CHICAGO – Despite reducing risk of death by 22% versus placebo and improving progression-free survival, pembrolizumab did not meet prespecified criteria for significance of these efficacy end points in a phase 3 study in advanced hepatocellular carcinoma, an investigator reported.
The magnitude of benefit seen with pembrolizumab was nevertheless on par with results of the study that led to accelerated approval of the PD-1 inhibitor for hepatocellular carcinoma, Richard S. Finn, MD, of the University of California, Los Angeles, said at the annual meeting of the American Society of Clinical Oncology.
“These data support that the risk-benefit balance for pembrolizumab is favorable in the second line setting in hepatocellular carcinoma,” he said in an oral presentation on the phase 3 KEYNOTE-240 study.
Pembrolizumab did demonstrate “strong trends” in survival and other clinical characteristics in KEYNOTE-240, including response rate, duration of response, and a “very favorable” toxicity profile, said William P. Harris, MD, of the University of Washington and Fred Hutchinson Cancer Research Center, Seattle.
“I plan to continue to prescribe PD-1 inhibitors in the second-line setting, especially for those patients who show relative intolerance to tyrosine kinase inhibitors,” Dr. Harris said in a podium discussion of the results.
The Food and Drug Administration granted accelerated approval to the PD-1 inhibitor nivolumab in September 2017, and to pembrolizumab in November 2018, for treatment of patients with hepatocellular carcinoma who previously received sorafenib.
The accelerated approval of pembrolizumab was based on KEYNOTE-224, a single-arm, multicenter trial enrolling 104 patients with Child-Pugh Class A liver impairment who had disease progression on or after sorafenib, or were intolerant to sorafenib. Overall response rate in the study was 17%, with response durations ranging from 3.1 to 16.7 months.
The phase 3 KEYNOTE-240 study was designed to confirm the efficacy and safety of pembrolizumab in patients with hepatocellular carcinoma, Dr. Finn said. The study comprised 413 patients with Child Pugh class A, Barcelona Clinic Liver Cancer stage B/C disease who had previously received sorafenib. They were randomized 2:1 to pembrolizumab or placebo in addition to best supportive care for up to 35 cycles, or approximately 2 years of treatment.
Median overall survival was 13.9 months for the PD-1 inhibitor and 10.6 months for placebo, but the P value (.0238) did not meet a prespecified threshold of 0.0174 required to demonstrate statistical significance, according to Dr. Finn. Median progression-free survival was 3.0 months for pembrolizumab and 2.8 months for placebo, with a P value of .0186 that did not meet a prespecified value of .002.
The objective response rate was 18.3% and 4.4% for pembrolizumab and placebo, respectively (P = .00007), Dr. Finn reported. Duration of response was a median of 13.8 months for pembrolizumab, ranging from 1.5+ months to 23.6+ months, while for placebo, median duration of response was not yet reached, with a range of 2.8 to 20.4+ months, according to his report.
Rates of adverse events were similar between arms, according to Dr. Finn. While rates of grade 3-4 adverse events were higher in the pembrolizumab arm, those leading to treatment discontinuation were relatively low, he added.
About 10% of patients in the placebo arm subsequently received treatment with PD-1 or PD-L1 inhibitors, in an analysis that was prespecified in anticipation of new drugs that might be approved, according to Dr. Finn.
Ongoing now is KEYNOTE-394, another phase 3 study of pembrolizumab in previously treated, advanced hepatocellular carcinoma ongoing in the Asia Pacific region, Dr. Finn said.
Results of that phase 3 investigation could have important implications for the FDA’s subsequent analyses of pembrolizumab in this setting, according to Dr. Harris, the abstract discussant.
“I would recommend that they consider continued approval until they see results of the KEYNOTE-394 study, and take those results in sum,” he said in his presentation.
Dr. Finn reported disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Lilly, Merck, Novartis, and Pfizer.
SOURCE: Finn RS, et al. ASCO 2019. Abstract 4004.