Effect of histology on the efficacy of first-line immune checkpoint inhibitors in advanced non-small cell lung cancer: a systematic review and network meta-analysis

Background: First-line immune checkpoint inhibitors (ICIs) have become the standard of care for advanced non-small cell lung cancer (NSCLC). However, whether tumor histology influences the efficacy of ICIs remains unclear. Methods: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, and Scopus for randomized controlled trials (RCTs) published up to February 28, 2026. Eligible studies compared ICIs with chemotherapy, or two ICI-based regimens, as first-line treatment for advanced squamous (SQ) or non-squamous (non-SQ) NSCLC. Trials that enrolled patients with NSCLC and reported outcomes stratified by histology were also eligible. The primary outcome was overall survival (OS), reported as hazard ratios (HRs) with 95% credible intervals. A fixed-effects consistency model was used for the statistical analysis. Results: Forty-one phase 3 RCTs comprising 23, 871 patients and 31 ICI-based regimens were included. The efficacy of individual ICI regimens varied by histological subtype. For example, toripalimab plus chemotherapy was associated with superior OS compared with most other ICI regimens (HR range: 0.42-0.65) and ranked as the best treatment in non-SQ-NSCLC (surface under the cumulative ranking curve [SUCRA] = 0.97). In contrast, the same regimen showed inferior OS relative to many comparators (HR range for comparators vs. toripalimab plus chemotherapy: 0.47-0.65) and had the lowest OS ranking in SQ-NSCLC (SUCRA = 0.09). In the PD-L1 < 1% subgroup, nivolumab plus ipilimumab demonstrated a trend toward better OS compared with pembrolizumab plus chemotherapy (HR = 0.59) and ranked as the best regimen for SQ-NSCLC (SUCRA = 0.83), whereas pembrolizumab plus chemotherapy provided the greatest OS benefit for non-SQ-NSCLC (SUCRA = 0.90). In the PD-L1 ≥ 50% subgroup, atezolizumab plus chemotherapy ranked second for OS benefit in SQ-NSCLC but was the least effective combination in non-SQ-NSCLC; conversely, cemiplimab plus chemotherapy was the least effective combination in SQ-NSCLC but ranked second in non-SQ-NSCLC. Conclusions: The efficacy of individual first-line ICI regimens appear to vary by histological subtype across PD-L1 expression levels. These findings suggest that PD-L1 status alone might not be sufficient to guide treatment selection, and that histological subtype could be considered in clinical decision-making for advanced NSCLC.