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Axitinib plus pembrolizumab promising for late-stage kidney cancer
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Combination therapy with axitinib plus pembrolizumab appeared promising and tolerable among patients with advanced renal cell carcinoma, according to findings from an ongoing open-label phase 1b trial.
“Our results are unprecedented. The combination doubled the efficacy of the drugs when used alone and the treatment was found to be tolerable,” Michael B. Atkins, MD, deputy director of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, said in a press release. “Specifically, over 90% of patients exhibited tumor shrinkage, and the disease was kept under control for a median of over 20 months.”
The researchers enrolled adults with advanced kidney cancer who had their primary tumors resected at 10 cancer centers in the U.S. Researchers enrolled 11 adults in a dose-finding phase performed between Sept. 23, 2014, and March 25, 2015, to find the maximum tolerated dose, and 41 patients in a dose-expansion phase from June 3, 2015, to Oct. 13, 2015.
Patients received 5 mg of oral axitinib (Inlyta, Pfizer) twice daily, along with 2 mg/kg IV pembrolizumab (Keytruda, Merck) every 3 weeks.
Atkins and colleagues evaluated safety among all patients who received at least one dose of either drugs, and assessed antitumor activity among all patients who received the study treatment and had an adequate baseline tumor assessment. Dose-limiting toxicity to determine maximum tolerated dose and subsequent recommended phase 2 dose served as the main outcome.
Three patients experienced dose-limiting toxicities in the dose-finding phase. One had a transient ischemic heart attack, and two more completed less than 75% of the planned dose of axitinib because they experienced treatment-related toxicity.
Researchers estimated a maximum tolerated dose of 5 mg twice daily axitinib plus 2 mg/kg pembrolizumab ever 3 weeks, which were full doses.
Twenty-five patients remained on study treatment by the data cutoff date of March 31, 2017.
More than half of patients (65%; n = 34) experienced grade 3 or higher treatment-related adverse events. Hypertension was the most common (23%), followed by diarrhea (10%), fatigue (10%) and increased alanine aminotransferase concentration (8%).
The most common adverse events considered immune related — likely due to pembrolizumab — included diarrhea (29%), increased concentrations of alanine aminotransferase (17%) or aspartate aminotransferase (13%), hypothyroidism (13%) and fatigue (12%).
More than half of patients (54%) experienced treatment-related serious adverse events.
Nearly three-quarters of patients (73%; 95% CI, 59-84.4) had achieved an objective response by the data cutoff. Forty-eight patients (94%) achieved some tumor shrinkage at a median follow-up of 20.4 months.
“A randomized phase 3 trial comparing our drug combination to the FDA-approved antiangiogenesis agent sunitinib [Sutent, Pfizer] is underway and it should tell us if this drug combination is better than the previous standard of care regimen,” Atkins said in the release. “We think this combination could present a major advance in the treatment of this disease, as well as help define effective combinations of similar drugs for other cancers.”
“The combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma,” Giuseppe Procopio, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and colleagues wrote in an accompanying editorial. “Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.” – by Andy Polhamus
Disclosures: Merck and Pfizer sponsored the study. Atkins reports consulting roles with Bristol-Myers Squibb, Eisai, Genentech/Roche, Merck, Novartis and Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures. Procopio reports advisory roles with Astellas, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Novartis and Pfizer. Another editorial author reports advisory roles with Ipsen, Janssen, Novartis and Pfizer.
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