Pembrolizumab prolongs survival in patients with advanced hepatocellular carcinoma

January 20, 2022

3 minute read



Qin S, et al. Abstract 383. Presented at: Symposium on Gastrointestinal Cancers; January 20-22, 2022: San Francisco.

Disclosures: Qin does not report any relevant financial information. Please see the summary for all relevant financial disclosures from other researchers.

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According to a phase 3 study conducted in Asia, pembrolizumab conferred a small but statistically significant survival benefit when added to best supportive care as a second-line treatment for patients with advanced hepatocellular carcinoma .

The addition of pembrolizumab (Keytruda, Merck), an anti-PD-1 antibody, also resulted in a higher objective response rate compared to placebo and best supportive care, with no new safety signals, the results showed. presented at the Symposium on gastrointestinal cancers.

Risk reports for study results.
Data derived from Qin S, et al. Abstract 383. Presented at: Symposium on Gastrointestinal Cancers; January 20-22, 2022: San Francisco.

“Advanced hepatocellular carcinoma is usually developed from background liver disease, such as hepatitis B/C, fatty liver disease, non-alcoholic fatty liver disease (NASH) and others,” shukui Qin, MD, PhD, director of Jinling Hospital Cancer Center and professor at Nanjing University of Chinese Medicine in China, Healio told Healio. “The majority of patients have cirrhosis and some degree of liver function deterioration. It is easier for them to develop some serious complications, like ascites, upper gastrointestinal bleeding, hepatic encephalopathy, hypoproteinemia, low platelet count, etc. This situation always makes the diagnosis, treatment and research of HCC more complex and difficult.


Pembrolizumab demonstrated antitumor activity and an acceptable safety profile in patients with previously treated advanced HCC in the global Phase 2 KEYNOTE-224 and Phase 3 KEYNOTE-240 trials. The drug received accelerated FDA 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 oncology drug advisory committee voted unanimously last year to keep fast-track approval, and Merck officials said KEYNOTE-394 could be evaluated as a possible study confirmation in the United States.


KEYNOTE-394 included 453 Asian patients with advanced HCC who experienced disease progression 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 up to 35 cycles plus best supportive care according to local guidelines. The treatment groups had similar baseline characteristics.

The operating system served as the main evaluation criterion. Secondary endpoints included PFS, ORR, duration of response, rate of disease control, time to progression, and safety.

The median follow-up was 33.8 months (range, 18.7-49) as of June 30, 2021, the cut-off date for the final analysis.

Main conclusions

The results showed a statistically significant improvement in OS with pembrolizumab compared to placebo (HR=0.79; 95% CI, 0.63-0.99). The researchers reported a median OS of 14.6 months with pembrolizumab versus 13 months with placebo and a 24-month OS rate of 34.3% versus 24.9%.

“The median SG score does not reflect the full benefit of pembrolizumab in [this] study, as Kaplan-Meier curves show greater separation at later time points,” 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 to placebo throughout the trial. At 36 months, OS rates were 23.4% in the pembrolizumab group and only 11% in the placebo group, which is clinically significant.”

Pembrolizumab also significantly improved PFS (HR=0.74; 95% CI, 0.6-0.92; median, 2.6 months versus 2.3 months) and ORR (estimated difference, 11. 4%; 95% CI, 6.7-16) at the second interim analysis. At the final analysis, pembrolizumab demonstrated higher ORR (13.7% vs. 1.3%), longer median duration of response (23.9 months vs. 5.6 months), control rate disease (52.7% versus 47.7%) and longer median time to progression (2.7 months versus 1.7 months; RR = 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 3-5 treatment-related adverse events (14.4% versus 5.9%) and immune-mediated adverse events (18.1% versus 10.5%) . Three treatment-related deaths occurred in the pembrolizumab group, due to gastrointestinal bleeding, autoimmune hepatitis, and soft tissue infection.


The KEYNOTE-394 results add to the body of evidence supporting the use of pembrolizumab as a second-line treatment for advanced HCC, the researchers wrote.

“Combination therapy primarily based on immune checkpoint inhibitors is becoming the mainstream therapy,” Qin told Healio. “Patients who experience immunotherapy treatment failure and the search for new drug strategies or combinations will be a focus in the coming years in the field of HCC.”

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