PD-(L)1 containing rechallenge strategies in patients with advanced NSCLC previously treated with immunotherapy: A systematic review and meta-analysis across resistance phenotypes

INTRODUCTION: Even though PD-(L)1 inhibitors have dramatically changed the prognosis of patients with advanced non-small-cell lung cancer (NSCLC), resistance to treatment remains common. Rechallenge with PD-(L)1 based regimens has been explored in this context, but clinical benefit remains uncertain. METHODS: Two independent reviewer teams performed parallel searches of MEDLINE and EMBASE from 2019 to 2025 to identify clinical trials evaluating PD-(L)1 inhibitor based rechallenge strategies in patients with advanced NSCLC previously treated with PD-(L)1-based regimens. Randomised controlled trials (RCTs) were included in quantitative meta-analysis, while non-randomised single-arm studies were synthesised descriptively. The primary endpoint was overall survival (OS). Sensitivity analyses examined outcomes according to resistance pattern. All analyses used fixed-effects models. FINDINGS: A total of 10 RCTs (n = 3,081) and 106 non-randomised interventional trials were included. Across RCTs, PD-(L)1 based rechallenge strategies yielded modest improvements in both OS (HR 0.91, 95%CI: 0.82-0.99) and PFS (HR 0.89, 95%CI: 0.81-0.99) compared with the control arms, with no improvement in objective response rate (ORR). In sensitivity analyses, no benefit was observed in patients with primary resistance, whereas those with acquired resistance features (i.e., clinical benefit to prior immunotherapy) demonstrated a more favourable effect for OS (HR 0.86, 95%CI: 0.77-0.97). A more restrictive analysis excluding patients with < 3 months of prior PD-(L)1 exposure confirmed this pattern. Across the 106 single-arm trials, ORR varied widely, with only speculative signals of higher activity in regimens incorporating VEGF-targeting or chemotherapy. CONCLUSIONS: In the largest synthesis of rechallenge strategies to date, PD-(L)1 rechallenge produced statistically significant but clinically marginal improvements in OS and PFS compared with standard treatments, with no benefit in patients with primary resistance. A signal of benefit was observed in patients with acquired resistance to prior immunotherapy although this exploratory analysis was limited by heterogeneous resistance definitions across trials and a non-significant interaction test.