Background Immune checkpoint inhibitors (IO) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). In the pre-IO era, patients (pts) with squamous cell carcinoma (SCC) had worse survival outcomes than non-squamous (nSCC) pts.¹ Landmark trials comparing IO to chemotherapy in SCC² and nSCC³ suggest a numerical survival advantage for pts with nSCC irrespective of PD-L1 status. However, no head-to-head comparison of the effect of histology on response to IO, and with respect to PD-L1 status has been done.

Methods A systematic search of the PubMed and EMBASE databases (January 1, 2010- December 31, 2022) with additional search of ASCO and ESMO conferences, identified relevant randomized control trials (RCTs). Eligible studies included phase II/III RCTs in NSCLC pts (≥ 18 years; clearly defined subtype: SCC vs. nSCC) treated with IO (monotherapy/combination), irrespective of treatment lines. In a meta-analysis, hazard ratios (HR) and 95% confidence intervals (CI) were pooled to estimate overall survival (OS) and progression-free survival (PFS). Heterogeneity was tested and when substantial, a random-effect model was used.

Results In total, 23 studies were identified [N= 14,171 pts (SCC: 4,398; nSCC: 9,773); table 1]. Overall, as will be reported at the World Conference on Lung Cancer, there was no difference in these outcomes between nSCC and SCC [OS (HR 1.06; P=0.406); PFS (HR 1.09; P=0.506)], irrespective of the line of therapy (1^st, P=0.341 vs. ≥ 2^nd line, P=0.625) or IO regimen (monotherapy, P=0.268 vs. chemo-IO, P=0.864;table 2).

Here we report subset analysis based on PD-L1 expression. There was no difference in OS between SCC and nSCC based on PD-L1 status (PD-L1+ pts: HR 1.05; P=0.598; PD-L1- pts: HR 1.01; P=0.945). Similarly, both subgroups did not significantly differ in PFS (PD-L1+: HR 1.40; P=0.068; PD-L1-: HR 0.90; P=0.685). Within the same histology subgroup, no difference in OS was seen between PD-L1+ and PD-L1- (SCC: HR 0.995; P=0.965; nSCC: HR 1.04; P=0.749). PD-L1 status did not affect PFS across histologies (SCC: HR 0.68; P=0.096; nSCC: HR 1.06; P=0.841) (table 3).

Conclusions Despite distinct molecular landscapes and poorer survival for SCC pts in the pre-IO era, outcomes from IO-based therapy in NSCLC did not differ based on histology, and irrespective of PD-L1 status. While previous differences may be explained by higher prevalence of targeted mutations in nSCC, the introduction of IO to the landscape of NSCLC may have helped bridge the gap between both subtypes, by targeting a shared immune mechanism.

References

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