The FDA has granted a priority review designation to a supplemental biologics license application for the combination of pembrolizumab and axitinib as a frontline treatment for patients with advanced renal cell carcinoma.
Roger M. Perlmutter, MD, PhD
The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) as a frontline treatment for patients with advanced renal cell carcinoma (RCC).1
The application is primarily based on data from the phase III KEYNOTE-426 study, which demonstrated that the frontline combination significantly improved progression-free and overall survival (OS) compared with sunitinib (Sutent) in patients with advanced RCC. Results showed that pembrolizumab/axitinib led to a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001).2
The sBLA also included data from the phase Ib KEYNOTE-035 trial, which also explored the combination in patients with advanced disease. Data showed that the combination had a tolerable safety profile and elicited a 73% objective response rate (ORR) in this patient population.3
Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sBLA by June 20, 2019.
“Many patients with advanced renal cell carcinoma face a poor prognosis and there remains a need for new and effective treatment options in the first-line setting,” said Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories. “KEYNOTE-426 demonstrated that an anti—PD-1 combination therapy significantly improved overall survival and progression-free survival versus sunitinib in the first-line treatment of advanced renal cell carcinoma. We look forward to working with the FDA to bring this Keytruda combination to patients.”
In the open-label KEYNOTE-426 study (NCT02853331), 861 patients with newly diagnosed or recurrent stage IV clear cell RCC were randomized 1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles plus axitinib at 5 mg orally twice daily or sunitinib at 50 mg orally once daily for the first 4 weeks of each 6-week cycle. Treatment was administered until disease progression, unacceptable toxicity, or if patients dropped out of the trial.
The median age was 62; 73% of patients were male and 27% were female. Patients were stratified by geographic region and by International Metastatic Renal Cell Carcinoma Database Consortium risk group as having favorable-, intermediate-, or poor-risk disease.
The coprimary endpoints were OS and PFS; secondary endpoints were ORR, duration of response (DOR), patient-reported outcomes, and safety.
To be eligible for enrollment, patients had no prior systemic treatment for advanced disease, had a Karnofsky performance status ≥70, measurable disease per RECIST v1.1 criteria, provision of a tumor sample for biomarker assessment, and adequate organ function.
At a median follow-up of 12.8 months, results showed that the median OS was not reached in either arm. The median progression-free survival (PFS) was 15.1 months (range, 12.6-17.7) for pembrolizumab/axitinib and 11.1 months (range, 8.7-12.5) with sunitinib. With the combination, there was a 31% reduction in the risk of disease progression (HR, 0.69; 95% CI, 0.57-0.84; P = .0001).
The 12- and 18-month OS rates were higher with pembrolizumab/axitinib than sunitinib, at 89.9% versus 78.3% and 82.3% versus 72.1%, respectively. The 12-month and 18-month PFS rates were also higher with pembrolizumab and axitinib (59.6% and 41.1%) compared with sunitinib (46.2% and 32.9%). The survival benefits were observed irrespective of PD-L1 status or risk group.
Additionally, the ORR was 59.3% (95% CI, 54.5-63.9) with the combination and 35.7% (95% CI, 31.1-40.4) with sunitinib (P <.0001). The median DOR was not reached (range, 1.4+ to 18.2+) in the pembrolizumab/axitinib arm and was 15.2 months (1.1+ to 15.4+) for sunitinib. Treatment is ongoing in 59.0% of patients on the immunotherapy/TKI arm and in 43.1% of those on the sunitinib arm.
Regarding safety, the incidence of all-grade adverse events (AEs) was comparable between the 2 arms, at 96.3% with the combination and 97.6% with sunitinib. Grade 3 to 5 AEs were higher with pembrolizumab/axitinib (62.9%) versus sunitinib (58.1%). A total of 0.9% of AEs led to death in the combination arm versus 1.6% in the sunitinib arm.
Moreover, 25.9% of patients who were treated with pembrolizumab/axitinib discontinued treatment of either drug, compared with 10.1% of patients who discontinued sunitinib. A total 8.2% of patients discontinued treatment with both pembrolizumab and axitinib.