Bradley A. McGregor, MD: Obviously, there has been a lot of excitement about TKI [tyrosine kinase inhibitors]–I/O [immuno-oncology] combinations. It’s very early on. Andrea Apolo did studies looking at cabozantinib combination immunotherapy: cabozantinib and nivolumab, or cabozantinib and nivolumab and ipilimumab. There are some very intriguing data. CheckMate 9ER was initially designed as a 3-arm trial of cabozantinib-nivolumab vs cabozantinib-nivolumab-ipilimumab vs sunitinib. At the exact time that the trial was about ready to open, we saw impressive data from CheckMate 214. Everything came to a halt. But the trial continued on, looking at cabozantinib and nivolumab vs sunitinib.

What separates this regimen apart from all the other phase 3 trials we’ve explored is the dosing of cabozantinib. If you look at lenvatinib-pembrolizumab, the dose is 20 mg. The dose for axitinib-pembrolizumab and axitinib-avelumab is 5 mg. But with cabozantinib-nivolumab, the cabozantinib dose is 40 mg daily, which is less than the standard approved dose of 60 mg. This is cabozantinib and nivolumab at a dose of 40 mg vs sunitinib. As we’ve alluded to, this showed an improvement in overall survival [OS] across these groups and improvement in progression-free survival [PFS]. There seemed to be an improvement: While there’s a deterioration of quality of life by PROs [patient-reported outcomes] with the sunitinib arm, that was not the case with the cabozantinib arm. It’s important to say that this dose of 60 mg is not the dose of 40 mg. This data set showed an impressive benefit, despite the fact that close to 60% of patients had a reduced dose of the cabozantinib. I’m hoping that there may be some synergy there, and that maybe cabozantinib does something to nivolumab and that we’re going to see some of those long-term, durable responses that we’ve seen with nivolumab-ipilimumab with I/O–TKI.

Sumanta Kumar Pal, MD: That was a really nice overview, Brad. Bob, do you have anything to add in terms of the CheckMate 9ER design or layout? Any thoughts on the trial?

Robert S. Alter, MD: The fact is that cabozantinib-nivolumab demonstrated superiority over sunitinib by doubling PFS, doubling response rate, and significantly improving OS. The AEs [adverse events] were not trivial but consistent with previous studies. There were no safety signals that were identified. There was slightly more diarrhea, but it was otherwise well balanced. When METEOR came out, we said that it met the trifecta of PFS, OS, and response rate. I believe we’re seeing that right now. Suddenly, it resonates as a single agent of cabozantinib as second-line therapy and in combination with an I/O in first-line therapy. It’s positioning itself well in favorable-risk as well as in intermediate- and poor-risk disease. This is something you can consider as being a first-line therapy; definitely in patients with favorable risk. It depends on the patient, as we talked about earlier. The fact that progression of disease was seen in 6% of patients as the best response is a great number in regard to how well these patients tolerate therapy and how effective these therapies can be.

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