Disparity in survival benefits of pembrolizumab between Asian and non-Asian patients with advanced cancers: A systematic review and meta-regression analysis

Abstract

Background: Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt.

Methods: In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non-Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) between these two subgroups, respectively. We used random-effects meta-analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta-regression analysis to identify significant covariates.

Results: A total of 17 and 11 trials were included in the meta-analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non-Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non-Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76-0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82-1.07; p = 0.2391). Both linear meta-regression analyses revealed an open-label design as a crucial covariate, which indicated more benefits for non-Asian participants.

Conclusions: Compared with non-Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta-analysis provides insight into clinical research design.

Keywords: Asian; advanced cancers; meta-analysis; overall survival; pembrolizumab.

FIGURE 1

PRISMA flow diagram of study selection. OS, overall survival; PFS, progression‐free survival. *Duplicates were removed automatically by the EndNote^TM software (version 20.3, 2022). ^†KEYNOTE (KN)‐048, ‐062, and ‐361 had three arms. ^aKN‐063 (gastric cancer), ‐183 (multiple myeloma), and ‐185 (multiple myeloma). ^bKN‐204 (Hodgkin's lymphoma) and ‐811 (gastric cancer). ^cKN‐394 (hepatocellular carcinoma). ^dKN‐006 (melanoma) and ETOP 9–15 PROMISE‐meso (pleural mesothelioma). ^eKN‐045 (urothelial carcinoma) and ‐189 (non‐small cell lung cancer, adenocarcinoma). ^fKN‐040 (head and neck squamous cell carcinoma), ‐119 (breast cancer), ‐361 (urothelial carcinoma), and ‐826 (cervical cancer). ^gKN‐062 pembrolizumab monotherapy arm (gastric cancer). ^hKN‐010 (non‐small cell lung cancer), ‐042 (non‐small cell lung cancer), ‐061 (gastric cancer), ‐122 (nasopharyngeal cancer), ‐181 (esophageal cancer).

FIGURE 2

Random‐effects meta‐analysis of overall survival differences with Knapp‐Hartung adjustment (m = 19). The pooled ratio of HRs for OS between the Asian and non‐Asian subgroups (0.87; 95% CI, 0.76–0.99; p = 0.0391; chi‐square Q test χ ² = 20.84; p = 0.29; I ² = 23.9%). Each paired arm corresponds to a square centered at the point estimate of the effect measure (i.e., the ratio of the HRs of the Asian to non‐Asian subgroup), with the size being proportional to the study weight. The horizontal line extending from both sides of the square represents the 95% CI. “RE” denotes “random‐effects.”

FIGURE 3

Random‐effects meta‐analysis of progression‐free survival differences with Knapp–Hartung adjustment (m = 12). The pooled ratio of HRs for PFS between the Asian and non‐Asian subgroups (0.93; 95% CI: 0.82–1.07; p = 0.2391; chi‐square Q test χ² = 7.37; p = 0.77; I ² ≈ 0%). Each paired arm corresponds to a square centered at the point estimate of the effect measure (i.e., the ratio of the HRs of the Asian to non‐Asian subgroup), with the size being proportional to the study weight. The horizontal line extending from both sides of the square represents the 95% CI. “RE” denotes “random‐effects.”