Frontline Pembrolizumab/Axitinib Approved in Japan for Advanced RCC

Japan’s Pharmaceuticals and Medical Devices Agency has approved the combination of pembrolizumab and axitinib for the first-line treatment of patients with radically unresectable or metastatic renal cell carcinoma.

Jonathan Cheng, MD

Jonathan Cheng, MD

Jonathan Cheng, MD

Japan’s Pharmaceuticals and Medical Devices Agency has approved the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) for the first-line treatment of patients with radically unresectable or metastatic renal cell carcinoma (RCC).

The approval is based on results from the phase III KEYNOTE-426 trial, in which pembrolizumab combined with axitinib demonstrated statistically significant improvements in both progression-free survival (PFS; HR, 0.69; 95% CI, 0.56-0.84; P = .00012) and overall survival (OS; HR, 0.53; 95% CI, 0.38-0.74; P = .00005) compared with sunitinib (Sutent) in this patient population.

“Advanced renal cell carcinoma and head and neck cancer have historically been associated with poor outcomes and new treatment options are needed in Japan,” Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories, stated in a press release. “Today’s approval of three new first-line Keytruda regimens represents a significant milestone for patients diagnosed with these aggressive forms of cancer and will provide patients in Japan with important alternatives to standard therapies.”

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 objective response rate (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.

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 FDA approved the combination of pembrolizumab and axitinib for this indication in April 2019; it was subsequently approved in the European Union in September 2019.


  1. Merck’s Keytruda (pembrolizumab) approved in Japan for three new first-line indications across advanced renal cell carcinoma (RCC) and recurrent or distant metastatic head and neck cancer [news release]. Published December 20, 2019. Accessed December 20, 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.
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