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KENILWORTH, N.J.—In the latest addition to its extensive treatment profile, Merck's Keytruda (pembrolizumab) has been approved by the U.S. Food and Drug Administration (FDA) in combination with Inlyta (axitinib), a tyrosine kinase inhibitor developed by Pfizer, as a first-line treatment for patients with advanced renal cell carcinoma (RCC). According to Merck, known as MSD outside the United States and Canada, this is the first indication for Keytruda in RCC, as well as the first anti-PD-1 therapy approved by the FDA as part of a combination treatment regimen that improved overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) compared to 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 Keytruda as part of a first-line combination regimen,” Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories, commented in a press release. “Today’s approval reflects Merck’s commitment to patients with cancer and further supports the use of Keytruda to help improve survival outcomes for patients with advanced renal cell carcinoma.”
The approval was fueled by the results from Merck's pivotal Phase 3 KEYNOTE-426 trial, in which the combination regimen of Keytruda and axitinib led to significant improvements in OS, PFS and ORR compared to sunitinib. The combination approach lowered the risk of death by 47 percent compared to sunitinib alone, and in terms of PFS, it reduced the risk of disease progression or death by 31 percent compared to sunitinib. ORR was 59 percent for patients who received the combination regimen vs. 36 percent for those in the sunitinib arm.
KEYNOTE-426 was a randomized, multi-center, open-label trial of 861 patients with advanced RCC who had not received systemic therapy. Participants were randomized to receive with 200 mg of Keytruda intravenously every three weeks for up to 24 months in combination with 5 mg axitinib orally twice daily, or 50 mg of sunitinib orally once daily for four weeks and then off treatment for two weeks.
Estimated 12-month OS rates were 90 percent for the combination group vs. 78 percent for the sunitinib group, with median PFS of 15.1 months and 11.1 months, respectively. The Keytruda and axitinib combination saw complete and partial response rates of 6 percent and 53 percent, respectively, while sunitinib saw complete and partial response rates of 2 percent and 34 percent, respectively.
Of the patients who received Keytruda and axitinib, 3.3 percent experienced fatal adverse reactions, with serious adverse reactions occurring in 40 percent of patients within the combination treatment group. Eight percent of patients in the combination group permanently discontinued treatment due to adverse reactions.
The most common adverse reactions (>1 percent) that led to permanent discontinuation of Keytruda, axitinib or the combination was hepatotoxicity (13 percent), diarrhea/colitis (1.9 percent), acute kidney injury (1.6 percent) and cerebrovascular accident (1.2 percent). The most common adverse reactions (≥20 percent) in patients receiving in patients receiving the combination regimen were diarrhea (56 percent), fatigue/asthenia (52 percent), hypertension (48 percent), hepatotoxicity (39 percent), hypothyroidism (35 percent), decreased appetite (30 percent), palmar-plantar erythrodysesthesia (28 percent), nausea (28 percent), stomatitis/mucosal inflammation (27 percent), dysphonia (25 percent), rash (25 percent), cough (21 percent) and constipation (21 percent).
“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.
Less than two weeks before this announcement, Merck also shared the news that the FDA had approved an expanded label for Keytruda as a monotherapy for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 (tumor proportion score [TPS] ≥1 percent) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. One day prior to that, the company announced yet another approval, though this time for Lynparza, the PARP inhibitor Merck has developed with AstraZeneca. The drug has been cleared by the European Commission as a monotherapy for adult patients with germline BRCA1/2-mutations (gBRCAm), and who have human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer.