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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
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Clinicogenomic Characteristics and Treatment Outcomes of Patients With Advanced ALK-Rearranged Squamous and

Emily A Miao1, Beow Yeap1, Sameh Daher2

  • 1Department of Medicine, Mass General Brigham Cancer Institute, Boston, MA.

JCO Precision Oncology
|March 30, 2026
PubMed
Abstract

Insights

Anaplastic lymphoma kinase (ALK) positive squamous and adenosquamous non-small cell lung cancer (NSCLC) are rare but distinct subtypes. These patients experience inferior outcomes with first-line ALK tyrosine kinase inhibitors (TKIs), necessitating novel treatment strategies.

Area of Science:

  • Oncology
  • Genetics
  • Thoracic Surgery

Background:

  • Anaplastic lymphoma kinase (ALK) is a key therapeutic target in non-small cell lung cancer (NSCLC), primarily observed in adenocarcinomas.
  • ALK rearrangements are also found in de novo squamous and adenosquamous NSCLCs, but their characteristics are not well understood.

Purpose of the Study:

  • To define the clinicogenomic features and treatment outcomes of patients with de novo ALK-positive (ALK+) squamous and adenosquamous NSCLCs.
  • To compare these outcomes with those of ALK+ adenocarcinoma patients treated with first-line alectinib.

Main Methods:

  • A multi-institutional retrospective analysis of advanced ALK+ NSCLC patients.
  • Identification and comparison of de novo ALK+ squamous and adenosquamous NSCLC cohorts with an ALK+ adenocarcinoma cohort.
  • Analysis of overall survival (OS), time to progression (TTP), and time to treatment discontinuation (TTD) using Kaplan-Meier methods.

Main Results:

  • Among 177 patients, 29 had ALK+ squamous (n=17) or adenosquamous (n=12) NSCLCs; 148 had ALK+ adenocarcinoma.
  • Patients with squamous and adenosquamous NSCLCs had significantly shorter OS and TTD compared to adenocarcinoma patients on first-line alectinib.
  • Squamous NSCLCs showed shorter TTP than adenocarcinomas, while adenosquamous TTP was comparable. Genomic profiling revealed more frequent TP53, PDGFRA, KIT, PIK3CA, and MYC co-alterations in squamous/adenosquamous tumors.

Conclusions:

  • ALK+ squamous and adenosquamous NSCLCs are rare and biologically distinct subtypes.
  • These subtypes exhibit inferior outcomes when treated with first-line ALK tyrosine kinase inhibitors (TKIs).
  • Further research is crucial to develop effective treatment strategies for these rare NSCLC variants.

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