Pembrolizumab extends survival among patients with advanced hepatocellular carcinoma
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Pembrolizumab conferred a small but statistically significant survival benefit when added to best supportive care as second-line treatment for patients with advanced hepatocellular carcinoma, according to a phase 3 study conducted in Asia.
The addition of pembrolizumab (Keytruda, Merck), an anti-PD-1 antibody, also resulted in a higher objective response rate compared with placebo and best supportive care, with no new safety signals, results presented at Gastrointestinal Cancers Symposium showed.
“Advanced hepatocellular carcinoma is usually developed from background liver disease, like hepatitis B/C, fatty liver, nonalcoholic steatosis hepatitis (NASH) and others,” Shukui Qin, MD, PhD, director of the cancer center of Jinling Hospital and professor at Nanjing University of Chinese Medicine in China, told Healio. “The majority of patients have cirrhosis and some degree of liver function damage. It’s easier for them to develop some severe complications, like ascites, upper gastrointestinal bleeding, hepatic encephalopathy, hypoproteinemia, decreased platelet count, etc. This situation always makes HCC diagnosis, treatment and research more complex and difficult.”
Background
Pembrolizumab had shown antitumor activity and an acceptable safety profile among patients with previously treated advanced HCC in the global phase 2 KEYNOTE-224 and phase 3 KEYNOTE-240 trials. The drug received FDA accelerated approval in 2018 for patients previously treated with sorafenib (Nexavar, Bayer) based on ORR and duration of response data from KEYNOTE-224. The FDA’s Oncologic Drugs Advisory Committee voted unanimously last year in favor of maintaining the accelerated approval, and Merck officials said KEYNOTE-394 may be evaluated as a possible confirmatory study in the U.S.
Methods
KEYNOTE-394 included 453 Asian patients with advanced HCC who experienced disease progression on or could not tolerate sorafenib or oxaliplatin-based chemotherapy. The vast majority (90.7%) had received first-line treatment with sorafenib.
Researchers randomly assigned patients 2:1 to 200 mg pembrolizumab (n = 300) or placebo (n = 153) every 3 weeks for no more than 35 cycles plus best supportive care according to local guidelines. The treatment groups had similar baseline characteristics.
OS served as the primary endpoint. Secondary endpoints included PFS, ORR, duration of response, disease control rate, time to progression and safety.
Median follow-up was 33.8 months (range, 18.7-49) as of June 30, 2021, the cutoff date for final analysis.
Key findings
Results showed a statistically significant improvement in OS with pembrolizumab compared with placebo (HR = 0.79; 95% CI, 0.63-0.99). Researchers reported median OS of 14.6 months with pembrolizumab vs. 13 months with placebo and a 24-month OS rate of 34.3% vs. 24.9%.
“The median OS index does not capture all the benefits of pembrolizumab in [this] study, as the Kaplan-Meier curves show greater separation at later timepoints,” Qin told Healio. “The Kaplan-Meier curves for pembrolizumab and placebo separated at approximately 10 months, and the pembrolizumab group continued to show greater OS compared with placebo for the duration of the trial. At 36 months, the OS rates were 23.4% in the pembrolizumab group and only 11% in the placebo group, which is clinical meaningful.”
Pembrolizumab also significantly improved PFS (HR = 0.74; 95% CI, 0.6-0.92; median, 2.6 months vs. 2.3 months) and ORR (estimated difference, 11.4%; 95% CI, 6.7-16) at second interim analysis. At final analysis, pembrolizumab demonstrated a higher ORR (13.7% vs. 1.3%), longer median duration of response (23.9 months vs. 5.6 months), higher disease control rate (52.7% vs. 47.7%) and longer median time to progression (2.7 months vs. 1.7 months; HR = 0.72; 95% CI, 0.58-0.9).
About two-thirds (66.9%) of patients in the pembrolizumab group experienced treatment-related adverse events, compared with about half (49.7%) of those in the placebo group. The most common adverse events included increased aspartate aminotransferase, increased alanine aminotransferase and rash. The pembrolizumab group had higher rates of grade 3 to grade 5 treatment-related adverse events (14.4% vs. 5.9%) and immune-mediated adverse events (18.1% vs. 10.5%). Three treatment-related deaths occurred in the pembrolizumab group, due to gastrointestinal hemorrhage, autoimmune hepatitis and soft tissue infection.
Implications
The results of KEYNOTE-394 add to the body of evidence supporting use of pembrolizumab as second-line therapy for advanced HCC, researchers wrote.
“Combination therapy mainly based on immune checkpoint inhibitors is becoming the dominant therapy,” Qin told Healio. “Patients who experience immunotherapy treatment failure and investigation of novel strategies or drug combinations will be the focus in the following years in HCC area.”
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Qin S, et al. Abstract 383. Presented at: Gastrointestinal Cancers Symposium; Jan. 20-22, 2022: San Francisco.
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