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Immunotherapy in Gastroesophageal Cancers: Current Evidence and Ongoing Trials

  • Upper Gastrointestinal Cancers (JD Berlin, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Data supporting the use of immunotherapy in the treatment of gastroesophageal cancer continues to evolve. The promising results from adjuvant immunotherapy and trials combining immunotherapy plus chemotherapy in the 1L setting have led to broad US FDA approvals. Among the PD-L1 negative subgroups, the magnitude of benefit is diminished; effective therapy for this population remains an unmet need. A detailed biologic understanding of the PD-L1 negative (and low) population represents a barrier to developing effective combination therapies, although combination angiogenesis inhibitors and immunotherapy look encouraging. Early phase clinical trials, particularly with pembrolizumab plus lenvatinib (EPOC 1706), demonstrated a clear signal independent of PD-L1, and a confirmatory phase III trial of pembrolizumab plus lenvatinib is planned. Conceptually, it is important to think of immune checkpoint inhibitor therapy as targeted therapy, most active in clearly defined biomarker-selected populations. Pre-planned analyses have reliably shown a clear trend toward a greater magnitude of benefit in patients with higher PD-L1 expression, particularly CPS ≥ 5 and ≥ 10. Whether there is a linear relationship at higher cutoffs is not well known, though it likely represents smaller and smaller populations. Although beyond the scope of this clinically oriented review, recognition of the spatial and temporal heterogeneity in PD-L1 expression is important and repeat testing from progression samples across lines of therapy should be considered. Questions about additional predictive biomarkers, particularly plasma-derived, remain. Responses by tumor histology and location also differ, and special attention to these factors as well as MSI-H, HER2, and EBV subgroups in future trials is warranted. Questions regarding the incorporation of immunotherapy after progression on 1L immunotherapy plus chemotherapy combinations will arise as these combinations are used more frequently, and this represents a key area of future investigation. Overall, the role of immunotherapy continues to expand in GEA, and we welcome any additional tools for this difficult-to-treat group of cancers.

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Funding

AGA Research Foundation’s AGA-Gastric Cancer Foundation Ben Feinstein Memorial Research Scholar Award in Gastric Cancer—AGA2020-13-02 (SJK), and Stand-Up-2-Cancer Gastric Cancer Interception Award (SJK).

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Authors and Affiliations

  1. University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Jasmine Huynh MD & Kanishka Patel MD

  2. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CA, USA

    Jun Gong MD

  3. University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA

    May Cho MD

  4. West Virginia Cancer Institute, Morgantown, WV, USA

    Midhun Malla MD

  5. Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA

    Aparna Parikh MD & Samuel Klempner MD

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Contributions

J.H. and K.P. performed the primary literature search and prepared the manuscript. S.J.K. conceived the concept for this manuscript and provided meaningful feedback and guidance on the manuscript. J.G., M.C., M.M., and A.P. critically revised the work.

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Correspondence to Samuel Klempner MD.

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Conflict of interest

Jasmine Huynh declares that she has no conflict of interest. Kanishka Patel declares that she has no conflict of interest. Jun Gong has received compensation for service as a consultant from Exelixis, QED Therapeutics, Elsevier, Basilea, and HalioDx. May Cho has received compensation for service on advisory boards for Amgen, Eisai, Taiho, Astellas, Exelixis, Ipsen, Seagen, QED Therapeutics, AstraZeneca, Basilea, and Genentech/Roche, and serves on the speaker’s bureau for Pfizer and Taiho. Midhun Malla is supported, in part, by a grant from the NIH National Institute of General Medical Sciences (Grant #5U54GM104942-05); and has received compensation for service as a consultant/advisor from AstraZeneca, QED Therapeutics, Omni Health, and Curio Science. Aparna Parikh has received institutional research funding from PureTech Health, PMV Pharmaceuticals, Plexxikon, Takeda, Bristol-Myers Squibb, and Novartis; has received compensation for service as a consultant/advisor from Natera, Foundation Medicine, PureTech Health, Checkmate Pharmaceuticals, Eli Lilly, and Pfizer; serves on the DSMC for Roche; and holds equity in C2i Genomics. Samuel Klempner has received compensation for service as a consultant/advisor from Eli Lilly, Bristol-Myers Squibb, Merck, Astellas, Daiichi-Sankyo, Natera, and Pieris, and owns stock/equity in Turning Point Therapeutics.

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Huynh, J., Patel, K., Gong, J. et al. Immunotherapy in Gastroesophageal Cancers: Current Evidence and Ongoing Trials. Curr. Treat. Options in Oncol. 22, 100 (2021). https://doi.org/10.1007/s11864-021-00893-6

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