PD-1 Vs PD-L1 Inhibition for Frontline mRCC

Sumanta Kumar Pal, MD: I'm going to quickly highlight some data emerging for other TKI [tyrosine kinase inhibitor]-I/O [immuno-oncology]-based combinations. One being the combination of cabozantinib with atezolizumab. This is part of the COSMIC-021 trial. It got pretty large data. Brad and I are both involved. It explored both 40 mg and 50 mg in renal cell carcinoma. The 2 response rates were pretty balanced outcomes at approximately 50%. The PFS [progression-free survival] with 40 mg was pretty consistent with what we saw in CheckMate 9ER in a frontline setting. That regimen is moving forward in a contact-free study, which is a second-line trial in patients with previous I/O-based therapy. It's cabozantinib plus or minus atezolizumab as a second-line treatment.

On this topic of cabozantinib-based combinations, what do you think about the differences between PD-1 vs PD-L1? This is a very controversial topic. I'm going to start with Dave. You're at 1 of the great centers that has been at the helm of a lot of research around PD-1 and PDL-1 with Gordon Freeman, PhD, and others. What are your thoughts there?

David F. McDermott, MD: In the narrow context of kidney cancer, at the moment you can say that PD-1 blockade is more active than PD-L1 blockade as both a single agent and as a combination. The PD-L1 combinations are either dead, which is atezolizumab-bevacizumab, or on a ventilator, which is avelumab-axitinib, until they can show OS [overall survival]. PD-L1 may be slightly more tolerable, but unless it translates into comparable efficacy, you can't advocate for its use over all these more active combinations. That might not be the case in other tumor types, such as bladder or lung. People can have those debates. In kidney cancer, it's not that controversial until axitinib-avelumab can show us OS. PD-1 is the way to go.

Sumanta Kumar Pal, MD: There has recently been a huge storm of retractions and FDA approvals. We just saw atezolizumab for bladder cancer pulled. It brings up this debate of PD-1 vs PD-L1. Bradley, I'll turn to you next. What are your thoughts? Are there any key differences? Are there any clues in the MOA [mechanism of action] that can give us insight into why there seems to be a difference here? Is there a difference?

Bradley A. McGregor, MD: I agree with Dave that it may be a disease-specific phenomenon. We have great data for PD-L1 inhibitors in other cancers, like durvalumab maintenance in lung cancer and avelumab in the switch maintenance approach in bladder cancer. PD-L1 inhibitors certainly have a role in certain spaces. The data we have so far in renal cell carcinoma would suggest that PD-1 inhibitors have the best activity either alone in second line—we've seen with nivolumab and we've seen the data with pembrolizumab in the frontline setting—or in combination with VEGF TKIs.

Sumanta Kumar Pal, MD: Fair enough. I'm going to move on from that topic because it's just so challenging for us to answer with the clinical and biological data that we have at hand.

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