Evolving Practice Patterns for Advanced Clear Cell Renal Cell Carcinoma - Episode 2

Review of the COSMIC 021 Study for mRCC

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Toni Choueiri, MD: CheckMate 9ER, despite being in the Presidential Symposium at the European Society for Medical Oncology Congress [ESMO], was not the only clinical trial or combination VEGF–I/O [immuno-oncology] presented. Dr Voss, you’ve been involved in several studies at Memorial Sloan Kettering Cancer Center, and you’ve seen the result that Drs Sumanta Pal and Bradley McGregor presented with another combination, with cabozantinib and atezolizumab. That study was named COSMIC-021. If you can discuss first with us the design, the result in your opinion—knowing these is not a randomized study. What’s the practical implication of COSMIC-021?

Martin Voss, MD: Thank you, Toni. COSMIC-021 was presented by Dr Pal at the ESMO meeting this year. This is a combination that conceptually is similar to the cabozantinib-nivolumab combo that we presented so far, but it’s much earlier in its development. Cabozantinib, the same TKI [tyrosine kinase inhibitor] backbone here, is now paired with atezolizumab, which is a PD-L1–directed monoclonal antibody that’s been in development for kidney cancer and has actually been approved for other cancers for some time. The data that were presented by the authors is taken from the COSMIC-021 study, which is a phase 1/2 study that explored this combination specifically in kidney cancer. The data that we saw included mostly patients from the expansion that was pursued in a phase 2 fashion on 2 different dose levels. That’s important to keep in mind.

Atezolizumab was being combined with cabozantinib at full dose, 60 mg per daily. That was a cohort of 30 patients. There was a second patient cohort equal in size, 30 also, who received the same dose of atezolizumab but attenuated dose cabozantinib at 40 milligrams daily. Similar to what was done on the CheckMate 9ER trial. The primary end point for the phase 2 analysis done here was objective response. This enrolled patients with clear cell histology in the first-line setting. Patients had not received other therapies, and patients who had enrolled in this study irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk status. As seen with the 9ER combination, we saw a high-level of activity here. This is not a randomized trial. There’s no comparator arm. But we got a very strong signal for efficacy in this study. On both arms, it appeared that cabozantinib was given at 60 mg. We saw a high objective rate. The response rate for the 40-mg dose was 50%. At 60 mg, it was 47%. There was some CR [complete response] seen on both of these combinations. Both in the same range. What was striking to me is there was very low failure rate on this regimen. Similar to the cabozantinib-nivolumab combination. Less than 5% of the patients treated on the COSMIC-021 study suffered primary disease progression, which is important as we keep these studies in mind.

Less can be said about progression-free survival with such a small cohort of patients, but it was promising. PFS was 19 months by median on the 1 arm, 15 months on the other. Bottom line here, what I would say in terms of effectiveness seen is, this certainly doesn’t fall short in terms of a signal from the other I/O–TKI combinations we’ve seen. A high objective response rate. Very good progression-free survival data. When you look at the waterfall plot taken from Dr Pal’s presentation, we see that the majority of patients benefit who are put on this regimen in the first-line setting. We can only speculate where this is going to go with further development, but certainly the signal is there.

Toni Choueiri, MD: No, that’s good. We’ll look at CONTACT-03 a bit later because, hopefully, this study—this pie to our right—was done in I/O naïve. The decision, or at least the consensus, was to move to a combination in the post–I/O setting. The 1 interesting thing—I don’t know if you all agree with me—is the fact that the type of TKI does matter for combination. Sunitinib and pazopanib are both front-runners. We didn’t know how to pick a front-runner. We end up with the COMPARZ study. Because we all struggled with whether we should do sunitinib or pazopanib. Both drugs, unfortunately, failed to combine with a checkpoint inhibitor. We couldn’t move to a phase 2. There was significant disease-limiting toxicity. Sunitinib was tried, and pazopanib was to be combined with nivolumab. Pazopanib was attempted to be combined with pembrolizumab. These didn’t move on. Drugs such as cabozantinib but also axitinib and lenvatinib did make it to phase 3 trial, so that’s refreshing to know. To know that the type of TKI does matter here.

Transcript Edited for Clarity