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The addition of pembrolizumab to best supportive care resulted in a statistically significant improvement in overall survival vs BSC alone in Asian patients with advanced hepatocellular carcinoma who previously received treatment with sorafenib, meeting the primary end point of the phase 3 KEYNOTE-394 trial.
The addition of pembrolizumab (Keytruda) to best supportive care (BSC) resulted in a statistically significant improvement in overall survival (OS) vs BSC alone in Asian patients with advanced hepatocellular carcinoma (HCC) who previously received treatment with sorafenib (Nexavar), meeting the primary end point of the phase 3 KEYNOTE-394 trial (NCT03062358).1
Pembrolizumab plus BSC also significantly improved progression-free survival (PFS) and objective response rate (ORR) over BSC alone in patients with advanced HCC who received prior sorafenib or oxaliplatin chemotherapy. No new safety signals were reported with this approach.
“Frequently diagnosed at an advanced stage, HCC has one of the highest mortality rates of solid cancers. Despite recent progress, there remains an unmet need for anti–PD-1 monotherapy after sorafenib, where [pembrolizumab] is an established treatment option for patients,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “It is very encouraging that [pembrolizumab] significantly improved OS in this study, and we look forward to engaging with regulatory authorities as quickly as possible.”
The double-blind, phase 3 KEYNOTE-394 trial enrolled patients with HCC and Barcelona Clinic Liver Cancer stage C or B disease that is not amenable to locoregional therapy or is refractory to locoregional therapy and is not amenable to a curative approach.2 Patients needed to have a Child-Pugh A liver score within 1 week before the first dose, have a life expectancy of more than 3 months, at least 1 measurable lesion per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.
Patients could not have received sorafenib or oxaliplatin-based chemotherapy within 14 days of the first study dose, nor could they have esophageal or gastric variceal bleeding within the past 6 months. If patients had clinically apparent ascites on physical examination, portal vein invasion at the main portal branch, inferior vena cava, or cardiac involvement of disease based on imaging, they were excluded.
A total of 453 patients were randomized to receive either intravenous pembrolizumab every 3 weeks for up to 35 treatment cycles plus BSC, which could include pain management and management of other possible complications like ascites per local standards of care, or placebo plus BSC.
The primary end point of the study is OS, and important secondary end points include progression-free survival (PFS), objective response rate (ORR), duration of response, and disease control rate.
Previously, in November 2018, the FDA granted an accelerated approval to pembrolizumab for the treatment of patients with HCC who previously received sorafenib3 based on data from the phase 2 KEYNOTE-224 trial (NCT02702414), which evaluated pembrolizumab at 200 mg given every 3 weeks for about 2 years in patients with HCC who had prior sorafenib and were either intolerant or showed radiographic progression of their disease following treatment.4
As of a data cutoff of February 13, 2018, 16% of 104 patients were still receiving the immunotherapy. Data revealed that the agent elicited an ORR of 17% (95% CI, 11%-26%) in this population, which included a complete response rate of 1% and a partial response rate of 16%. Moreover, 44% of patients achieved stable disease and 33% experienced disease progression.
The continued approval of the immunotherapy was contingent on positive data from the phase 3 KEYNOTE-240 trial (NCT02702401); however, the study failed to meet its co-primary end points of OS and PFS, with 1-sided alphas of .023 and .002, respectively.5
In this trial, patients who had progressed on, or were intolerant to, sorafenib were randomized to receive pembrolizumab at 200 mg every 3 weeks plus BSC (n = 278) vs placebo plus BSC (n = 135).
Results showed that the median PFS with pembrolizumab/BSC was 3.0 months vs 2.8 months with placebo/BSC (HR, 0.775; 95% CI, 0.609-0.987; P = .0186). The median OS in the investigative and control arms was 13.9 months and 10.6 months, respectively (HR, 0.781; 95% CI, 0.611-0.998; P = .0238). With long-term follow-up, the median PFS was 3.3 months with the immunotherapy vs 2.8 months with the control (HR, 0.70; 95% CI, 0.56-0.89; P = .0011). The median OS in these arms was 13.9 months and 10.6 months, respectively (HR, 0.77; 95% CI, 0.62-0.96; P = .0112).
Pembrolizumab/BSC induced an ORR of 18.3% (95% CI, 14.0%-23.4%) vs 4.4% (95% CI, 1.6%-9.4%) with BSC alone.
The regulatory decision was discussed during the FDA’s Oncologic Drugs Advisory Committee meeting on April 29, 2021, and despite the KEYNOTE-240 data, the committee unanimously voted 8 to 0 in favor of supporting the approval of pembrolizumab monotherapy in this patient population.5
In explaining his decision, Colin D. Weekes, MD, PhD, FASCO, said, “I voted yes because although the results [of KEYNOTE-240] are not statistically significant, I believe they are clinically significant, bore out by the persistent benefit demonstrated in the OS curves. In addition, with the results of the KEYNOTE-394 study…we will be able to have a definitive answer as to whether there is truly benefit or not of single-agent pembrolizumab in the second-line setting.”
During the meeting, KEYNOTE-394 was discussed as a potential confirmatory trial to verify the clinical benefit of pembrolizumab in this patient population.
Data from the trial are anticipated to be presented at an upcoming medical conference, according to Merck.