Since 2012 when immune checkpoint inhibitors reported the first signals of activity in advanced non–small cell lung cancer (NSCLC),^1,2 immunotherapy has progressively revolutionized the therapeutic landscape of this disease moving from pretreated metastatic disease to earlier stages, including the resectable setting.³ Platinum-based chemotherapy has been the mainstay of treatment for early-stage NSCLC over the last few decades with a modest but clinically significant survival advantage of approximately 5% at 5 years either as adjuvant⁴ or neoadjuvant therapy.⁵ However, long-term outcomes of resected NSCLC are still modest, and a significant percentage of patients’ disease still recurs after a curative intent treatment. The feasibility and safety of neoadjuvant immunotherapy was first evaluated in a small seminal pilot study⁶ with nivolumab monotherapy in 2018. Neoadjuvant single agent programmable cell death-1 (PD-1) blockage with nivolumab at a dose of 3 mg/kg every 2 weeks and surgery planned approximately 4 weeks after the first dose was feasible with few adverse events and no surgery delay, and induced a major pathological response (MPR) in 45% of resected stage I-IIIA tumors, with responses occurring in both programmed cell death ligand 1 (PD-L1)–positive and PD-L1–negative tumors. This prompted the design of several phase II/III trials evaluating different immunotherapy-based regimens including single-agent PD-1/PD-L1 inhibitors, dual-checkpoint blockage with PD-1/CTLA-4 inhibitors and chemoimmunotherapy combinations. Among these strategies, chemoimmunotherapy has emerged as the most promising in terms of efficacy and tolerability, as chemotherapy-free regimens are collectively associated with lower overall response rates and MPR rates.⁷

In JAMA Oncology, Sorin et al⁸ reported the results of a meta-analysis comparing chemoimmunotherapy with chemotherapy alone in resectable NSCLC. Data of 4045 patients from 39 eligible studies, including 5 randomized clinical trials, were analyzed, showing that neoadjuvant chemoimmunotherapy was superior to chemotherapy alone in terms of overall survival (OS) (hazard ratio [HR], 0.65), event-free survival (EFS) (HR, 0.59), MPR (risk ratio [RR], 3.42), and complete pathological response (pCR) (RR, 5.52).⁸ EFS benefit was observed regardless of disease age (HR, 0.54 in patients <65 years and HR, 0.66 in patients ≥65 years), sex, histology (squamous vs nonsquamous), and PD-L1 expression, including PD-L1–negative tumors (HR, 0.74; 95% CI, 0.62-0.89; I²â€‰= 0%), albeit the magnitude of benefit was higher in PD-L1 of 1% to 49% (HR, 0.56; 95% CI, 0.42-0.73; I²â€‰= 41.3%) and PD-L1 strong expressors (HR, 0.40; 95% CI, 0.28-0.56; I²â€‰= 32.1%).

The role of neoadjuvant chemoimmunotherapy in PD-L1–negative tumors is one of the most significant data emerging from the present meta-analysis.⁸ This is particularly relevant, given the recent restriction of neoadjuvant chemoimmunotherapy with nivolumab to patients with PD-L1 more than 1% by the European Medicine Agency, based on the subgroup analysis of the CheckMate-816 study⁹ demonstrating a lower EFS, OS, pCR, and MPR benefit in patients with a tumor PD-L1 expression level less than 1% compared with those with a tumor PD-L1 expression of 1% or higher. A similar trend of higher efficacy for neoadjuvant chemoimmunotherapy with increasing PD-L1 expression was observed also in the 2 perioperative randomized phase 3 trials AEGEAN¹⁰ and KEYNOTE-671,¹¹ suggesting that activity of these combinations is independent of tumor PD-L1 expression. A longer follow-up of these studies should confirm these findings and whether the survival benefit seen in these patients might be considered clinically significant. To date, the only study with a 3-year follow-up, the CheckMate-816 study, exceeds the more than 5% improvement of survival at 3 years’ follow-up or longer, which is the threshold considered by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 for scoring the highest grade for new potentially curative therapies,¹² in both PD-L1–negative (OS rate at 3 years 71% vs 60% for chemoimmunotherapy and chemotherapy alone, respectively) and PD-L1–positive tumors (OS rate at 3 years 84% vs 68%).⁹ Furthermore, the present meta-analysis confirmed the significant EFS benefit for chemoimmunotherapy in both patients with stage II (HR, 0.71; 95% CI, 0.55-0.92; I²â€‰= 0%) and patients with stage III (HR, 0.54; 95% CI, 0.48-0.62; I²â€‰= 0%).⁸ Future meta-analyses should also address a clinically relevant question regarding the utility of the adjuvant part of perioperative regimens, such as those evaluated in AEGEAN,¹⁰ KEYNOTE-671,¹¹ and CheckMate 77T,¹³ compared with neoadjuvant chemoimmunotherapy alone without postoperative therapies, such as the CheckMate 816 regimen.⁹ Approximately 15% to 20% of the patients undergoing neoadjuvant chemoimmunotherapy do not proceed to surgical resection due to disease progression, adverse events, or other causes.^9-11,13 This subgroup of patients is not well defined, and it is unclear if alternative therapeutic strategies might be more effective, such as, for example, upfront surgery followed by adjuvant chemotherapy and immunotherapy. For instance, in the IMpower010, adjuvant atezolizumab for year following postoperative platinum-based chemotherapy was associated with a 3-year EFS rate of 75.1% in stage II-IIIA EGFR/ALK wild-type PD-L1 tumor PD-L1 expression 50% or more, which is the approved indication in Europe. These data are quite similar to the 71% EFS rate at 3 years with neoadjuvant nivolumab plus chemotherapy in the CheckMate 816 in stage II-IIIA NSCLC PD-L1 1% or more,⁹ raising the question of which is the best therapeutic strategy in these patients.

An important aspect of novel neoadjuvant therapies is the impact on planned surgery in terms of delays, type of surgery, and complications. Collectively, the results of the present meta-analysis⁸ suggest that neoadjuvant chemoimmunotherapy is safe, with no significant differences in the relative risk for grade 3 to 4, grade 5, and total adverse events compared with chemotherapy alone. Surgical outcomes were comparable, with an advantage for neoadjuvant chemoimmunotherapy in terms of increased relative risk of undergoing surgery (RR, 1.05; 95% CI, 1.02-1.09; I²â€‰= 31.8%) and R0 resection (RR, 1.05; 95% CI, 1.03-1.08; I²â€‰= 0%), suggesting that this strategy might increase the chances of curative-intent surgery.

MPR (10% or less residual viable tumor after neoadjuvant chemotherapy) has been proposed as a surrogate end point for survival in neoadjuvant trials of resectable lung cancers¹⁴ and was evaluated in most of the neoadjuvant studies with chemoimmunotherapy as an exploratory end point together with pCR. The results of the present meta-analysis showed that the relative risk for both MPR and pCR was significantly increased for neoadjuvant chemoimmunotherapy in randomized clinical trials.⁸ Whether patients with pCR and/or MPR could benefit from deintensified regimens (for example, neoadjuvant chemoimmunotherapy without postoperative immunotherapy) compared with those not reaching a pCR/MPR still remains unclear.

Recently, liquid biopsy has emerged as a potential novel biomarker for minimal residual disease (MRD) detection, identifying patients at higher risk of relapse after surgery and might be used for selecting patients to escalating or de-escalating therapeutic strategies.¹⁵ Further prospective studies will be necessary to assess the role of circulating tumor DNA levels as surrogate end point of efficacy to neoadjuvant therapies in resectable NSCLC and whether preoperative and postoperative circulating tumor DNA detection might allow patients selection to the most appropriate therapeutic strategies. The availability of tissue for tumor whole-exome sequencing after surgery can allow the implementation of tumor-informed strategies for MRD detection during treatment follow-up, tracking in the blood unique variant panels built for each patient, based on the specific mutation profile of the tumor. The most significant challenge for clinical implementation of liquid biopsy in this setting is the high heterogeneity of the assays used to date and the relatively still low sensitivity to detect MRD-positive patients. Integration of multiomics analyses, combining genomics, methylomics or fragmentomics, can increase the sensitivity of currently available tests, reducing the risk of false-negative results. Finally, the integration with other known prognostic and/or predictive factors, such as MPR/pCR, PD-L1 expression, and clinical other clinicopathological features (spread though air spaces, lymphovascular invasion, etc) will likely further refine the accuracy of these assays, favoring the implementation of risk scores that can drive the therapeutic decision-making.

Corresponding Author: Christian Rolfo, MD, PhD, MBA, Drhc, Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, 1470 Madison Ave, New York, NY 10029 (christian.rolfo@mssm.edu).

Published Online: March 21, 2024. doi:10.1001/jamaoncol.2024.0043

Conflict of Interest Disclosures: Dr Rolfo reported speaker honoraria from AstraZeneca, Roche, and MSD; honoraria for serving on advisory boards of Bayer, Inivata, Archer, Boston Pharmaceuticals, MD Serono, Novartis, Bostongene, Invitae, Regeneron, and Imagene Scientific; institutional research funding from Pfizer, NCRF, and EMD Serono; nonfinancial support from GuardantHealth and Foundation Medicine outside the submitted work; and nonrenumerated leadership roles at the International Society of Liquid Biopsy, the International Association for Study of Lung Cancer, the European School of Oncology, and Oncology Latin American Association. Dr Russo reported advisory board and speaker honoraria and compensated activity for editorial projects from AstraZeneca, MSD, and Novartis; advisory board honoraria from BMS, Amgen, and Pfizer; and personal fees from Roche for compensated activity for editorial projects outside the submitted work.