Clinicopathological characteristics and targeted therapy response in <i>ALK</i> fusion–positive lung squamous cell carcinoma: A multicenter retrospective real-world study.

e20709 Background: Anaplastic lymphoma kinase (ALK) rearrangements are rare in lung squamous cell carcinoma (SqCC), and real-world data on the clinicopathological features and therapeutic efficacy of ALK tyrosine kinase inhibitors (TKIs) in this subset are limited. This study aimed to characterize ALK-positive SqCC and evaluate the outcomes of ALK-targeted therapies. Methods: This multicenter, retrospective real-world study analyzed 15 patients with advanced ALK-rearranged SqCC (including 4 adenosquamous carcinoma) treated with ALK-TKIs. Clinicopathological features were collected. The primary objective was to assess progression-free survival (PFS) and objective response rate (ORR). A pooled analysis integrated data from published literature, creating a combined cohort of 54 patients (including 39 historical controls treated with crizotinib/alectinib) for broader comparison. Statistical analysis included Kaplan-Meier method for PFS estimation and log-rank test for comparisons, with a two-sided p&lt;0.05 considered significant. Results: Among 19 TKI treatment events in our cohort, the overall ORR was 52.6% and disease control rate (DCR) was 100.0%. Lorlatinib (n=10 events) showed superior efficacy vs. alectinib (n=7): ORR 70.0% vs. 28.6%; median PFS (mPFS) 16.0 vs. 12.0 months (hazard ratio [HR]=0.43, 95% CI: 0.21–0.96; P=0.026). The pooled analysis (n=54 patients) confirmed the significant advantage of lorlatinib-based strategy (n=10) over earlier-generation TKIs (crizotinib/alectinib, n=49): mPFS 16.0 vs. 7.1 months (HR=0.21, 95% CI: 0.10–0.44; P&lt;0.0001), representing a 79% reduction in progression/death risk. The cohort was characterized by a predominance of never-smoking (53.3%) and female (60.0%) patients. Conclusions: This real-world study provides the first evidence suggesting that lorlatinib may offer improved efficacy over earlier-generation ALK inhibitors in patients with ALK-rearranged SqCC. These exploratory findings highlight the clinical activity of lorlatinib in this rare subset and underscore the necessity of ALK testing in SqCC patients with relevant clinicopathological features. Prospective studies are warranted to validate these observations and define the optimal therapeutic strategy. Efficacy outcomes of ALK-TKIs in the study and pooled analysis. Treatment Group n (Events) ORR,% (n) DCR,% (n) Median PFS,months (95% CI) Lorlatinib 10 70.0 (7/10) 100.0 (10/10) 16.0 (11.0–26.0) Alectinib 7 28.6 (2/7) 100.0 (7/7) 12.0 (10.7–15.0) Crizotinib 2 50.0 (1/2) 100.0 (2/2) Not reported All TKIs (Study Cohort) 19 52.6 (10/19) 100.0 (19/19) 15.0 (11.0–20.4) Earlier-gen TKIs (Pooled Data) 49 Not pooled Not pooled 7.1 (6.0–9.0)