Impact of the timing of immunotherapy administration on overall survival for resectable non-small cell lung cancer (iACORN study): A systematic review and meta-analysis of randomised trials

Abstract

Background: We sought to investigate the relative impact of the timing of the administration of immunotherapy on survival in patients with resectable lung cancer.

Methods: We conducted a systematic review and meta-analysis of randomised controlled trials in this setting. We searched MEDLINE, EMBASE, LILACS and Cochrane Library databases from 1st January 1980 onwards. We excluded case reports; non-randomised studies; studies without an immunotherapy arm and if there was incomplete reporting on outcome data including conference abstracts. A standardised, pre-piloted form was used to extract data from the included studies for the assessment of study quality and for evidence synthesis. The primary outcome measure was overall survival which was assessed using random-effects meta-analyses (DerSimonian and Laird). The study was registered with PROSPERO (CRD42023407825).

Findings: We screened 865 studies and assessed 58 full text articles after removing non-human, non-surgical studies. These studies collectively enrolled 4982 participants and 4425 were included in the respective analyses. Hazard ratios (HRs) for death by timing of administration of immunotherapy, i.e., Neoadjuvant (pre-operative), peri-operative and post-operative were 0.57 (95 % CI 0.302-1.08), 0.67 (95 % CI 0.39-1.13) and 0.94 (95 % CI 0.29-3.06) respectively. The timing of administration accounted for 100 % of the difference in true effect size (test of moderators (QM p = 0.127), residual I2 0 %, p = 0.561). OR for adverse events was higher in the neoadjuvant setting compared to the peri-operative setting; 1.49 (0.64-3.47) and 1.34 (1.08-1.66) respectively. Bias assessment found the majority of studies to be low risk with respect to random sequencing, incomplete outcomes, and selective reporting.

Interpretation: In resectable non-small cell lung cancer, administration of adjuvant chemo-immunotherapy regimens in clinical trials did not lead to statistically significant survival benefits. Overall survival outcomes of neoadjuvant and peri-operative chemo-immunotherapy were comparable, but given the shorter duration and lower costs, neoadjuvant chemo-immunotherapy can be considered the current multimodality combination of choice.