First-line therapy with a combination of an immune checkpoint inhibitor and a tyrosine kinase inhibitor (TKI) improved outcomes in patients with clear-cell metastatic renal cell carcinoma (mRCC), as compared with the current standard of care, according to new findings.
Pembrolizumab (Keytruda, Merck) and the VEGF-targeted TKI axitinib (Inlyta, Pfizer) significantly extended both overall and progression-free survival, and elicited a higher objective response rate than sunitinib (Sutent, Pfizer) in patients with previously untreated mRCC.
“The risk of death was reduced by almost 50% with pembrolizumab plus axitinib,” said study author Thomas Powles, MD, professor of urology oncology at Barts Cancer Institute in London, England. “The benefit of pembrolizumab plus axitinib was seen irrespective of risk group or PD-L1 status.”
Based on these results, “pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.” Powles added.
The findings were presented at a press briefing held in advance of the upcoming Genitourinary Cancers Symposium (GUCS) 2019 in San Francisco.
“This is a very significant trial and it’s going to have an impact on patient management going forward, as it works through the regulatory process,” commented Robert Dreicer, MD, MACP, FASCO, professor of medicine and urology at the University of Virginia School of Medicine in Charlottesville.
“Metastatic kidney cancer has very low survival rates and there have been few significant advances in treating this advanced form of the disease,” he said. “These findings may help provide an important new option for patients.”
Both pembrolizumab and axitinib have demonstrated efficacy when used alone in treatment-naive patients with mRCC, Powles noted. A phase 1b study showed that pembrolizumab and axitinib given together showed manageable safety and a high response rate (73%) in this population, and served as the impetus for this phase 3 trial, he explained.
The KEYNOTE-426 clinical trial was conducted in 861 patients, who were randomized to receive either pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles plus axitinib 5 mg orally twice daily, or sunitinib 50 mg orally once daily for the first 4 weeks of each 6-week cycle.
Treatment was given until disease progression, intolerable toxicity, or patient/investigator decision to discontinue therapy.
Superior at All Endpoints
At a median follow-up of 12.8 months, overall survival was higher among patients receiving pembrolizumab and axitinib and was associated with a 47% reduction in the risk of death compared with sunitinib (hazard ratio [HR] 0.53; P < .0001).
The 12-month overall survival rate was 89.9% in the combination group vs 78.3% in the sunitinib group, and at 18 months, it was 82.3% vs 72.1%. These benefits were seen across all risk groups and PD-L1 status.
Median progression-free survival was 15.1 vs 11.1 months favoring combination therapy (HR 0.69; P = .0001), with a 12 month rate of 59.6% vs 42.6%. At 18 months it was 41.1% vs 32.9%.
For secondary endpoints, the overall response rate was 59.3% vs 35.7%, favoring combination therapy (P < .0001), and duration of response was also prolonged with pembrolizumab plus axitinib (median not reached vs 15.2 months).
Powles noted that 59% of the patients in the combination group are still being treated, as compared to 43.1% with sunitinib.
Grade 3-5 adverse events were slightly higher in the combination group (62.9% vs 58.1%), and more treatment discontinuations were observed in that group as well (25.9% vs 10.1%).
The study was funded by Merck Sharp & Dohme. Powles reports consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; other relationship with Ipsen and Bristol-Myers Squibb; honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; research funding from AstraZeneca/MedImmune and Roche/Genentech. Other coauthors also report relationships with industry as noted in the abstract.
Genitourinary Cancers Symposium (GUCS) 2019: Abstract 543. To be presented February 16, 2019.