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Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC

Abstract

The treatment landscape of driver-negative non-small-cell lung cancer (NSCLC) is rapidly evolving. Immune-checkpoint inhibitors, specifically those targeting PD-1 or PD-L1, have demonstrated durable efficacy in a subset of patients with NSCLC, and these agents have become the cornerstone of first-line therapy. Approved immunotherapeutic strategies for treatment-naive patients now include monotherapy, immunotherapy-exclusive regimens or chemotherapy–immunotherapy combinations. Decision making in this space is complex given the absence of head-to-head prospective comparisons, although a thorough analysis of long-term efficacy and safety data from pivotal clinical trials can provide insight into the optimal management of each subset of patients. Indeed, histological subtype and the extent of tumour cell PD-L1 expression are paramount to regimen selection, although other clinicopathological factors and patient preferences might also be relevant in certain scenarios. Finally, several emerging biomarkers and novel therapeutic strategies are currently under investigation, and these might further refine the current treatment paradigm. In this Review, we discuss the current treatment landscape and detail our approach to first-line immunotherapy regimen selection for patients with advanced-stage, driver-negative NSCLC.

Key points

  • For patients with advanced-stage NSCLC lacking a targetable driver alteration, anti-PD-1/PD-L1 antibodies are now the cornerstone of first-line therapy.

  • Anti-PD-1/PD-L1 antibody-containing regimens can be broadly classified as immunotherapy-exclusive or chemotherapy–immunotherapy combinations, although all therapies or regimens have received approval based on their superiority to platinum-doublet chemotherapy; head-to-head comparisons of efficacy are currently lacking.

  • Tumour cell PD-L1 expression remains the most robust clinical predictor of response to anti-PD-1/PD-L1 antibodies, although we envision the future integration of various other novel biomarkers for a more personalized approach to immunotherapy selection.

  • First-line anti-PD-1/PD-L1 antibodies as monotherapies are favoured for most patients with advanced-stage NSCLC with high levels of tumour cell PD-L1 expression (≥50%) that lack a targetable driver alteration.

  • For patients with low or absent PD-L1 expression, or those with high PD-L1 expression with an immediate need for cytoreduction, combination regimens containing anti-PD-1/PD-L1 antibodies plus histology-selected platinum-doublet chemotherapies are favoured.

  • Trials seeking to refine the existing treatment strategies and integrate novel therapies to enhance the efficacy of currently approved agents are currently ongoing.

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Fig. 1: Milestone overall survival outcomes for select immunotherapy-based regimens as first-line therapies for driver-negative NSCLC.
Fig. 2: Incidence of selected toxicities among patients receiving first-line immunotherapy-based regimens for advanced-stage NSCLC.
Fig. 3: Immunotherapy-based management of patients with advanced-stage driver-negative NSCLC.
Fig. 4: Existing and emerging therapeutic targets for NSCLC.

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Sarah B. Goldberg.

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S.B.G. has acted as a consultant of AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Blueprint Medicine, Daiichi–Sankyo, Genentech, Janssen, Regeneron, Sanofi-Genzyme and Takeda, and has received research funding from AstraZeneca and Boehringer Ingelheim. R.S.H. has acted as a consultant of Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Biodesix, Bolt Biotherapeutics, Bristol–Myers Squibb, Cybrexa Therapeutics, DynamiCure Biotechnology, eFFECTOR Therapeutics Inc., Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Johnson and Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Refactor Health, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals Inc., Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems and WindMIL Therapeutics, has served on the advisory boards of AstraZeneca, Bolt Biotherapeutics, Candel Therapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Neon Therapeutics, Novartis, Ocean Biomedical, Ribbon Therapeutics, STCube Pharmaceuticals Inc, and Xencor, and has received research funding from AstraZeneca, Eli Lilly and Company, Genentech/Roche, and Merck and Company, is a Board Member (non-executive/independent) for Immunocore Holdings Limited and Junshi Pharmaceuticals, and is a member of the Board of Directors for the International Association for the Study of Lung Cancer and the American Association for Cancer Research. M.J.G. declares no competing interests.

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Nature Reviews Clinical Oncology thanks M. Garassino, T. Mok and M. Reck for their contribution to the peer review of this work.

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Grant, M.J., Herbst, R.S. & Goldberg, S.B. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-021-00520-1

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