Clinicogenomic Characteristics and Treatment Outcomes of Patients With Advanced <i>ALK</i>-Rearranged Squamous and Adenosquamous Non-Small Cell Lung Cancers.

Abstract

Anaplastic lymphoma kinase (ALK) is an established therapeutic target in non-small cell lung cancer (NSCLC), predominantly identified in adenocarcinomas. However, <i>ALK</i> rearrangements also occur in de novo squamous and adenosquamous NSCLCs and their clinicogenomic features remain poorly defined. 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. 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; <i>P</i> < .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 (<i>P</i> < .001), although the adenosquamous cohort had comparable TTP (median, 20.0 months [95% CI, 9.4 to 30.6]) with the adenocarcinoma cohort (<i>P</i> = .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]; <i>P</i> < .001). Genomic profiling revealed more frequent <i>TP53</i> (53% <i>v</i> 25%; <i>P</i> = .026), <i>PDGFRA</i> (16% <i>v</i> 0%; <i>P</i> = .009), <i>KIT</i> (11% <i>v</i> 0%; <i>P</i> = .045), <i>PIK3CA</i> (11% <i>v</i> 0%; <i>P</i> = .045), and <i>MYC</i> (11% <i>v</i> 0%; <i>P</i> = .045) coalterations in the squamous/adenosquamous cohort. 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.