Chemoimmunotherapy Improves Survival in PD-L1-High NSCLC; Chronotherapy Trial Retracted

First-line chemoimmunotherapy was associated with significantly longer overall survival and progression-free survival compared with PD-(L)1 inhibitor monotherapy in patients with untreated advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression (≥50%), according to a systematic review and meta-analysis of 24 phase 3 randomized clinical trials involving more than 5,500 patients. In a separate development, a randomized phase 3 trial on time-of-day immunochemotherapy in NSCLC has been retracted from Nature Medicine after editors lost confidence in the integrity of the results.

The meta-analysis, published in JAMA Oncology, found a median progression-free survival of 11.3 months with chemoimmunotherapy versus 6.8 months with immunotherapy alone (hazard ratio [HR] 0.67) and overall survival of 29.2 versus 19.8 months (HR 0.74). The benefits persisted across multiple analytic methods, including reconstructed individual patient data and sensitivity analyses with long-term follow-up. Results were consistent regardless of analytic approach, suggesting a robust advantage for chemoimmunotherapy in this population. However, treatment-related adverse events and discontinuation rates were higher with chemoimmunotherapy. The findings suggest that first-line combination chemoimmunotherapy may provide greater clinical benefit than immunotherapy monotherapy for patients with high PD-L1 advanced NSCLC, pending results of direct comparative trials.

A post-hoc analysis of the PACIFIC trial in stage III NSCLC found that the use of proton pump inhibitors or antibiotics was linked to worse outcomes in patients receiving durvalumab, but not in those on placebo, suggesting these common drugs may weaken the benefits of immune checkpoint inhibitors.

A systematic review and meta-analysis of 10 randomized controlled trials including 3,081 patients examined PD-(L)1 rechallenge in advanced NSCLC previously treated with immunotherapy. Rechallenge provided modest overall survival (HR 0.91) and progression-free survival (HR 0.89) benefits, with no objective response rate improvement. No benefit was observed in primary resistance, while patients with acquired resistance appeared more likely to benefit (overall survival HR 0.86). The analysis indicated that resistance phenotype matters.

Real-world evidence from the I-STOP study of 173 patients with advanced NSCLC who achieved disease control after at least 24 months of single-agent PD-1/PD-L1 therapy showed no overall survival difference between stopping and continuing treatment (HR 1.22; 95% CI 0.50–2.95; p=0.66), although the risk of progression was higher after discontinuation (HR 2.16; 95% CI 1.04–4.48; p=0.035). Subgroups at higher risk if stopping included those with PD-L1 ≤50%, brain metastases, ECOG performance status ≥1, and KRAS mutations. ICI rechallenge was effective, with a 62.5% response rate in relapsing patients, and late grade 3–4 immune-related adverse events were uncommon (3.5%).

The retraction note for the time-of-day immunochemotherapy trial, originally published in Nature Medicine, states that the editors no longer have confidence in the integrity of the results. Concerns included substantial changes made to the study registration on ClinicalTrials.gov (NCT05549037), with key elements including endpoints, eligibility criteria, sample size, and study design inconsistently reported and modified over time. In addition, the translated version of the study protocol was dated 2022 but contained references to studies published in 2023 and 2024. Other discrepancies were identified between the original Chinese protocol and translated versions. There were also concerns surrounding unexpected data patterns, including the shape of the progression-free survival curve, absence of censoring in the first year, absence of adverse events leading to treatment discontinuation, and similar rates of immune-related adverse events in the two arms despite differences in therapeutic efficacy. The source data indicated that randomization was performed on the day of treatment for almost all patients, and there were deviations from fixed-calendar imaging schedules due to COVID-19-related delays, indicating a lack of adherence to standard RECIST timing recommendations.