Pembrolizumab/Axitinib Combo Receives Priority Review From FDA for Frontline RCC

A supplemental biologics license application for the combination of pembrolizumab and axitinib has received a priority review designation from the FDA as a frontline treatment for patients with advanced renal cell carcinoma, primarily based on data from the phase III KEYNOTE-426 study.

Roger M. Perlmutter, MD, PhD

A supplemental biologics license application (sBLA) for the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) has received a priority review designation from the FDA as a frontline treatment for patients with advanced renal cell carcinoma (RCC), primarily based on data from the phase III KEYNOTE-426 study.1

Results from the study demonstrated that the frontline combination significantly improved progression-free and overall survival (OS) compared with sunitinib (Sutent) in patients with advanced RCC. 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 evaluated the combination in patients with advanced disease. In results from that trial, 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.


  1. FDA Grants Priority Review to Merck&rsquo;s Supplemental Biologics License Application for KEYTRUDA&reg; (pembrolizumab) in Combination with Inlyta&reg; (axitinib) as First-Line Treatment for Advanced Renal Cell Carcinoma. Merck. Published February 15, 2019. Accessed February 15, 2019.
  2. Powles T, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib vs sunitinib as first-line therapy for advanced renal cell carcinoma: KEYNOTE-426.J Clin Oncol. 2019;37 (suppl; abstr 543).
  3. Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC).J Clin Oncol. 2018;36 (suppl; abstr 579). doi: 10.1200/JCO.2018.36.6_suppl.579.