Pembrolizumab shows promising OS for previously untreated advanced HCC
Click Here to Manage Email Alerts
First-line pembrolizumab induced durable antitumor activity and promising OS among patients with advanced hepatocellular carcinoma, according to data from the phase 2 KEYNOTE-224 study presented at Gastrointestinal Cancers Symposium.
Immunotherapy as monotherapy can offer “excellent benefit” for around 25% to 30% of patients in this setting, or it can be used in combinations to provide new treatment options for patients with hepatocellular carcinoma, according to Jean-Luc Van Laethem, MD, PhD, of the department of gastroenterology and digestive oncology at Hôpital Erasme - Université Libre de Bruxelles in Belgium.
“Immunotherapy can offer a good [complement] beside antiangiogenics or associated treatments,” he told Healio. “Chemotherapy is poorly active in HCC, and there are contradictions for angiogenic therapy, like variceal bleeding or varices.”
Previously reported data from cohort 1 of KEYNOTE-224, a single-arm, multi-country trial, showed pembrolizumab (Keytruda, Merck) was effective and safe among patients with advanced HCC who had previously received sorafenib (Nexavar, Bayer).
In the current analysis, Van Laethem and colleagues evaluated data of 51 patients (median age, 68 years; range, 41-91; 86% men) enrolled in cohort 2 of the trial who received 200 mg IV pembrolizumab every 3 weeks for 2 years as first-line therapy. All patients had incurable HCC not amenable or refractory to locoregional therapy, Child-Pugh class A liver disease, ECOG performance status of 0 or 1 and Barcelona Clinic Liver Cancer stage C (67%) or B (33%) disease. Alcohol use was a predisposing factor for HCC in 47% of cases, 18% of patients had vascular invasion and 35% had extrahepatic disease.
The rationale for studying pembrolizumab, an anti-PD-1 agent, in this population is that these are “heterogeneous tumors, and a part are inflammatory (mainly hepatitis C virus or hepatitis B virus derived), with overexpression of PD-L1,” Van Laethem said.
Overall response rate served as the study’s primary endpoint. Secondary endpoints included duration of response, disease control rate, time to progression, PFS and OS.
Median time from first dose to data cutoff was 21 months (range, 17-23).
Researchers reported an ORR of 16% (95% CI, 7-29), all of which were partial responses, and ORR appeared similar across patient subgroups. Forty-one percent of patients achieved stable disease, for a disease control rate of 57%.
Median duration of response was not reached (range, 3-20+ months), although researchers estimated 70% of responses lasted for at least 12 months.
Median time to progression was 4 months (95% CI, 3-8).
Twenty-four percent of patients achieved 12-month PFS, and median PFS was 4 months (95% CI, 2-6). Fifty-eight percent of patients achieved 12-months OS, with median OS of 17 months (95% CI, 8 to not estimable).
Any-grade adverse events occurred among 53% of patients — the most common of which were diarrhea (10%), fatigue (8%), hypothyroidism (8%) and myalgia (8%) — with 14% of patients experiencing a grade 3 to grade 5 adverse event.
“Although this does not provide cross-comparison as a phase 2 trial, these data show pembrolizumab as monotherapy compares favorably to other treatments; for example, in CheckMate 459 of nivolumab [Opdivo, Bristol Myers Squibb] vs. sorafenib, nivolumab had median OS of 16.4 months, and atezolizumab [Tecentriq, Genentech/Roche] plus bevacizumab [Avastin, Genentech] had median OS of 19 months, and here, OS is 17 months,” Van Laethem told Healio.
Future areas of research include to “identify predictive biomarkers to immunotherapy, [further] evaluate pembrolizumab alone in this subset and combine pembrolizumab with a tyrosine kinase inhibitor antiangiogenic,” he added.
References:
Finn RS, et al. Abstract 267. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
Van Laethem J-L, et al. Abstract 297. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan 15-17, 2021.
Yau T, et al. Abstract LBA30_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct.1, 2019; Barcelona, Spain.
Perspective
Back to Top
The FDA approved pembrolizumab for patients with HCC who progressed after or were intolerant of sorafenib, based on an ORR of 17% and stable disease rate of 44% among 104 patients in the initial cohort of the KEYNOTE-224 study. Zhu and colleagues reported median PFS of 4.9 months, with 28% free of progression at 12 months in this second-line setting.
Van Laethem and colleagues reported on a second cohort of patients with unresectable HCC who had not received prior systemic therapy. These patients had good hepatic function (Child-Pugh class A), good functional status (ECOG performance status of 0-1) and measurable disease by RECIST version 1.1. Two notable aspects of the patient population included the median age of 68 years, which is older than that of most studies, and that very few of the enrolled patients, about 10%, had viral hepatitis, whereas about 80% were alcohol users.
Compared with the first cohort of patients in KEYNOTE-224 — that is, patients treated in the second-line setting —patients in the second cohort (first-line setting) showed similar results, suggesting comparable anticancer activity in the two settings, regardless of prior anti-VEGF therapy, such as sorafenib.
These results also appear comparable to those of a cohort of 59 patients treated with single-agent atezolizumab, compared with atezolizumab plus bevacizumab, in a randomized study by Lee and colleagues. Atezolizumab conferred an objective response rate (by RECIST version 1.1) of 17%, with stable disease in 32% of patients. Median PFS was 3.4 months, and results were inferior to those of the 60 patients treated with atezolizumab plus bevacizumab in terms of disease control rate and PFS.
Although pembrolizumab as a single agent is not likely to be pursued given the outcomes of atezolizumab plus bevacizumab, these results provide a greater understanding of the anticancer efficacy of single-agent PD-1/PD-L1 inhibitors, which will assist our understanding of other regimens currently being investigated, such as pembrolizumab with lenvatinib (Lenvima, Eisai).
In addition, these results may provide greater comfort to clinicians about the activity of pembrolizumab for patients who may not have been candidates for the combination of atezolizumab and bevacizumab, especially recognizing that although the second-line study, KEYNOTE-240, was statistically negative as reported by Finn and colleagues, updated results reported by Merle and colleagues at this year’s Gastrointestinal Cancers Symposium appeared to be clinically significant, with a 24-month OS of 28.8% compared with 20.4% with placebo (HR = 0.77; P = .012).
References:
Finn FS, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.01307.
Lee MS, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30156-X.
Merle P, et al. Abstract 268. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
Zhu AX, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30351-6.
Levine Cancer Institute at Atrium Health
Collapse
Van Laethem J-L, et al. Abstract 297. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan 15-17, 2021.
Click Here to Manage Email Alerts