PD-L1 as a predictive biomarker for pembrolizumab in HER2-positive gastric or gastro-esophageal junction adenocarcinoma—a commentary on KEYNOTE-811
Editorial Commentary

PD-L1 as a predictive biomarker for pembrolizumab in HER2-positive gastric or gastro-esophageal junction adenocarcinoma—a commentary on KEYNOTE-811

James Yu1 ORCID logo, Anwaar Saeed2,3

1Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Division of Hematology & Oncology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA; 3UPMC Hillman Cancer Center, Pittsburgh, PA, USA

Correspondence to: Anwaar Saeed, MD. Division of Hematology & Oncology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, UPMC Cancer Pavilion, 5th Floor Room 556, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. Email: saeeda3@upmc.edu.

Comment on: Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastrooesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 2023;402:2197-208.

Keywords: Gastric cancer; gastro-esophageal junction cancer (GEJ cancer); pembrolizumab; PD-L1; predictive biomarker

Submitted Feb 29, 2024. Accepted for publication May 06, 2024. Published online Jun 05, 2024.

doi: 10.21037/cco-24-28

HER2 (also known as ERBB2) amplification or overexpression is observed in approximately 20–25% of advanced gastric or gastro-esophageal junction (GEJ) adenocarcinomas (1-4). In 2010, the landmark phase 3 ToGA randomized clinical trial (RCT; NCT01041404) revealed a promising survival benefit by adding trastuzumab (anti-HER2) to chemotherapy (fluoropyrimidine and platinum), and this combination became the established first-line treatment for a decade in patients with advanced HER2-positive gastric or GEJ adenocarcinomas (5). Recently, several preclinical studies demonstrated findings supportive of combining anti-PD-1/PD-L1 agents with trastuzumab in HER2-positive malignancies. Additionally, a couple of single-arm early-phase clinical trials showed potential efficacy benefits, along with manageable safety profiles, when adding pembrolizumab to trastuzumab and chemotherapy for patients with advanced gastric and GEJ adenocarcinoma (6,7).

Based on the aforementioned preclinical and clinical data, the phase 3 multicenter, double-blind, placebo-controlled RCT (KEYNOTE-811, NCT03615326) was initiated in treatment-naive patients with HER2-positive advanced gastric or GEJ adenocarcinoma with overall survival (OS) and progression-free survival (PFS) as co-primary endpoints (3). Patients were randomized in a 1:1 ratio and received pembrolizumab (200 mg) or placebo every 3 weeks, in combination with trastuzumab and chemotherapy (fluoropyrimidine and platinum) (3). The trial included three protocol-specified interim analyses and a final analysis (3,4,8). In 2021, the first interim analysis for hypothesis testing of the objective response rate (ORR) was presented, involving the first 264 enrolled patients (3,8). The ORR was significantly higher in the pembrolizumab arm compared to the placebo arm (74% vs. 52%), and the median duration of response (DoR) was 10.6 (range, 1.1+ to 16.5+) months in the pembrolizumab arm and 9.5 (range, 1.4+ to 15.4+) months in the placebo arm (3,8). In subgroup analysis, a more substantial difference in ORR with pembrolizumab was observed in the PD-L1 combined positive score (CPS) ≥1 subgroup compared to the CPS <1 subgroup (25% vs. 5%) although the 95% confidence intervals for both CPS ≥1 and <1 subgroups overlapped (3,8). Based primarily on the findings from this KEYNOTE-811 first interim analysis, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab in 2021 regardless of PD-L1 status, in combination with trastuzumab and chemotherapy for the first-line treatment of patients with HER2-positive advanced gastric or GEJ adenocarcinoma (9).

Afterward, in October 2023, the prespecified second and third interim analyses (final analysis of PFS and interim analysis of OS) from KEYNOTE-811 were presented (4). At the third interim analysis, 698 patients were assigned to receive pembrolizumab (n=350) or placebo (n=348) (4). A significantly superior PFS was observed with pembrolizumab in the overall population [median PFS: 10.0 vs. 8.1 months; hazard ratio (HR), 0.73] and the PD-L1 CPS ≥1 subgroup (median PFS: 10.9 vs. 7.3 months; HR, 0.71), but PFS did not differ in PD-L1 CPS <1 subgroup (median PFS: 9.5 vs. 9.5 months; HR, 1.03) (4). OS was also superior in the CPS ≥1 subgroup (median OS: 20.0 vs. 15.7 months; HR, 0.81), but there was no significant OS difference in the PD-L1 CPS <1 subgroup (HR, 1.41) (4,10). Therefore, and based on this updated third interim analysis, which indicated limited pembrolizumab benefit in the CPS <1 subgroup, the US FDA amended their accelerated approval in November 2023, restricting pembrolizumab use to patients with PD-L1 positive disease (CPS ≥1) (10). Similarly, the European Medicines Agency (EMA) has also approved pembrolizumab for HER2-positive gastric or GEJ adenocarcinoma with PD-L1 CPS ≥1 (11). Table 1 summarizes the clinical benefits of adding pembrolizumab in gastric and GEJ adenocarcinoma.

Table 1

Efficacy benefits of pembrolizumab addition by PD-L1 CPS status in gastric or GEJ adenocarcinomas

Trial (ref.), population Intervention PD-L1 CPS <1 PD-L1 CPS ≥1
KEYNOTE-811 (4,10), HER2+ gastric or GEJ adenocarcinomas SOC† + pembrolizumab vs. SOC† + placebo Number: 52 vs. 52 Number: 298 vs. 296
mPFS: 9.5 vs. 9.5 months; HR, 1.03; 95% CI: 0.65–1.64 mPFS: 10.9 vs. 7.3 months; HR, 0.71; 95% CI: 0.59–0.86
mOS: HR, 1.41; 95% CI: 0.90–2.20 mOS: 20.0 vs. 15.7 months; HR, 0.81; 95% CI: 0.67–0.98
KEYNOTE-859 (12), HER2− gastric or GEJ adenocarcinomas SOC‡ + pembrolizumab vs. SOC‡ + placebo Number: 172 vs. 172 Number: 618 vs. 617
mPFS: HR, 0.90; 95% CI: 0.70–1.15 mPFS: 6.9 vs. 5.6 months; HR, 0.72; 95% CI: 0.63–0.82
mOS: HR, 0.92; 95% CI: 0.73–1.17 mOS: 13.0 vs. 11.4 months; HR, 0.74; 95% CI: 0.65–0.84

Survival benefit with pembrolizumab is significant in CPS ≥1 disease and limited in CPS <1 disease across HER2-negative and HER2-positive disease in gastric or GEJ adenocarcinomas. Interpretation should be cautious, as these subgroup analyses are not powered sufficiently. †, trastuzumab + fluoropyrimidine and platinum; ‡, fluoropyrimidine and platinum. CPS, combined positive score; GEJ, gastro-esophageal junction; ref., reference; SOC, standard of care; mPFS, median progression-free survival; HR, hazard ratio; CI, confidence interval; mOS, median overall survival.

We concur with the recent amendment by the US FDA, supported by several compelling reasons. Firstly, while considering the limitation of an unplanned subgroup analysis in KEYNOTE-811 being underpowered, pembrolizumab exhibited limited survival benefit in PD-L1 negative (CPS <1) tumors. Secondly, there exists a robust mechanistic rationale explaining the limited efficacy of pembrolizumab in PD-L1 negative tumors, given its nature as an anti-PD-L1 agent. Thirdly, PD-L1 expression using CPS methodology stands as the most validated predictive biomarker for pembrolizumab, as well as other immune checkpoint inhibitors (ICIs) in this disease population and various other cancer types (13,14). The correlation between pembrolizumab clinical benefit and PD-L1 status was well demonstrated in other upper gastrointestinal (GI) tumor studies, such as KEYNOTE-859, which involved HER2-negative gastric and GEJ adenocarcinoma, and KEYNOTE-181, which involved esophageal cancer (12,13).

In the phase 3 KEYNOTE-859 RCT (NCT03675737), pembrolizumab plus chemotherapy (fluoropyrimidine and platinum) was compared to chemotherapy alone in patients with treatment-naive HER2-negative gastric or GEJ adenocarcinoma, with OS as the primary endpoint (12). OS was superior in the pembrolizumab arm (n=790) compared to the placebo arm (n=789) in the overall population (12). Subgroup analysis revealed a greater survival benefit with pembrolizumab in those with a higher PD-L1 CPS, while there was limited survival benefit in the CPS <1 subgroup (Table 1) (12). Under the US FDA approval in November 2023, however, pembrolizumab can be used irrespective of the tumor’s PD-L1 status in HER2-negative gastric or GEJ adenocarcinoma (15). In contrast, the EMA only approved pembrolizumab for the same type of disease with CPS ≥1 (11). The correlation between pembrolizumab clinical benefit and PD-L1 CPS status was also demonstrated in esophageal cancer in KEYNOTE-181 and KEYNOTE-590 (13,16).

Platinum and fluoropyrimidine-based chemotherapy have demonstrated benefits, such as promoting immune cell tumor infiltration, depleting immune suppressive cells, and inducing dendritic cell maturation, supporting the rationale for combining these chemotherapeutic agents with ICIs (17). Currently, ICIs combined with fluoropyrimidine and platinum-based chemotherapy is a standard of care in multiple solid malignancies, supported by compelling pivotal clinical trials data (18,19). Fluoropyrimidine and platinum-based chemotherapy also serve as a major backbone for upper GI tumors. However, the primary rationale for incorporating pembrolizumab (or other ICIs) in HER2-positive tumors in the upper GI is the expected synergistic effect with anti-HER2 agents. Upregulation of PD-1 and PD-L1 expression by trastuzumab induced HER2-specific T-cell responses, and promotion of tumor-infiltrating lymphocytes have been reported as supporting rationales for incorporating ICI with anti-HER2 agents (3,20,21). Nevertheless, adding pembrolizumab to anti-HER2 showed limited benefit in HER2-positive, PD-L1-negative gastric and GEJ adenocarcinoma as demonstrated by KEYNOTE-811 (4). Interestingly, the combination of anti-HER2 and ICI also showed limited efficacy benefits in other cancer types, such as HER2-positive breast cancer. For instance, in the phase 3 IMpassion050 (NCT03726879) RCT, adding atezolizumab (anti-PD-L1) to neoadjuvant anti-HER2 therapies (pertuzumab plus trastuzumab) and chemotherapy in early-stage HER2-positive breast cancer did not enhance pathologic complete response rates (22). Considering results of those large studies, it is possible that pembrolizumab and trastuzumab exhibit additive effects rather than synergistic effects in gastric and GEJ adenocarcinoma. To be more specific, the degree of OS and PFS benefit in PD-L1 positive (CPS ≥1) disease from adding pembrolizumab compared to placebo is similar in KEYNOTE-811 (HR, 0.71–0.81) and KEYNOTE-859 (HR, 0.72–0.74; Table 1). If pembrolizumab and trastuzumab truly had a synergistic effect, one would anticipate more significant benefits with a lower HR in KEYNOTE-811 compared to KEYNOTE-859. The observed similar magnitude of survival benefit with pembrolizumab addition in KEYNOTE-811 and KEYNOTE-859 supports an additive effect of pembrolizumab and trastuzumab. In addition, in both KEYNOTE-811 and KEYNOTE-859 trials, adding pembrolizumab showed limited survival benefit in PD-L1 negative disease. If pembrolizumab and trastuzumab indeed had a synergistic effect, one would expect benefits even in PD-L1 negative disease in KEYNOTE-811. Nonetheless, proving this theoretical concept will be challenging without well-designed trials specifically targeting this hypothesis.

In summary, recent findings from KEYNOTE-811 indicate that PD-L1 CPS is a predictive biomarker for pembrolizumab in HER2-positive gastric and GEJ adenocarcinoma. The prespecified final analysis to confirm OS benefit in KEYNOTE-811 is underway, and we eagerly anticipate the results. In the meantime, HER2-positive PD-L1 negative gastric and GEJ adenocarcinomas continue to be treated with the historic regimen of trastuzumab with chemotherapy. This PD-L1 negative space remains intriguing for further investigations.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-28/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-28/coif). A.S. reports a leadership role with Autem therapeutics, Exelixis, KAHR Medical, and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio Therapeutics, Taiho, Amgen, Autem Therapeutics, KAHR Medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate Therapeutics, Incyte Corporation, Daiichi Sankyo, Five Prime Therapeutics, Amgen, Innovent biologics, Dragonfly Therapeutics, Oxford Biotherapeutics, Arcus Therapeutics, and KAHR Medical; and participation as a data safety monitoring board chair for Arcus Therapeutics. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Yu J, Saeed A. PD-L1 as a predictive biomarker for pembrolizumab in HER2-positive gastric or gastro-esophageal junction adenocarcinoma—a commentary on KEYNOTE-811. Chin Clin Oncol 2024;13(4):59. doi: 10.21037/cco-24-28

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