KEYNOTE-240 4.5-year follow-up supports pembrolizumab’s role in 2L advanced HCC treatment

An extended 4.5-year follow-up of the phase III KEYNOTE-240 trial showed that pembrolizumab continued to provide clinically meaningful improvements in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS), with a manageable safety profile, vs placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC).

Median OS was 13.9 months in the pembrolizumab group compared with 10.6 months in the placebo group (hazard ratio [HR], 0.77; 95 percent confidence interval [CI], 0.62–0.96). Estimated OS rates at 36 months and 48 months were 17.9 percent vs 11.1 percent and 13.0 percent vs 6.6 percent, respectively. [Edeline J, et al, ESMO 2022, abstract 713P]

Median PFS was 3.0 months for pembrolizumab vs 2.8 months for placebo (HR, 0.73; 95 percent CI, 0.58–0.91). Estimated PFS rates at 36 months and 48 months were 8.6 percent vs 0 percent and 5 percent vs 0 percent, respectively.

Subgroup analysis suggested greater OS and PFS benefits with pembrolizumab in Asian patients (excluding Japanese), patients with Eastern Cooperative Oncology Group performance status 0, alpha-fetoprotein <200 ng/mL, extrahepatic spread, or Barcelona Clinic Liver Cancer (BCLC) stage C disease, and those who discontinued sorafenib due to progressive disease. Additionally, patients with hepatitis B virus aetiology appeared to obtain greater OS benefit while those with hepatitis C virus aetiology appeared to obtain greater PFS benefit from pembrolizumab treatment.

With extended follow-up, objective response rate (ORR) was 18.3 percent with pembrolizumab vs 4.4 percent with placebo, with complete response achieved in 3.6 percent vs 0 percent and partial response achieved in 14.7 percent vs 4.4 percent of the patients, respectively. The median duration of response was 13.9 months vs 15.2 months. The rate of disease control for ≥12 months was 53.7 percent vs 50.0 percent, while median time to progression was 3.8 months vs 2.8 months.

“Previously published results of KEYNOTE-240 showed similar ORR and clinically meaningful improvements in OS and PFS, although the prespecified statistical significance criteria for OS and PFS were narrowly missed,” the investigators noted. [J Clin Oncol 2020;38:193-202]

“[With extended 4.5-year follow-up,] no new or unexpected adverse events [AEs] occurred,” they reported.

Grade 3/4 treatment-related AEs occurred in 19.7 percent vs 7.5 percent of patients in the pembrolizumab vs placebo group, with the most common AEs being increased aspartate aminotransferase (5.7 percent vs 1.5 percent) and alanine aminotransferase (3.9 percent vs 1.5 percent). Grade 3/4 immune-mediated AEs occurred in 7.2 percent vs 0.7 percent of patients, the most common events being severe skin reactions (2.2 percent vs 0 percent), pneumonitis (1.4 percent vs 0 percent), and hepatitis (1.4 percent vs 0 percent).