Toni Choueiri, MD
With the recent FDA approval of nivolumab (Opdivo) and the progression-free survival (PFS) benefit demonstrated with cabozantinib (Cometriq) over everolimus (Afinitor), the second-line treatment paradigm for advanced renal cell carcinoma (RCC) is rapidly evolving.
Nivolumab’s approval in November 2015 was based on the CheckMate-025 study, which showed a median overall survival (OS) of 25.0 months with nivolumab compared with 19.6 months for everolimus (HR, 0.73; P
The drug is also being investigated in combination with ipilimumab (Yervoy) in the first-line setting of RCC in the ongoing CheckMate-214 trial.
Regarding cabozantinib, the FDA granted the agent a priority review designation in January 2016 and is currently considering data from the METEOR trial, which showed a 42% reduction in the risk of progression or death for cabozantinib versus everolimus (HR, 0.58; 95% CI, 0.45-0.75; P
After a minimum of 11 months of follow-up, median PFS with cabozantinib was 7.4 months compared with 3.8 months with everolimus.
At a planned interim analysis, OS was longer with cabozantinib versus everolimus (HR, 0.67; 95% CI, 0.51-0.89; P
= .005); however, a P value of ≤.0019 was required to achieve significance. The survival follow-up will continue until the data mature.
Under the Prescription Drug User Fee Act, the agency is scheduled to make a decision on the cabozantinib application by June 22, 2016.
Subgroup analyses of both trials were recently presented at the 2016 Genitourinary Cancers Symposium in January. In an interview with OncLive
, Toni Choueiri, MD, clinical director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, Dana-Farber Cancer Institute, discusses those analyses and the potential for both agents in the first- and second-line settings.
OncLive: What did we learn from the subgroup analysis of the Checkmate-025 trial?
: This was a randomized phase III trial of standard everolimus versus nivolumab, a PD-1 inhibitor, in patients with metastatic RCC after progression with 1 or more VEGF tyrosine kinase inhibitors (TKIs). We know the drug is already approved and resulted in an OS benefit of nivolumab versus everolimus. The data were published in The New England Journal of Medicine
At the 2016 GU Cancers Symposium, an analysis was presented. The patients were broken down into several subgroups: good, intermediate, poor risk, the number of prior lines of therapy, the absence or presence of liver metastasis, and the absence or presence of bone metastasis.
If you look at all of these subgroup analyses, there is always a benefit in terms of OS from nivolumab over everolimus, especially in the patients with poor risk. It is a confirmation that there isn’t a subgroup that does much better on everolimus. The quality of life data with nivolumab is also very interesting. We now have a better understanding of Checkmate-025.
How did the subgroup analysis of the METEOR trial compare to Checkmate-025, and what did we learn from it?
METEOR is a similar design to Checkmate-025. Patients with prior exposure to VEGF TKIs had been randomized to receive standard everolimus or cabozantinib. Cabozantinib is an oral drug—a small molecule that inhibits the VEGF receptors, MET and AXL. We already know the results of this trial; cabozantinib prolonged PFS as the primary endpoint. This is different than the primary endpoint of OS in Checkmate-025.
At the GU Cancers Symposium, Bernard J. Escudier, MD, presented the PFS for the whole population of 658 patients. He confirmed the same findings that PFS is statistically significantly over everolimus and clinically relevant. He also did an extensive subgroup analysis and broke down the patient population by risk, tumor burden, the number of metastatic sites, the presence or not and number of bone and liver metastasis, and prior exposure to a PD-1 inhibitor or not. He confirmed the PFS advantage of cabozantinib over everolimus in all subgroups. The results look good for both studies, but there is still a lot to learn from them.
Is it possible for either cabozantinib or nivolumab to move up to the frontline setting in RCC?
It is possible for both drugs, but more so for nivolumab. Nivolumab has been combined with ipilimumab in a phase III study versus sunitinib. This study has finished accrual. The study had coprimary endpoints of PFS and OS, and it focused mostly on patients with intermediate and poor risk. If the results are positive, I imagine nivolumab will likely move to the frontline setting.
With cabozantinib, there isn’t a phase III trial ongoing in the frontline setting. There is a small 150-patient phase II trial in poor- and intermediate-risk patients that randomized patients to cabozantinib or sunitinib. That has also finished accrual, but we don’t know yet what the results will be.
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823.