FDA Approves Merck’s Keytruda® (pembrolizumab) in Combination with Inlyta® (axitinib) as First-Line Treatment for Patients With Advanced Renal Cell Carcinoma (RCC)

Approval Based on Results of KEYNOTE-426, Where KEYTRUDA in Combination with Axitinib Reduced the Risk of Death by Nearly Half Compared to Sunitinib


San Francisco, CA (UroToday.com) -- The U.S. Food and Drug Administration (FDA) has approved pembrolizumab, Merck’s anti-PD-1 therapy, in combination with Inlyta (axitinib), a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). The approval is based on findings from the pivotal Phase 3 KEYNOTE-426 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for pembrolizumab in combination with axitinib (pembrolizumab-axitinib combination) compared to sunitinib. Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status. For the main efficacy outcome measures of OS and PFS, the pembrolizumab-axitinib combination reduced the risk of death by 47% compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001); for PFS, the pembrolizumab-axitinib combination showed a reduction in the risk of progression of disease or death of 31% compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The ORR, an additional efficacy outcome measure, was 59% for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36% for those who received sunitinib (95% CI, 31-40) (p<0.0001). This is the first indication for pembrolizumab in advanced RCC, the most common type of kidney cancer, and the first anti-PD-1 therapy FDA-approved as part of a combination regimen that significantly improved OS, PFS, and ORR versus sunitinib in patients with advanced RCC.

“This represents a new treatment option for patients with advanced renal cell carcinoma, who will now have access to pembrolizumab as part of a first-line combination regimen,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “Today’s approval reflects Merck’s commitment to patients with cancer and further supports the use of pembrolizumab to help improve survival outcomes for patients with advanced renal cell carcinoma.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate. pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

“Given the aggressive nature of the disease, many patients with advanced renal cell carcinoma need additional treatment options that can help improve survival outcomes,” said Dr. Brian Rini, medical oncologist at Cleveland Clinic Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. “Pembrolizumab in combination with axitinib offers an important new therapeutic option for physicians to consider when approaching initial treatment for patients newly diagnosed with advanced renal cell carcinoma.” Dr. Rini reports consulting and research funding from Merck.

About KEYNOTE-426 - NCT02853331
The approval was based on data from the pre-specified interim analysis of the Phase 3 KEYNOTE-426 trial, a randomized, multi-center, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”). Patients with active autoimmune disease requiring systemic immunosuppression within the last two years were ineligible.

Patients were randomized (1:1) to one of the following treatment arms:
  • pembrolizumab 200 mg intravenously every three weeks up to 24 months in combination with axitinib 5 mg orally, twice daily (n=432).
  • Sunitinib 50 mg orally, once daily for four weeks and then off treatment for two weeks (n=429).
Among the 861 patients, the study population characteristics were: median age of 62 years (range, 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline Karnofsky Performance Status (KPS) of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor.

Treatment with the pembrolizumab-axitinib combination continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease or unacceptable toxicity. The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR.

The trial demonstrated statistically significant improvements in OS, PFS, and ORR in patients randomized to receive the pembrolizumab-axitinib combination compared to sunitinib.

With a median follow-up time of 12.8 months (range, 0.1 to 22 months), OS was significantly improved in patients who received the pembrolizumab-axitinib combination compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). Estimated 12-month OS rates were 90% (95% CI, 86-92) with the pembrolizumab-axitinib combination versus 78% (95% CI, 74-82) with sunitinib. Median OS was not reached with either treatment regimen. Progression-free survival was also significantly improved with the pembrolizumab-axitinib combination compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). Median PFS was 15.1 months (95% CI, 12.6-17.7) in patients receiving the pembrolizumab-axitinib combination versus 11.1 months (95% CI, 8.7-12.5) with sunitinib. In the study, the ORR was 59% for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36% for those who received sunitinib (95% CI, 31-40) (p<0.0001), with a complete response rate of 6% and 2% and a partial response rate of 53% and 34%, for patients receiving the pembrolizumab-axitinib combination versus sunitinib, respectively.

In KEYNOTE-426, the safety of pembrolizumab in combination with axitinib was investigated in patients with previously untreated, advanced RCC. The median duration of exposure to the combination therapy of pembrolizumab and axitinib was 10.4 months (range, 1 day to 21.2 months). Fatal adverse reactions occurred in 3.3% of patients receiving pembrolizumab in combination with axitinib. Serious adverse reactions occurred in 40% of patients receiving pembrolizumab in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving pembrolizumab in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either pembrolizumab or axitinib occurred in 31% of patients; 13% pembrolizumab only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of pembrolizumab, axitinib or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) in patients receiving in patients receiving pembrolizumab and axitinib were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).


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