Paradigm Changing Data for Kidney Cancer - Primo Lara

Primo Lara and Monty Pal discuss this exciting time in the evolving paradigm for the treatment of kidney cancer.  They focus their discussion on the groundbreaking data presented at ASCO GU on the KEYNOTE 426 trial which demonstrated that the combination of pembrolizumab plus axitinib was superior to the VEGF RTKI, sunitinib.  Overall survival with the combination demonstrated a 46% reduction in the risk of death with corresponding improvements in response rates and PFS while toxicity appeared to be reasonable with doublet therapy.  The question is how does this data stand up to nivolumab plus ipilimumab in CHECKMATE 214?  Dr. Lara admits that it is difficult to make cross-trial comparisons, but even with those limitations, the combination stacks up favorably.  Lastly, Dr. Lara provides his thoughts on the JAVELIN 101 trial which evaluated avelumab plus axitinib versus sunitinib monotherapy.  What was striking in the JAVELIN 101 study was that the combination had advantages in all risk groups, which was similar in KEYNOTE 426 versus VEGF TKI monotherapy.  However, this was not the case in CHECKMATE 214 where nivo/ipi appeared to benefit patients who were intermediate and poor risk preferentially leading clinicians to believe that IO based doublets with a VEGF TKI may be able to cross that divide and provide a broader spectrum of activity across all risk groups.

Biographies:

Primo N. Lara, Jr. MD, Professor, Director, UC Davis Comprehensive Cancer Center, Sacramento, CA

Sumanta (Monty) Kumar Pal, MD, is an internationally recognized leader in the area of genitourinary cancers, including kidney, bladder, and prostate cancer. He is the Co-director of City of Hope's Kidney Cancer Program and is the head of the kidney and bladder cancer disease. Dr. Pal sits on the Editorial Board for clinical genitourinary cancer and is a reviewer for multiple journals including The Journal of Clinical Oncology, The Journal of Urology, European Urology, and many others.
Read the Full Video Transcript

Monty Pal: Welcome to UroToday. My name is Dr. Monty Pal and I'm a Medical Oncologist at the City of Hope Comprehensive Cancer Center. I'm here with my dear friend and mentor, Dr. Primo Lara, who's actually Director of the UC Davis Cancer Center. Dr. Lara, thanks so much for joining us.

Primo Lara: Monty, you know I've said this, many times, someday we'll all work for you.

Monty Pal: Doubtful, but okay.

Primo Lara: Just saying.

Monty Pal: Lucky, this meeting has just been incredible when it comes to data for kidney cancer, and one of the abstracts that I think has really sort of rocked our world in kidney cancer, is KEYNOTE-426. Tell us a little bit about that study.

Primo Lara: Well, it is a pivotal study in that it provides a brand new option for our patients with metastatic renal cell carcinoma. The study is a very simple one. It actually echoes what everyone else is doing. It's a comparison between an IO-based combination versus a VEGF RTKI. In this case, it's pembrolizumab in combination with axitinib versus the now whipping boy, sunitinib. And as you know, we were all pleasantly pleased to see that the experimental arm in that study, the combination of pembro plus axi, improved overall survival. The hazard ratio was remarkable. It was .53, a 47% reduction in the risk of death. It's remarkable, with corresponding improvements in response rates and PFS. Toxicity seems to be reasonably acceptable for a doublet. So in my view, that is a practice-changing study.

Monty Pal: You know, I think you bring up some great points around KEYNOTE-426, but the question is, how does the data for axi and pembro stack up against nivo and ipi?

Primo Lara: Well, at least from an imperfect cross-trial comparison, I think it stacks favorably well. Now it's always hazardous to do cross-trial comparisons. We always warn people against doing that. However, having said that, the trials were essentially comparing these doublets to a common control arm, which is sunitinib, so in that respect, they're fairly analogous.

At least, at first blush, it appears that the pembro/axi combination seems to be associated with a higher response rate. That's 59%, as reported in the 426 trial. That's among the highest response rates we've seen in a Phase 3 trial. With the nivo/ipi combo, it's hovering a little under 50%, so even though it's a small delta between those trials, any increase in response rate is favorable in our opinion, because say what you must about all the other end points, it's just overall survival. In daily clinical practice, patients and their doctors appreciate a response, right? There's nothing like sitting in the clinic with your patient with metastatic kidney cancer and getting the satisfaction from seeing that the treatment that they're receiving is actually shrinking tumor on a CT scan or an x-ray.

Monty Pal: I agree with you. One of the greatest pleasures, without a doubt. Now I would be remiss not to ask you about a third dataset that's been hanging over us over the past couple of months, and that’s the JAVELIN-101 study. It's so interesting to me how studies so similar to KEYNOTE-426, so this was axitinib/avelumab against sunitinib, to produce what I think are somewhat different results when it comes to, for instance, overall survival and so forth.

Primo Lara: Sure.

Monty Pal: What are your perspectives on JAVELIN?

Primo Lara: Well, JAVELIN was originally presented at ESMO 2018, and at that presentation, we were not surprised to see that a doublet that's IO based, avelumab in this case, in combination with the VEGF RTKI would have some efficacy benefits over a single-agent VEGF RTKI, in this case, sunitinib. At the time of that presentation, we were left with a gnawing, that's with a G, a knowing sense of unfulfillment, because the events for overall survival had not yet been reached.

Essentially, what we were pining for was some harder evidence that this would replace the existing standard of care. Now what we took from the avelumab/axitinib study, however, was that regardless of risk category, IMDC risk category, whether you're an intermediate or good risk, it appears that the doublet had efficacy advantages over sunitinib. That wasn't the case, as you know, with nivo/ipi, wherein that particular study, the nivo/ipi doublet appeared to benefit patients with intermediate and poor risk preferentially, while those who had favorable risk disease appeared to benefit from the VEGF RTKI. So what we're seeing here is that the doublets that are IO-based, but have a VEGF RTKI as the doublet partner, appear to cross that divide. They're able to then become more user-friendly for patients and physicians alike, because they have a broader spectrum of activity across risk groups.

Monty Pal: Well said. Well said. So great perspectives from you on CHECKMATE-214, JAVELIN-101, KEYNOTE-426. Thank you so much, Lucky, for joining us.

Primo Lara: Thank you, Monty. Any time.

Monty Pal: And from UroToday, this is Monty Pal, signing off. Please join us for more of Dr. Lara in the coming weeks. Thank you.
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