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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Monday, April 29, 2019

FDA Approves Pembrolizumab in Combination With Axitinib as First-Line Treatment for Advanced Renal Cell Carcinoma

The FDA has approved pembrolizumab in combination with 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 III 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 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 percent 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 percent compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The ORR, an additional efficacy outcome measure, was 59 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent 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.

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.

"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 Brian Rini, MD, a 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." 

Study Details

The approval was based on data from the pre-specified interim analysis of the phase III 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 vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. "Rest of the World"). Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible.

Patients were randomized (1:1) to one of the following treatment arms:

  • pembrolizumab 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily (n=432).
  • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks (n=429).

Among the 861 patients, the study population characteristics were: median age of 62 years (range, 26 to 90); 38 percent age 65 or older; 73 percent male; 79 percent white and 16 percent Asian; 19 percent and 80 percent of patients had a baseline Karnofsky Performance Status of 70-80 and 90-100, respectively; and patient distribution by IMDC risk categories was 31 percent favorable, 56 percent intermediate, and 13 percent 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. PFS 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 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent for those who received sunitinib (95% CI, 31-40) (p<0.0001), with a complete response rate of 6 percent and 2 percent and a partial response rate of 53 percent and 34 percent, for patients receiving the pembrolizumab-axitinib combination versus sunitinib, respectively.

Safety & Adverse Events

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 percent of patients receiving pembrolizumab in combination with axitinib. Serious adverse reactions occurred in 40 percent of patients receiving pembrolizumab in combination with axitinib. 

Serious adverse reactions in ≥1 percent 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 percent of patients; 13 percent pembrolizumab only, 13 percent axitinib only, and 8 percent 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%).