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Neoadjuvant Immunotherapy for Non-Small Cell Lung Cancer

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Abstract

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced non-small cell lung carcinoma (NSCLC). Building off of this, it has been hypothesized that the utilization of ICB early during the disease course may be advantageous, particularly in the neoadjuvant setting prior to definitive surgical resection. Preclinical studies have suggested that a more potent immune response may be induced by neoadjuvant ICB in the presence of a higher antigen burden and intact tumor draining lymph nodes. Recent clinical trials evaluating neoadjuvant ICB with or without chemotherapy combinations in patients with resectable NSCLC led to improved pathological responses and longer event-free survival when neoadjuvant ICB was added to chemotherapy. Surgical outcomes were also supportive of this approach, with encouraging rates of pathological downstaging. Additionally, the availability of pre-treatment biopsy samples and post-treatment surgical resection tissues facilitates the conducting of correlative studies that continue to improve our understanding of the mechanisms of response and resistance to ICB. As long-term survival outcomes from ongoing clinical trials are awaited, several important questions require further investigation, including the optimal duration of neoadjuvant therapy, the clinical endpoints most predictive of long-term outcomes, and translational studies that should be investigated in future trial designs. Additionally, the optimal clinical management of patients with residual disease at the time of surgical resection and those who experience recurrence remains to be determined. In this review, we will (1) discuss the rationale behind neoadjuvant ICB-based therapy in NSCLC, (2) summarize the clinical data available thus far, and (3) highlight unanswered questions that need to be addressed in future studies to maximize the clinical benefits of this approach.

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Fig. 1

Source: Adapted from “Overview of Metastatic Cascade,” by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates

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  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 301 Mason Lord Drive, Suite 4500, Baltimore, MD, 21224, USA

    Khaled Sanber, Samuel Rosner, Patrick M. Forde & Kristen A. Marrone

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  1. Khaled Sanber
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  2. Samuel Rosner
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Correspondence to Kristen A. Marrone.

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KS, SR, PMF, and KAM all (1) contributed to the design of the article, or the acquisition, analysis, or interpretation of data for the article AND (2) drafted the article or revised it critically for important intellectual content AND (3) approved the version to be published.

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KS: R37 CA251447/CA/NCI NIH HHS/United States; SR: American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award; KAM: LUNGevity Career Development Award

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KS and SR declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. PMF: Consult/Advisory: AstraZeneca, Bristol-Myers Squibb, Genetech, Merck, Novartis, Janssen, G1, Iteos, Daiichi-Sankyo, F Star, Gritsone, Enable; DSMB: Polaris; Research funding: AstraZeneca, Bristol-Myers Squibb, Novartis, Regeneron, BioNTech; KAM: Consult/Advisory: Daiichi-Sankyo, Regeneron, Janssen, Mirati, Puma, AstraZeneca; Research funding: Mirati, Bristol-Myers Squibb.

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Sanber, K., Rosner, S., Forde, P.M. et al. Neoadjuvant Immunotherapy for Non-Small Cell Lung Cancer. BioDrugs 37, 775–791 (2023). https://doi.org/10.1007/s40259-023-00614-5

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