2018 GU CANCERS SYMPOSIUM: Combination Therapy Shows Antitumor Activity in Advanced Renal Cell Carcinoma
Combining the antiangiogenic agent axitinib (Inlyta) with the immunotherapy pembrolizumab (Keytruda) was found to have promising antitumor activity and no unexpected side effects in an early-phase clinical trial in patients with advanced kidney cancer who had not been previously treated.
The full findings of the study to date involving the treatment combination will be presented February 10 by Atkins et al at the 2018 ASCO Genitourinary Cancers Symposium (Abstract 579), with context and additional information about the primary endpoint to be published simultaneously in The Lancet Oncology.
Axitinib was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of patients with advanced kidney cancer after one prior systemic therapy has failed. The drug has been shown to be selective in how it works, resulting in a strong effectiveness-to-toxicity ratio, said principal study investigator Michael B. Atkins, MD, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center and the Scholl Professor and Vice Chair of the Department of Medical Oncology at Georgetown University Medical Center.
Pembrolizumab is FDA-approved for the treatment of patients with several cancer types including melanoma, lung, bladder, and head and neck cancers, but has only had limited study in patients with kidney cancer.
Earlier attempts to develop combinations of antiangiogenic agents and checkpoint inhibitor–based immunotherapies to treat patients with advanced kidney cancer resulted in unacceptably high levels of toxicity, and the combinations were not pursued further. In contrast, the axitinib/pembrolizumab combination was sufficiently tolerable to enable the agents to be given at their FDA-approved single-agent dose levels.
“Our results are unprecedented. The combination doubled the efficacy of the drugs when used alone, and the treatment was found to be tolerable,” said Dr. Atkins.
Study Findings
The investigators started their phase I clinical trial of this combination in 2014 and enrolled 52 patients with treatment-naive advanced renal cell carcinoma. Their goal was to find out what dose of the drug could be tolerated by a subset of 11 patients during the first 6 weeks of the trial, then gauge the effectiveness of the therapy in all 52 patients.
All enrollees received an intravenous infusion of pembrolizumab at the start of the trial and then every 3 weeks thereafter. Patients also took axitinib twice daily until they could no longer tolerate the therapy or until no benefit was seen. The researchers looked at tumor size at trial enrollment, then 12 weeks later and every 6 weeks thereafter.
In the 11-patient subgroup, 3 of the patients were not able to tolerate axitinib and received less than 75% of the planned dose due to toxicities, whereas 8 patients experienced manageable side effects, thus establishing this dose level and the recommended dose level for further investigation in a group of 41 additional patients. Significantly, patients had fewer liver abnormalities and less fatigue than those treated with other similar combination therapies, Dr. Atkins said. Also, with the axitinib/pembrolizumab combination, tumor shrinkage or stabilization was better than that seen in patients taking just one of the two drugs alone.
Seventy-three percent of patients experienced significant tumor shrinkage in response to the combination therapy, and the median time to disease progression was 20.3 months. Overall survival results are incomplete, but 88% of the patients were still alive at a minimum of 18 months after starting therapy. By March 2017, 25 patients were still being treated, with 22 receiving the drug combination and 3 receiving pembrolizumab only.
“A randomized phase III trial comparing our drug combination to the FDA-approved antiangiogenesis agent sunitinib is underway, and it should tell us if this drug combination is better than the previous standard-of-care regimen,” said Dr. Atkins. “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 work was sponsored by Pfizer in collaboration with Merck (known as MSD outside the United States and Canada).
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