Sequential chemo-immunotherapy followed by standard versus reduced thoracic radiotherapy for older and/or frail stage III non-small-cell lung cancer: A randomized open-label cohort trial

Clinical Snapshot

Key Findings

• P Value: Not reported (non-comparative design)

• Effect Size: 13.6% absolute difference in 1-year PFS favoring standard RT

• Primary Outcome: 1-year progression-free survival: 84.3% (standard RT) vs 70.7% (reduced RT)

• Nnt Or Sensitivity: Cannot calculate NNT due to overlapping confidence intervals and non-comparative design

• Confidence Interval: Standard RT: 95% CI [70.3%, 98.3%]; Reduced RT: 95% CI [54.3%, 87.1%]

Clinical Application

Sequential approach may be more feasible than concurrent treatment in frail patients; reduced RT potentially decreases treatment burden Relevant to Australian practice where treatment decisions for older cancer patients increasingly consider frailty assessments; aligns with COSA guidelines for individualized care in older adults Older adults (≥70 years) and/or frail patients with stage III unresectable NSCLC who are unsuitable for concurrent chemoradiotherapy

Abstract

BACKGROUND: The appropriateness of concurrent chemoradiotherapy (cCRT) for older or clinically vulnerable stage III unresectable non-small-cell lung cancer (NSCLC) patients remains contentious. Furthermore, the survival implications of de-escalating thoracic radiotherapy (RT) intensity in this population have not been conclusively elucidated. METHODS AND FINDINGS: We conducted a phase II randomized, open-label, two-cohort (non-comparative) trial at a tertiary hospital in China (NCT05557552). Between September 30, 2022 and April 30, 2024, we enrolled 56 older and/or frail patients with stage III NSCLC who were ineligible for cCRT. The primary endpoint was the 1-year progression-free survival (PFS) rate estimated using the Kaplan-Meier method. Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. In the intention-to-treat (ITT) set, which included all 56 randomized patients who received at least one dose of study treatment, the 1-year PFS was 84.3% (95% confidence interval [CI] [70.3%, 98.3%]) in the standard RT group and 70.7% (95% CI [54.3%, 87.1%]) in the reduced RT group. In the per-protocol set (53 patients), the 1-year PFS was 82.9% (95% CI [68.9%, 98.8%]) in the standard RT group and 73.4% (95% CI [58.3%, 92.4%]), with a median follow-up of 24 months. Among 56 patients in the safety analysis set, 71.4% of patients experienced grade 3/4 adverse events (AEs) in the standard RT group and 53.6% in the reduced RT group. One patient (3.6%) in the reduced RT and three patients (10.7%) in the standardized RT experienced grade 5 AEs. The main limitations are the non-comparative design, small sample size, and lack of power to establish non-inferiority or superiority. CONCLUSION: The current study suggested that reduced RT combined with sequential chemo-immunotherapy might be feasible for older/frail patients intolerant to cCRT, showing numerically similar survival outcomes. These exploratory findings warrant confirmation in larger, adequately powered randomized trials. TRIAL REGISTRATION: The trial had been registered on ClinicalTrials.gov on Sep 30, 2022. ClinicalTrials.gov NCT05557552.

References

1. 1.Qi, W. X., Li, S., Wang, M., Li, H., Xu, F., Yao, L., Yu, B., Chen, L., Cai, G., Xu, C., Sun, X., Bao, Z., Chen, J., Xiang, Y., & Zhao, S. (2026). Sequential chemo-immunotherapy followed by standard versus reduced thoracic radiotherapy for older and/or frail stage III non-small-cell lung cancer: A randomized open-label cohort trial. *PLoS Medicine*, *23*(5), e1005111. https://doi.org/10.1371/journal.pmed.1005111