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At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC

Abstract

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1–PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.

Key points

  • In the era of immuno-oncology, emerging evidence indicates that driver oncogenes have different effects on the immune tumour microenvironment that influence the potential for clinical benefit from treatment with immune-checkpoint inhibitors (ICIs).

  • Patients with non-small-cell lung cancer (NSCLC) harbouring BRAF mutations or KRAS and TP53 co-mutations benefit the most from ICIs, whereas EGFR mutations or ALK or ROS1 rearrangements are commonly associated with lower tumour PD-L1 levels and mutational burdens, limited immune infiltration of the tumour microenvironment and resistance to ICIs.

  • Understanding factors resulting in resistance to ICIs is crucial for developing approaches for (re-)sensitizing tumours to these immunotherapies.

  • A meaningful understanding of NSCLC genomics and immunophenotypes might provide a stratification for the selection of patients most likely to benefit from ICI-based therapies.

  • Combination strategies with agents targeting oncogenic signalling-related immune-inhibitory mechanisms might increase tumour immunogenicity and sensitize oncogene-driven NSCLC to ICIs.

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Fig. 1: Oncogenic driver diversity of advanced-stage LUAD and associated clinical responses to ICIs.
Fig. 2: Summary of the immune landscape of oncogene-driven LUADs and potential therapeutic strategies.

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Acknowledgements

The work of I.O. is supported by The Spanish Association Against Cancer (AECC) Investigator fellowship award 2020. The L.P.-A. laboratory is supported by grants from Fundación CRIS Contra El Cáncer (2021/0091), Instituto de Salud Carlos III (PI20/00870 and AC20/00070), AECC (2018/0145/A) and Asociación Española de Alpinistas con Cáncer (2021/0157).

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I.O. conceived the article, I.O.; A.C.U. and J.Z. wrote the manuscript with critical input from L.P.-A.; A.C.U. and I.O. prepared displayed items under the supervision of L.P.-A.; J.Z. prepared the tables under the supervision of L.P.-A. All authors approved the final version of the article.

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Correspondence to Itziar Otano or Luis Paz-Ares.

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Competing interests

I.O. declares no competing interests. A.C.U. has received honoraria for participation at meetings from AstraZeneca Spain. J.Z. has received honoraria for participation at meetings from AstraZeneca Spain, Bristol Myers Squibb/Celgene, Guardant Health, NanoString Technologies, Pfizer and Roche/Genentech; speakers’ bureau fees from AstraZeneca, Bristol Myers Squibb/Celgene, Guardant Health, MSD Oncology, NanoString Technologies, Pfizer, and Roche; research funding (via his institution) from AstraZeneca and Roche/Genentech; travel and accommodation expenses from Bristol Myers Squibb/Celgene; and declares consultancy or advisory roles with AstraZeneca, Bristol Myers Squibb/Celgene, Guardant Health, Novartis and Pfizer. L.P.-A. has leadership interest (board member) in ALTUM Sequencing and Genomica; has received honoraria for participation at meetings from Amgen Sanofi, AstraZeneca Spain, Bayer, Blueprint Medicines, Bristol Myers Squibb/Celgene, Daiichi Sankyo, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, Novartis, Pfizer, PharmaMar, Roche/Genentech, Servier and Takeda; speakers’ bureau fees from AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD Oncology, Pfizer and Roche/Genentech; research funding (via his institution) from AstraZeneca, Bristol Myers Squibb, Kura Oncology, MSD, Pfizer and PharmaMar; and travel and accommodation expenses from AstraZeneca, Bristol Myers Squibb/Celgene, MSD, Pfizer Roche/Genentech and Takeda. L.P-A. also declares other relationships with Amgen, Ipsen, Merck, Novartis, Pfizer, Roche, Sanofi and Servier (as sponsors of clinical trials).

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Otano, I., Ucero, A.C., Zugazagoitia, J. et al. At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC. Nat Rev Clin Oncol (2023). https://doi.org/10.1038/s41571-022-00718-x

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