Safety profiles of current and emerging neoadjuvant immune-modulatory and combination strategies in borderline resectable stage III non-small cell lung cancer: a narrative review
- 1Department of Thoracic Surgery, Guy’s and St Thomas’ NHS Foundation Trust
- 2Department of Medicine, London Northwest University Healthcare NHS Trust
- 3Institute of Immunology and Immunotherapy, University of Birmingham
Abstract
Borderline resectable stage III non-small cell lung cancer (NSCLC) has no consensus definition. In an international multidisciplinary survey of stage III TNM subsets, no agreement on resectability was reached for 11 of 37 subsets, and the multisocietal consensus exercise conducted alongside it left the same anatomical configurations unresolved. This review adopts those non-consensus subsets as its working definition and asks how the safety profiles of current and emerging neoadjuvant immune-modulatory and combination strategies, spanning PD-1 and PD-L1 blockade, emerging checkpoint and immune-metabolic targets, antibody-drug conjugates and bispecific antibodies, bear on surgical decision-making within them. Six phase 3 trials now support neoadjuvant or perioperative PD-1 or PD-L1 blockade with platinum doublet chemotherapy in resectable disease, with pathological complete response rates of 17.2%–40.7% and event-free survival hazard ratios of 0.40–0.68. Grade 3 or higher treatment-related adverse events ranged from 32.5% to 73.0%, immune-mediated adverse events from 25.3% to 42.1% where an aggregate was reported, and treatment-related cancellation of surgery remained below 2% in every trial reporting it. Most patients who never reached resection did so for reasons other than toxicity. Among emerging targets, monospecific TIGIT blockade has failed in three randomised settings and the most advanced TIM-3 programme was discontinued on company-reported evidence, which recontextualises the earlier phase 2 signals for both classes. NKG2A, CD73 and TROP2-directed combinations have produced neoadjuvant pathological response signals without loss of surgical feasibility, although each rests on a single-arm platform cohort of fewer than 80 patients. One PD-1 and VEGF bispecific antibody has positive peer-reviewed phase 3 data in advanced disease and no neoadjuvant data. The operative question in borderline resectable disease is not whether response rates rise but whether toxicity, surgical delay and functional decline shift the risk-benefit balance in patients already marginal for resection. Answering it requires prospective cohorts in which borderline status is defined before treatment, of which MDT-BRIDGE and NEOINSPIRE are the first.
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BibTeX
@article{berjaoui2026safety,
title = {{Safety profiles of current and emerging neoadjuvant immune-modulatory and combination strategies in borderline resectable stage III non-small cell lung cancer: a narrative review}},
author = {Nabih Berjaoui and Yee Tung (Ruby) Siu and Andrea Bille and Akshay J. Patel},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1929734},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1929734/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Safety profiles of current and emerging neoadjuvant immune-modulatory and combination strategies in borderline resectable stage III non-small cell lung cancer: a narrative review
AU - Nabih Berjaoui
AU - Yee Tung (Ruby) Siu
AU - Andrea Bille
AU - Akshay J. Patel
PY - 2026
DA - 2026/10/23
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1929734
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1929734/full
AB - Borderline resectable stage III non-small cell lung cancer (NSCLC) has no consensus definition. In an international multidisciplinary survey of stage III TNM subsets, no agreement on resectability was reached for 11 of 37 subsets, and the multisocietal consensus exercise conducted alongside it left the same anatomical configurations unresolved. This review adopts those non-consensus subsets as its working definition and asks how the safety profiles of current and emerging neoadjuvant immune-modulatory and combination strategies, spanning PD-1 and PD-L1 blockade, emerging checkpoint and immune-metabolic targets, antibody-drug conjugates and bispecific antibodies, bear on surgical decision-making within them. Six phase 3 trials now support neoadjuvant or perioperative PD-1 or PD-L1 blockade with platinum doublet chemotherapy in resectable disease, with pathological complete response rates of 17.2%–40.7% and event-free survival hazard ratios of 0.40–0.68. Grade 3 or higher treatment-related adverse events ranged from 32.5% to 73.0%, immune-mediated adverse events from 25.3% to 42.1% where an aggregate was reported, and treatment-related cancellation of surgery remained below 2% in every trial reporting it. Most patients who never reached resection did so for reasons other than toxicity. Among emerging targets, monospecific TIGIT blockade has failed in three randomised settings and the most advanced TIM-3 programme was discontinued on company-reported evidence, which recontextualises the earlier phase 2 signals for both classes. NKG2A, CD73 and TROP2-directed combinations have produced neoadjuvant pathological response signals without loss of surgical feasibility, although each rests on a single-arm platform cohort of fewer than 80 patients. One PD-1 and VEGF bispecific antibody has positive peer-reviewed phase 3 data in advanced disease and no neoadjuvant data. The operative question in borderline resectable disease is not whether response rates rise but whether toxicity, surgical delay and functional decline shift the risk-benefit balance in patients already marginal for resection. Answering it requires prospective cohorts in which borderline status is defined before treatment, of which MDT-BRIDGE and NEOINSPIRE are the first.
SN - 1663-9812
ER -