Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups

Abstract

Background: While the benefit of immune checkpoint inhibitors (ICI) is well established in programmed death-ligand 1 high (PD-L1_high) advanced gastroesophageal adenocarcinoma (GEAC), there remains significant controversy about their benefit in PD-L1_low GEAC. To elucidate the benefit of ICI in PD-L1_low and PD-L1_negative GEAC, we conducted an analysis leveraging individual patient data (IPD) extracted from Kaplan-Meier (KM) plots of pivotal trials.

Methods: KM curves from randomized clinical trials investigating the efficacy of ICI for advanced GEAC were extracted from published articles. IPD were extracted from the reported curves, and, in the case of unreported KM plots, KMSubtraction was used to retrieve survival data. A patient-level meta-analysis was conducted for PD-L1_low tumors.

Results: In the human epidermal growth factor receptor 2 (HER2)-negative setting, pooled PD-L1 combined positive score (CPS) 1-4 subgroup KM plots from KEYNOTE-859, CHECKMATE-649, and RATIONALE-305 showed a modest overall survival (OS) benefit with the addition of an anti-programmed cell death protein 1 (anti-PD-1) agent [hazard ratio (HR) 0.868, P = 0.018]. Similarly, a modest OS benefit was shown by our IPD meta-analysis of PD-L1 CPS 1-9 subgroups from KEYNOTE-859, KEYNOTE-062, and RATIONALE-305 (HR 0.840, P = 0.002.) Conversely, when CPS 5-9 subgroup KM plots from KEYNOTE-859 and RATIONALE-305 were pooled together, no significant OS benefit was found in the ICI-chemotherapy arm (HR 0.867, P = 0.181), although this subgroup was relatively small.

Conclusions: In PD-L1_low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.

Keywords: PD-L1; gastroesophageal adenocarcinoma; immune checkpoint inhibitors.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchartdiagram. IPD, individual patient data; ITT, intention to treat; KM, Kaplan–Meier; PD-L1, programmed death-ligand 1; RCT, randomized controlled trial.

Figure 2

KMSubtraction-derived PD-L1_lowsubgroup Kaplan–Meier plots for RATIONALE-305. (A) RATIONALE-305 PD-L1 CPS 1-9 OS; (B) RATIONALE-305 PD-L1 CPS 1-4 OS; (C) RATIONALE-305 PD-L1 CPS 5-9 OS. CI, confidence interval; CPS, combined positive score; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1.

Figure 3

KMSubtraction-derived PD-L1_lowor PD-L1_negativesubgroup Kaplan–Meier plots for KEYNOTE-859. (A) KEYNOTE-859 PD-L1 CPS <1 OS (PD-L1_negative). (B) KEYNOTE-859 PD-L1 CPS 1-9 OS (PD-L1_low). (C) KEYNOTE-859 PD-L1 CPS 1-4 OS (PD-L1_low). (D) KEYNOTE-859 PD-L1 CPS 5-9 OS (PD-L1_low). (E) KEYNOTE-859 PD-L1 CPS <1 PFS (PD-L1_negative). (F) KEYNOTE-859 PD-L1 CPS 1-9 PFS (PD-L1_low). (G) KEYNOTE-859 PD-L1 CPS 1-4 PFS (PD-L1_low). (H) KEYNOTE-859 PD-L1 CPS 5-9 PFS (PD-L1_low). CI, confidence interval; CPS, combined positive score; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival. Note: For the purposes of this study, we defined PD-L1_negative as a PD-L1 expression <1, PD-L1_low as PD-L1 expression ranges excluding PD-L1 <1 tumors and PD-L1 ≥10, and PD-L1_high as a PD-L1 expression including ≥10.

Figure 4

Pooled analysis of PD-L1_lowsubgroups in human epidermal growth factor receptor 2 (HER2)-advanced GEAC. (A) OS outcomes for the PD-L1 CPS 1-9 subgroup comprising KEYNOTE-859, KEYNOTE-062, and RATIONALE-305. (B) OS outcomes for the PD-L1 CPS 1-4 subgroup comprising KEYNOTE-859, CHECKMATE-649, and RATIONALE-305. (C) OS outcomes for the PD-L1 CPS 5-9 subgroup comprising KEYNOTE-859 and RATIONALE-305. CI, confidence interval; CPS, combined positive score; GEAC, gastroesophageal adenocarcinoma; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1.