Clinicopathologic and molecular characteristics of small-scale ROS1-mutant non-small cell lung cancer (NSCLC) patients

Background: ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mu-tations are largely unknown. We exploratively analyzed the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. Methods: Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed clinical characteristics of patients harboring small-scale ROS1-mutations, ROS1- and co-occurring mutations, and their response to systemic therapy. Results: Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. Median overall survival (mOS) differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p = 0.02) and in patients treated with or without immune-checkpoint blockade (ICB) during treatment (21.5 vs 4.4 months, p = 0.003). Conclusion: The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Automated summary

In this study, we explored the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC patients without ROS1 fusions or SFMs. We found that approximately 1.0% of patients harbored small-scale ROS1 mutations. Compared to ROS1-fused patients, co-occurrence of KRAS mutations led to shorter survival and immune-checkpoint blockade therapy was beneficial for patients.