Clinicogenomic Characteristics and Treatment Outcomes of Patients With Advanced ALK -Rearranged Squamous and Adenosquamous Non–Small Cell Lung Cancers

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PURPOSE Anaplastic lymphoma kinase (ALK) is an established therapeutic target in non–small cell lung cancer (NSCLC), predominantly identified in adenocarcinomas. However, ALK rearrangements also occur in de novo squamous and adenosquamous NSCLCs and their clinicogenomic features remain poorly defined. METHODS This multi-institutional retrospective analysis included patients with advanced ALK+ NSCLC. Patients with de novo ALK+ squamous and adenosquamous NSCLCs were identified and compared with an ALK+ adenocarcinoma cohort treated with first-line (1L) alectinib. Overall survival (OS), time to progression (TTP), and time to treatment discontinuation (TTD) were analyzed using the Kaplan-Meier methodology. RESULTS Among 177 patients, 29 had ALK+ squamous (n = 17) and adenosquamous (n = 12) NSCLCs and 148 had ALK+ adenocarcinoma treated with 1L alectinib. Among patients receiving 1L alectinib, OS was significantly shorter for patients with adenosquamous (median, 31.0 months [95% CI, 17.0 to not reached {NR}]) and squamous (27.0 months [95% CI, 5.0 to 35.0]) tumors compared with that for patients with adenocarcinoma (median NR; median follow-up 51.2 months; P < .001). TTP was shorter for squamous (median, 8.0 months [95% CI, 2.0 to 12.0]) versus adenocarcinoma (median, 19.0 months [95% CI, 12.6 to 25.0]) cohorts ( P < .001), although the adenosquamous cohort had comparable TTP (median, 20.0 months [95% CI, 9.4 to 30.6]) with the adenocarcinoma cohort ( P = .70). TTD was significantly shorter for squamous (median, 9.5 months [95% CI, 1.5 to 13.0]) and adenosquamous (median, 20.0 months [95% CI, 3.0 to 24.0]) versus adenocarcinoma cohorts (52.3 months [95% CI, 40.5 to 57.5]; P < .001). Genomic profiling revealed more frequent TP53 (53% v 25%; P = .026), PDGFRA (16% v 0%; P = .009), KIT (11% v 0%; P = .045), PIK3CA (11% v 0%; P = .045), and MYC (11% v 0%; P = .045) coalterations in the squamous/adenosquamous cohort. CONCLUSION ALK+ squamous and adenosquamous NSCLCs are rare, but biologically distinct, with inferior outcomes on 1L ALK TKI, highlighting the need for further research to develop effective treatment strategies.

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