Clinicopathological characteristics and targeted therapy response in ALK fusion-positive lung squamous cell carcinoma: a multicenter retrospective real-world study

Abstract Background ALK rearrangements occur in less than 1% of lung squamous cell carcinoma (SqCC). Real-world data comparing lorlatinib with earlier-generation ALK-TKIs in this rare subgroup remain limited, and optimal targeted strategies have not been well defined. Methods In this multicenter retrospective study, 15 patients (19 treatment episodes) with ALK-rearranged squamous/adenosquamous carcinoma from six tertiary centers were analyzed alongside 39 published cases, totaling 54 patients (58 episodes). Progression-free survival (PFS) was evaluated via the Kaplan–Meier method, log-rank tests, and univariate Cox regression. Objective response rate (ORR) and disease control rate (DCR) were assessed per RECIST 1.1. Results In our primary cohort (19 episodes), overall ORR was 52.6% with a median PFS of 13.0 months; patients were predominantly female (66.7%) and never-smokers (53.3%). Lorlatinib ( n = 10) numerically prolonged mPFS versus alectinib ( n = 7) (not reached [NR] vs. 12.9 months; HR = 0.47, 95% CI: 0.13–1.79; P = 0.261). In pooled analysis (58 episodes, 54 patients), lorlatinib yielded an ORR of 70.0% and 100.0% disease control. Lorlatinib significantly improved PFS compared with earlier-generation TKIs (mPFS: NR vs. 7.1 months; HR = 0.27, 95% CI: 0.09–0.77; log-rank P = 0.007), reducing progression risk by 73%. Conclusions Lorlatinib achieves durable antitumor activity in ALK-rearranged SqCC with better PFS than earlier ALK inhibitors. We recommend prioritizing ALK molecular testing for young, non-smoking female patients with squamous NSCLC.