New pathways for secondary-line treatment are coming available to patients with advanced renal cell carcinoma.
Patients with advanced renal cell carcinoma (RCC) now have more second-line treatment options. In fact, the FDA recently approved Opdivo (nivolumab) and Cometriq (cabozantinib) has demonstrated a benefit in progression-free survival (PFS) compared with Afinitor (everolimus).
Opdivo’s approval in November 2015 was based on the CheckMate-025 study, which showed a median overall survival (OS) of 25.0 months with the agent compared with 19.6 months for Afinitor.
The drug is also being investigated in combination with Yervoy (ipilimumab) in the first-line setting of RCC in the ongoing CheckMate-214 trial.
Regarding Cometriq, 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 percent reduction in the risk of progression or death for Cometriq versus Afinitor. After a minimum of 11 months of follow-up, median PFS with Cometriq was 7.4 months compared with 3.8 months with Afinitor.
At a planned interim analysis, OS was longer with Cometriq versus Afinitor, though the data were not significant. 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 Cometriq application by June 22, 2016.
What did we learn from the subgroup analysis of CheckMate-025?
Subgroup analyses of both trials were recently presented at the 2016 Genitourinary (GU) Cancers Symposium, a meeting of hundreds of oncologists and other oncology professionals in January. In an interview with CURE, Toni Choueiri, clinical director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, Dana-Farber Cancer Institute, discussed those analyses and the potential for both agents in the first- and second-line settings.This was a randomized phase 3 trial of standard Afinitor versus Opdivo, a PD-1 inhibitor, in patients with metastatic RCC after progression with one or more VEGF tyrosine kinase inhibitors (TKIs). We know the drug is already approved and resulted in an OS benefit of Opdivo versus Afinitor. The data were published in The New England Journal of Medicine.
How did the subgroup analysis of the METEOR trial compare to the CheckMate-025 and what did we learn from it?
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 Opdivo over Afinitor, especially in the patients with poor risk. It is a confirmation that there isn’t a subgroup that does much better on Afinitor. The quality of life data with Opdivo is also very interesting. We now have a better understanding of CheckMate-025.METEOR is a similar design to Checkmate-025. Patients with prior exposure to VEGF TKIs had been randomized to receive standard Afinitor or Cometriq. Cometriq is an oral drug — a small molecule that inhibits the VEGF receptors, MET and AXL. We already know the results of this trial; Cometriq prolonged PFS as the primary endpoint. This is different than the primary endpoint of OS in CheckMate-025.
Is it possible for either Cometriq or Opdivo to move up to the frontline setting in RCC?
At the GU Cancers Symposium, Bernard J. Escudier, presented the PFS for the whole population of 658 patients. He confirmed the same findings that PFS is statistically significantly over Afinitor 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 Cometriq over Afinitor in all subgroups. The results look good for both studies, but there is still a lot to learn from them.It is possible for both drugs, but more so for Opdivo. Opdivo has been combined with Yervoy in a phase 2 study versus Sutent (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 Opdivo will likely move to the frontline setting.
With Cometriq, there isn’t a phase 3 trial ongoing in the frontline setting. There is a small 150-patient phase 2 trial in poor- and intermediate-risk patients that randomized patients to Cometriq or Sutent. That has also finished accrual, but we don’t know yet what the results will be.