Pembrolizumab Monotherapy May Play Role in Treatment-Naive HCC

Pembrolizumab monotherapy demonstrated durable antitumor activity and encouraging effects on survival in an evaluation of patients with previously untreated hepatocellular carcinoma.

Pembrolizumab (Keytruda) monotherapy demonstrated durable antitumor activity and encouraging effects on survival in an evaluation of patients with previously untreated hepatocellular carcinoma (HCC), which suggests there may be a role for immunotherapeutic regimens in this setting, according to findings presented during the 2021 ASCO Gastrointestinal Cancers Symposium.1

Of note, 22 of 51 patients demonstrated at least some reduction in the size of their target lesion from baseline while on therapy with the PD-1 inhibitor.

“These findings clearly support further evaluation of pembrolizumab-based regimens in the therapeutic landscape of HCC,” Jean-Luc Van Laethem, MD, PhD, of Hôpital Erasme–Université Libre de Bruxelles (ULB), Brussels, Belgium, said in a presentation of the data.

The recently reported data were from cohort 2 of the single-arm, multicenter phase 2 KEYNOTE-224 trial (NCT02702414) in which study participants received pembrolizumab every 3 weeks for up to 35 initial cycles, or approximately 2 years, followed by a potential re-treatment phase of 1 year. The primary end point of the trial was objective response rate (ORR) with secondary end points of duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety. The median time from the first dose of therapy to data cutoff was 21 months (range, 17-23).

In 51 patients enrolled and treated with pembrolizumab, the ORR was 16% (95% CI, 7%-29%), which was comprised exclusively of partial responses. There were 21 patients (41%) with stable disease. The median duration of response was not reached (range, 3 to 20+ months), with 70% of patients estimated as having a response duration of 12 months or more. Response rates appeared to be consistent across key patient subgroups.

Median TTP was 4 months (95% CI, 3-8) with a rate at 12 months of 31%. The PFS rate at 12 months was 24%, with a median of 4 months (95% CI, 2-6). For OS, the median was 17 months (95% CI, 8-NA), with a rate at 12 months of 58%.

Treatment-related adverse events (TRAEs) occurred in 27 patients (53%), with 7 of those being grade 3 or greater in severity. The most common all-grade events noted were diarrhea (10%), fatigue (8%), hypothyroidism (8%), and myalgia (8%). There was 1 occurrence of a hepatic immune-mediated event, with no viral flares reported. Three patients had TRAEs leading to treatment discontinuation and there was 1 resulting death.

“The safety profile with pembrolizumab was generally consistent with that previously observed for [the agent] in advanced HCC in the second-line setting,” Van Laethem said. 

Key eligibility criteria in this cohort were the presence of radiologically, histologically, or cytologically confirmed, incurable HCC not amenable or refractory to locoregional therapy; measurable disease per RECIST 1.1 by blinded-independent central review; Child Pugh class A status; and ECOG performance status of 0 or 1; a Barcelona Clinic Liver Cancer Stage B or C; and a life expectancy of 3 months or more. 

Patients had a median age of 68 years (range, 41-91) and were mostly men (86%). About a third of patients (37%) had an a-fetoprotein level higher than 200 ng/mL and half (47%) reported alcohol use predisposing to HCC. Extrahepatic disease was present in 35% and vascular invasion in 18%.

Results from cohort 1 of this trial, which included patients who had received prior sorafenib therapy, also suggested antitumor activity of the single agent and led to the FDA granting accelerated approval to pembrolizumab alone in patients with previously treated disease in 2018.2 In 2019, Merck announced that a confirmatory phase 3 trial assessing the agent’s efficacy versus best supportive care in the indicated patient population did not meet its dual primary end points of OS and PFS.3


1. Van Laethem JL, Borbath I, Karwal M, et al. Pembrolizumab (pembro) monotherapy for previously untreated advanced hepatocellular carcinoma (HCC): Phase II KEYNOTE-224 study. J Clin Oncol. 39(suppl 3):297.

2. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. November 8, 2018. Accessed January 18, 2021.

3. Merck provides update on KEYNOTE-240, a phase 3 study of Keytruda (pembrolizumab) in previously treated patients with advanced hepatocellular carcinoma. Merck. February 20, 2019. Accessed January 18, 2021.