitors with immunotherapy drugs, PD-1 or PD-L1 inhibitors. There’s also a trial that’s combining a CTLA4 inhibitor with a PD-1 inhibitor. So, I think, the results of these trials are awaited and we will need to see which way that action of treatment goes in the future.

Dr. Haffizulla: Yes. Absolutely. Now I want to switch gears and talk about urothelial cancer for a moment. So how does one go about deciphering which immunotherapy agents to use in advanced recurrent urothelial cancer after failing chemotherapy?

Dr. Sonpavde: Yeah. The easy answer to that question is that the only positive trial has been in the second-line, in a post-platinum second or third line setting, has been with pembrolizumab a PD-1 inhibitor. So, pembrolizumab in the Phase 3 KEYNOTE-045 trial extended survival compared to chemotherapy, which was mostly a taxane sometimes vinflunine and that trial showed a three-month extension in median survival. All of the other PD-1 or PD-L1 inhibitors have been looked at only in nonrandomized Phase 2 trials or a negative Phase 3 trial, in the case of atezolizumab, which unfortunately could not extend survival compared to the standard arm, which was either vinflunine or a taxane, but the majority of patients, in fact, got vinflunine. So, we don’t know why atezolizumab could not beat chemotherapy in that Phase 3 trial, but that might have some influence on the practicing physician.

Dr. Haffizulla: Sure. Any other lessons learned from the KEYNOTE trials that you’d like to highlight for our viewership?

Dr. Sonpavde: In addition to pembrolizumab extending survival in the KEYNOTE trial in the post-platinum setting, pembrolizumab has also been FDA approved now in the first-line setting in cisplatin ineligible patients, so in that same space there’s atezolizumab. So both atezolizumab and pembrolizumab have been approved in the first-line space of cisplatin ineligible patients based on nonrandomized Phase 2 trials. So, I think atezolizumab and pembrolizumab still both would have a role in the first-line space and that would depend on physician comfort with which agent they’re used to.

Dr. Haffizulla: Of course. That makes sense. Now, going back to renal cell carcinoma, why haven’t approaches in the metastatic setting translated to the adjuvant setting just yet?

Dr. Sonpavde: That is a difficult question to answer, so we have two negative Phase 3 trials in the adjuvant space in renal cell carcinoma. One is the ASSURE trial that looked at sunitinib or sorafenib versus placebo, giving one year of therapy. There were a lot of toxicities in that trial with both the TKIs and delivery of the dose was difficult, so that was a negative trial, and we had one more negative trial at this year’s ASCO reported with pazopanib. And therefore, two negative trials, but there is one positive trial, the S-TRAC trial, which looked at sunitinib for a year, and this was somewhat a higher-risk population with predominant...with only clear cell RCC patients included.

So it might be that the more VEGF driven tumors, predominantly clear cell, higher risk, higher stage patients may have some benefit, but again, in the S-TRAC trial the benefit has been with PFS or progression-free survival and not survival. So, some of us look at that and say, you want to wait for the survival data, but we do discuss these data with the patients and see if the patients want to try the adjuvant sunitinib in that situation.

Dr. Haffizulla: Of course. Well, you mentioned some ways that we can identify patients who might benefit from adjuvant therapy. Any other ways you want to highlight, perhaps, to identify such patients?

Dr. Sonpavde: At the moment, the best we have is to use the trial eligibility criteria of S-TRAC, which was the high-risk patients with clear cell RCC that benefited in that trial. There is not a molecular biomarker I can point to right now. There is an Oncotype-type gene expression profiling that’s been presented by Brian Rini in a paper a couple years ago that did show that that might help improve the prognostication of patients who are undergoing nephrectomy, but we don’t know how to use that to select patients for sunitinib or not.

Dr. Haffizulla: Sure. I see, so more information needed in that front.

Dr. Sonpavde: Yes.

Dr. Haffizulla: We want to thank you, again, for joining us on Practice Update, and bringing your expertise to the table. We appreciate it, and good luck on your move to Dana Farber.

Dr. Sonpavde: Thank you.

Dr. Haffizulla: Excellent, and to our viewers, thank you again for joining us for this PracticeUpdate. I’m Dr. Farzanna Haffizulla. Please join us again soon.