Pembrolizumab/Axitinib Combo Approved in Europe for Frontline RCC

The European Commission has approved the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) for the frontline treatment of patients with advanced renal cell carcinoma.

Thomas Powles, MD, MBBS, MRCP

The European Commission has approved the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) for the frontline treatment of patients with advanced renal cell carcinoma (RCC).1

The approval is based on findings from the phase III KEYNOTE-426 trial, in which the combination led to a 47% reduction in the risk of death compared with sunitinib (Sutent) in this patient population (HR, 0.53; 95% CI, 0.38-0.74; P = .0005).2 The pembrolizumab/axitinib combination also showed an improvement in both progression-free survival (PFS) and objective response rate (ORR) versus sunitinib, stated Merck, the developer of pembrolizumab, in a press release.

“Advanced renal cell carcinoma is one of the most lethal types of cancer, with the majority of patients dying within five years of their initial diagnosis,” lead study investigator Thomas Powles, MD, MBBS, MRCP, director of Barts Cancer Centre, stated in the press release. “It’s encouraging that we can now offer patients in Europe the Keytruda with axitinib combination as a first-line treatment option.”

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 overall survival (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.

Results showed that, at a median follow-up of 12.8 months, the median OS was not reached in either arm. The median 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 = .00012).

Moreover, 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.

The ORR was 59% (95% CI, 54%-64%) with the combination and 36% (95% CI, 31%-40%) with sunitinib (P <.0001). The complete response rates were 6% and 2%, respectively, and the respective partial response rates were 53% and 34%. 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.

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 3/4 increased alanine aminotransferase (ALT; 20%) and increased aspartate aminotransferase (AST; 13%) were said to be higher with the combination arm compared with single-agent pembrolizumab.

The most frequent adverse events (AEs) were diarrhea (54%), hypertension (45%), fatigue (38%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia syndrome (28%), nausea (28%), ALT increased (27%), AST increased (26%), dysphonia (25%), cough (21%) and constipation (21%). Incidences of Grades 3/5 AEs were 76% in the pembrolizumab/axitinib arm and 71% in the sunitinib group.

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. A total of 0.9% of AEs led to death in the combination arm versus 1.6% in the sunitinib arm.

“The European approval of the Keytruda with axitinib combination for the treatment of advanced RCC marks an important milestone in our efforts for patients with this aggressive disease,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, said in the press release. “Offering an additional treatment option in the first-line setting is particularly important in patients with advanced RCC and underscores our commitment to develop Keytruda in areas of unmet need.”

With the approval, the combination is now available for us in all 28 European Union member states, as well as Iceland, Lichtenstein, and Norway. The regimen was also approved by the FDA in April 2019.


  1. European Commission Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination with Inlyta® (axitinib) as First-Line Treatment for Patients with Advanced Renal Cell Carcinoma (RCC). Merck. Published September 4, 2019. Accessed September 4, 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). doi: 10.1200/JCO.2019.37.7_suppl.543.