The benefits of the combination were seen across the board in all patient subgroups.
“These results are exciting. By adding the checkpoint inhibitor pembrolizumab to a VEGF-targeted tyrosine kinase inhibitor we are seeing powerful anticancer responses, including improved survival and…across broad subgroups of patients,” said lead investigator Thomas Powles, MD, PhD, FRCP, Professor of Urology Oncology, Barts Cancer Institute, London, England. “In my opinion, these data suggest that pembrolizumab plus axitinib should be a new standard of care for this population,” he added.
Dr Powles presented the results of KEYNOTE-426, a randomized, open-label phase 3 clinical trial at the 2019 Genitourinary Cancers Symposium.
KEYNOTE-426 is the first phase 3 trial to show a survival benefit with a checkpoint inhibitor plus axitinib versus sunitinib in patients with metastatic RCC. At ESMO 2018, the JAVELIN 101 trial showed that avelumab (Bavencio) plus axitinib extended PFS in patients with metastatic RCC, but no survival benefit was seen.
“The combination of pembrolizumab and axitinib appears to be superior to that of avelumab and axitinib as reported in JAVELIN 101 at the 2018 meeting of ESMO,” said ASCO Expert Sumanta K. Pal, MD, Co-Director, Kidney Cancer Program, City of Hope, Duarte, CA. “The improvement in survival makes it more likely that pembro and axitinib will be preferred to avelumab and axitinib.”
KEYNOTE-426 enrolled 861 patients with clear-cell metastatic RCC who had not received systemic therapy for metastatic disease. Patients were randomized in a 1:1 ratio to receive pembrolizumab 200 mg intravenously every 3 weeks, for a maximum of 35 cycles, plus oral axitinib 5 mg twice daily versus oral sunitinib 50 mg every day on a 4-week on, 2-week off schedule. Treatment was continued until disease progression, unacceptable toxicity, or at the investigator’s decision.
Patients were stratified by risk group according to the International Metastatic RCC Database Consortium as favorable-, intermediate-, or poor-risk disease and according to geographic region.
Approximately 66% of the patients had intermediate or poor risk, and 75% had metastatic disease in 2 or more organs. The median follow-up was 12.8 months.
Improved Outcomes, Increased Survival
The 12-month OS was 89.9% in the combination therapy group versus 78.3% in the sunitinib group (P = .0001). The 18-month OS rates were 82.3% versus 72.1%, respectively. The 12-month PFS was 59.6% with the combination therapy versus 41.1% with sunitinib alone; the 18-month PFS rates were 46.2% versus 32.9%, respectively. The median PFS was 15.1 months with the combination versus 11.1 months with sunitinib (P = .0001).
The objective response rate was 59.3% with the checkpoint inhibitor plus axitinib versus 35.7% with sunitinib (P <.0001). The duration of response was not yet reached in the combination arm versus a median of 15.2 months with sunitinib.
The number of treatment-related adverse events of any grade was 96% in both treatment arms. Grade 3 to 5 adverse events were higher (62.9%) with the combination therapy versus 58.1% with sunitinib alone. Adverse events leading to death were reported in 0.9% and 1.6% of patients, respectively.
The rate of treatment discontinuation was 25.9% in the combination arm (discontinuation of 1 of the drugs) versus 10.1% with sunitinib. Discontinuation of both pembrolizumab and axitinib was reported in 8.2% of patients.
“Both KEYNOTE-426 and JAVELIN 101 are practice-changing,” said study discussant, Lori Wood, MD, FRCPC, Medical Oncologist, Dalhousie University, Halifax, Canada. “In 2019, we have a new standard of care. The majority of patients with clear-cell advanced RCC will be eligible to receive combination therapy with a checkpoint inhibitor and axitinib.”
But, she noted “there are important issues to resolve—Which treatment is better? Can we afford it? And can it be safely delivered to all patients?”
Based on the results of the KEYNOTE-42 clinical trial, on April 19, 2019, the FDA approved the combination of pembrolizumab plus axitinib for the first-line treatment of patients with advanced RCC.