Pembrolizumab (Keytruda) added to best supportive care (BSC) improved outcomes including overall survival (OS) versus BSC alone in Asian patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), according to final results from the KEYNOTE-394 trial.
Patients treated with pembrolizumab plus BSC had a median OS of 14.6 months (95% confidence interval [CI], 12.6-18.0) compared with 13.0 months (95% CI, 10.5-15.1) for those treated with placebo plus BSC, corresponding to a 21% reduction in the risk for death in the pembrolizumab group (hazard ratio [HR], 0.79; P = .0180), reported Shukui Qin, MD, Director, Cancer Center of Jinling Hospital, Nanjing Chinese Medicine University, China, at the 2022 ASCO Gastrointestinal Cancers Symposium.
“These data reinforce the benefit–risk balance for pembrolizumab observed in globally conducted studies in the second-line treatment of advanced HCC and provide support for the generalizability of data worldwide,” said Dr Qin.
“Although globally-approved antiangiogenic therapy has improved clinical outcomes in the second-line treatment setting, available treatment options benefit a minority of patients. There is a high unmet medical need for therapies that prolong survival and are tolerable,” he said. “Pembrolizumab demonstrated efficacy and a manageable adverse event [AE] profile in sorafenib-treated patients with advanced HCC in the global phase 2 and 3 studies KEYNOTE-224 and KEYNOTE-240, respectively, though prespecified statistical significance criteria for OS and progression-free survival were narrowly missed in KEYNOTE-240.”
KEYNOTE-394 was a double-blind phase 3 trial of 453 Asian patients with advanced HCC previously treated with sorafenib or oxaliplatin (Eloxatin)-based chemotherapy. Patients (N = 300) were randomized to pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles (approximately 2 years) plus BSC consisting of pain management and management of other potential complications (including ascites per local standards of care) or placebo plus BSC.
Approximately three-fourths of patients in both arms had extrahepatic spread of their cancer and 11% had macrovascular invasion. Some 90% received sorafenib as first-line treatment and 9% received oxaliplatin-based chemotherapy.
A total of 50.7% of patients in the pembrolizumab arm and 66.7% of those in the placebo arm received a systemic anticancer therapy after discontinuation of study treatment, and 20.7% and 28.1%, respectively, previously received a PD-1 or PD-L1 inhibitor, Dr Qin noted.
The 24-month OS rate was 34.3% in the pembrolizumab arm versus 24.9% in the placebo arm. Median progression-free survival was 2.6 months with pembrolizumab plus BSC compared with 2.3 months with BSC alone (HR, 0.74; P = .0032).
A meta-analysis of data from KEYNOTE-394 and KEYNOTE-240 showed a median OS of 14.2 months in patients randomized to pembrolizumab versus 12.5 months in those randomized to placebo (HR, 0.79; 95% CI, 0.67-0.93). KEYNOTE-240 also compared pembrolizumab and BSC with placebo and BSC in patients with advanced HCC treated previously with sorafenib. However, as Dr Qin mentioned, it narrowly missed statistical significance per specified criteria.
The objective response rate in the pembrolizumab arm was 12.7% compared with 1.3% in the placebo arm (P <.0001). There were 6 (2.0%) complete responses in the pembrolizumab arm versus 1 (0.7%) in the placebo arm. The median duration of response was 23.9 and 5.6 months, respectively.
The AE profile of pembrolizumab was manageable and consistent with previous reports in this patient population.
Treatment-related AEs occurred in 66.9% of patients in the pembrolizumab plus BSC arm and 49.7% of those in the placebo plus BSC arm. Grade 3 to 5 treatment-related AEs occurred in 14.4% of patients who received pembrolizumab and 5.9% of those who received placebo. Immune-mediated AEs of any grade occurred in 18.1% and 10.5% of patients, respectively, with grade 3 to 5 immune-mediated AEs occurring in 3.0% of those randomized to pembrolizumab. There were 3 deaths due to gastrointestinal hemorrhage, autoimmune hepatitis, and soft tissue infection in the pembrolizumab arm related to the study medication.