Results from the randomized, phase III KEYNOTE-426 clinical trial show that first-line therapy with a combination of pembrolizumab and axitinib extended both overall survival (OS) and progression-free survival (PFS) for patients with clear cell metastatic renal cell carcinoma compared with the current standard of care, sunitinib. Findings from this international study will be presented by Powles et al at the upcoming 2019 Genitourinary Cancers Symposium in San Francisco, California (Abstract 543).
“These results are exciting,” said co-lead study author Thomas Powles, MD, Professor of Genitourinary Oncology at Barts Cancer Institute. “By adding pembrolizumab to a VEGF-targeted therapy [axitinib], we are seeing powerful anticancer responses, including improved survival—and importantly, the results are seen across broad subgroups of patients.”
About the Study
In the study, 861 people with untreated clear cell metastatic renal cell carcinoma were randomly assigned to oral sunitinib once daily or to combination therapy with pembrolizumab given intravenously every 3 weeks along with oral axitinib twice daily. Treatment continued until the disease progressed, patients developed high toxicity, or they dropped out of the study. The median patient age in the trial was 62, and 73% of the participants were male and 27% were female.
These results build on findings from an earlier phase Ib trial that found pembrolizumab plus axitinib had a manageable safety profile and a high response rate (73%) among patients with metastatic renal cell carcinoma. Following these positive results, investigators proceeded directly to this phase III trial.
“Both pembrolizumab and axitinib have shown efficacy against metastatic renal cell carcinoma on their own,” said Dr. Powles. “Antiangiogenic therapy such as axitinib facilitates immune T-cell infiltration.” According to Dr. Powles, phase Ib study results indicated that axitinib was easier to combine with pembrolizumab than some other antiangiogenic drugs in the same class as sunitinib.
At a median follow-up of 12.8 months, combination therapy was associated with a 47% reduction in the risk of death compared with sunitinib (hazard ratio [HR] = 0.53); the 12-month overall survival rate was 89.9% in the combination group vs 78.3% in the sunitinib group. These benefits were seen irrespective of risk group or programmed death-ligand 1 (PD-L1) status. Patients treated with the combination therapy lived a median of 15.1 months without disease progression vs 11.1 months with sunitinib. The overall response rate was 59.3% with the combination vs 35.7% with sunitinib, and duration of response was longer in patients treated with combination therapy, with a median not yet reached vs 15.2 months with sunitinib.
With the combination, 59.0% of patients continue to be treated vs 43.1% with sunitinib.
Serious treatment-related side effects were seen in 62.9% of patients on the combination therapy compared to 58.1% who received sunitinib. These side effects led to discontinuation of all treatment in 8.2% vs 10.1% of the groups, respectively.
“We have a number of unanswered questions at this point, particularly the absence of biomarkers to predict response. PD-L1 levels, which have been markers for immunotherapy success in other cancers, remain unproven in renal cancer. It is possible that by combining pembrolizumab with axitinib, the predictive value of PD-L1 is being masked,” said Dr. Powles. “Overall, we have not previously seen a renal cancer study which has improved response, progression-free survival, and overall survival. This is therefore a major step forward in renal cancer.”
Disclosure: This study was funded by Merck Sharp & Dohme. The study authors' full disclosures can be found at coi.asco.org.
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The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.