1. Fuerst, Mark L.

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Pembrolizumab significantly improves overall survival (OS) compared to placebo in advanced hepatocellular carcinoma (HCC) patients previously treated with sorafenib. The Phase III KEYNOTE-394 trial found the anti-PD-1 immunotherapy plus best supportive care (BSC) reduced the risk of death by 21 percent compared to placebo plus BSC in Asian patients who were previously treated for advanced HCC.

Liver Cancer. Liver ... - Click to enlarge in new windowLiver Cancer. Liver Cancer

Previously, pembrolizumab showed efficacy and manageable safety in the global Phase II KEYNOTE-224 and Phase III KEYNOTE-240 studies of patients with previously treated advanced HCC, a population of high unmet need. KEYNOTE-394 is a randomized, double-blind, Phase III study conducted in Asia to evaluate the efficacy and safety of pembrolizumab versus placebo, both given with BSC, as second-line therapy for previously treated advanced HCC.


The final results of the KEYNOTE-394 study were presented at the 2022 ASCO Gastrointestinal Cancers Symposium (Abstract 383) by Shukui Qin, MD, PhD, Director of the Cancer Center of Jinling Hospital, and Professor at Nanjing University of Chinese Medicine.


"Hepatocellular carcinoma is a leading cause of cancer death across the world, and there are limited treatment options shown to extend survival for patients following treatment with sorafenib," Qin stated. "These overall survival data are very encouraging for patients with HCC previously treated with sorafenib and show the potential of pembrolizumab to extend the lives of these patients."


In the U.S., pembrolizumab is indicated for the treatment of patients with HCC who have been previously treated with sorafenib based on overall response rate (ORR) and duration of response (DOR) data from KEYNOTE-224. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Data from KEYNOTE-394 are being discussed with global regulatory authorities and will be evaluated as a potential confirmatory study in the U.S.


Liver cancer is one of the leading causes of cancer-related deaths worldwide. It is estimated there were more than 905,000 new cases of liver cancer and more than 830,000 deaths from the disease globally in 2020. In the U.S., it is estimated there will be more than 41,000 new cases of liver cancer diagnosed and more than 30,000 deaths from this disease in 2022. The vast majority, from 75 percent to 90 percent, of primary liver cancer cases are HCC.


Study Design

KEYNOTE-394 is a randomized, double-blind Phase III trial evaluating pembrolizumab plus BSC versus placebo plus BSC in Asian patients with advanced HCC previously treated with sorafenib or oxaliplatin-based chemotherapy. The primary endpoint is OS. Additional endpoints include progression-free survival (PFS), ORR, and DOR. The study enrolled 453 patients who were randomized to receive either pembrolizumab intravenously every 3 weeks for up to 35 cycles of treatment for up to approximately 2 years plus BSC, which included pain management and management of other potential complications including ascites per local standards of care, or placebo plus BSC.


Baseline characteristics were generally balanced between the two arms, Qin noted, and 90.7 percent of patients had received sorafenib as first-line therapy. Median study follow-up was 33.8 months.


Key Results

Pembrolizumab plus BSC demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of OS. For patients treated with pembrolizumab plus BSC, median OS was 14.6 months compared to 13 months for patients treated with placebo plus BSC. The percentage of patients who were alive at 2 years was 34.3 percent for pembrolizumab plus BSC compared to 24.9 percent for placebo plus BSC.


In addition, pembrolizumab plus BSC reduced the risk of disease progression or death by 26 percent compared to placebo plus BSC. Median PFS was 2.6 months for pembrolizumab plus BSC and 2.3 months for placebo plus BSC. Pembrolizumab plus BSC showed an ORR of 12.7 percent and a median DOR of 23.9 months; in comparison, placebo plus BSC showed an ORR of 1.3 percent and a median DOR of 5.6 months.


Treatment-related adverse events (TRAEs) occurred in 66.9 percent of patients in the pembrolizumab plus BSC arm and 49.7 percent of patients in the placebo plus BSC arm. Grade 3-5 TRAEs occurred in 14.4 percent of patients in the pembrolizumab plus BSC arm and 5.9 percent of patients in placebo plus BSC arm.


Immune-mediated adverse events of any grade occurred in 18.1 percent of patients receiving pembrolizumab plus BSC and 10.5 percent of patients receiving placebo plus BSC. Grade 3-5 immune-mediated adverse events occurred in 3 percent of patients receiving pembrolizumab plus BSC.


There were three deaths (due to gastrointestinal hemorrhage, autoimmune hepatitis, and soft tissue infection) in the pembrolizumab arm related to the study intervention.


Qin concluded: "Pembrolizumab plus BSC significantly improved OS, PFS, and ORR compared with placebo plus BSC as second-line therapy for patients from Asia with advanced HCC. The pembrolizumab safety profile was as expected. Overall, results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and thus add to the body of evidence supporting the use of pembrolizumab as second-line therapy for advanced HCC."


Mark L. Fuerst is a contributing writer.