Dr. Gong: Welcome everyone to PracticeUpdate. I'm Jun Gong from Cedars-Sinai Medical Center, a GU medical oncologist. I am proud to introduce my mentor, friend and one of the renowned experts in GU medical oncology, Dr. Monty Pal from City of Hope. Welcome, Dr. Pal.
Dr. Pal: Hey, great to be here, Jun. Thanks for having me.
Dr. Gong: My pleasure. I wanted to jump right in. You were one of the lead investigators on a very interesting and impactful study, COSMIC-021, that investigated cohort one of cabozantinib and atezolizumab in clear-cell renal cell carcinoma. Firstly, I want to ask you, what other combination immunotherapy-based treatments have been established in advanced RCC thus far?
Dr. Pal: The ones that we typically talk about in the clinic are axitinib with pembrolizumab, axitinib with avelumab. We've discussed in the past these more recent data from cabozantinib with nivolumab in the context of the CheckMate 9ER study, and we saw some significant improvements in quality of life, progression-free survival, overall survival, with that regimen. I really think there's something to these cabozantinib-based combos.
Dr. Gong: Absolutely. There's some solid pre-clinical rationale, and you were one of the investigators is the pivotal METEOR trial too, that established cabozantinib in a second-line study. What was the design of this trial?
Dr. Pal: The design of COSMIC-021 was essentially conducted in patients with untreated metastatic disease. We did a quick-dose escalation. We migrated from 40 mg of cabozantinib to 60, and within cohort 1-we actually had two distinct cohorts. We had a cohort of patients treated at 40 mg of cabozantinib with standard doses of atezolizumab, and a separate cohort treated at 60 mg. That really was a great opportunity for us to dive deep in this question of whether or not 40 or 60 was the most appropriate starting dose.
Dr. Gong: Great. What an interesting design, and very important design for the cabozantinib dosing strategy. What were the key findings, Monty?
Dr. Pal: I would suggest that on all accounts, the data were impressive, and fairly comparable between the 40 mg and 60 mg doses. You know, one thing I think we probably have to caution is that when you dive deep into some of the data, it really is important to keep in mind that with the 60 mg cohort, follow-up is still ongoing, and the degree of follow-up was less than we have thus far in the 40 mg cohort, which was established sooner.
But what I would propose is that progression-free survival in both arms, for 40 mg and 60 mg, is quite impressive, 15 months and 19 months for 60 mg and 40 mg respectively. Response rates were in the ballpark of 55 to 60%, which, again, is quite impressive, and on par with what we're seeing, if not better, than other TKI plus IO regimens.
Again, the other thing that really stands out to me is this rate of very, very low progressive disease, and that's so important to our patients in the clinic, right? Because, you know, first and foremost, they just want to know whether or not they're going to get some benefit, and whether or not the regimen is going to work. It's impressive to state that the regimen is only going to fail in about one in 20 patients.
Dr. Gong: Right. That's very, very promising finding. You touched a little bit about it. There's a efficacy difference, possibly, between 60 and 40 mg. What about the toxicity of this regimen?
Dr. Pal: I would say, again, too, what was quite surprising is that 40 mg and 60 mg didn't really result in terms of a world of difference in toxicity. I really think that the toxicity profiles are fairly comparable. You have to take this with a grain of salt, because each cohort just had patient census in the mid-30s or so, so it's hard to draw far-reaching conclusions around toxicity. But I would say that no major differences were seen at 40 mg versus 60 mg.
Dr. Gong: That's really reassuring to hear. A lot of members in the audience, and the scientific community at large, Dr. Pal, are going to ask, should this regimen be advanced as a new standard? Or are there other developments, trials that need to be performed first before this combination gets advanced?
Dr. Pal: It's a great question. You know, one of the things that we really sort of were looking at in developing the regimen is how to carve a unique niche for it. While I do think that cabozantinib with nivolumab, you know, based on the CheckMate 9ER data, should represent a new standard, you know, I think one thing that we've got to acknowledge is that we're still going to partners in the community who are using regimens like nivo and ipi, perhaps axi and pembro, and we therefore designed the CONTACT-03 trial, a phase III study, to really reflect that practice. Patients who progress on nivo-ipi, patients who progress on axi-pembro, they can potentially come onto CONTACT-03, where they're randomized to either cabozantinib at 60 mg or cabozantinib with atezolizumab, again, using that 60 mg dose.
There are so many folks in the community at this point who continue to utilize checkpoint inhibition after failure of a prior checkpoint inhibitor, and I think this study is really going to drive home whether or not that practice is reasonable, and results in clinical benefit.
Dr. Gong: I agree. That's a very important practice-changing potential question that needs to be answered, and I'm glad that you are one of the pioneers leading the way to answer this question. Again, thank you for your time, Dr. Pal.
Dr. Pal: Thank you, Jun. It's a pleasure to be here.