Clinicopathological characteristics and outcome of advanced ROS1-positive non-small cell lung cancer in Asian patients

Abstract

Background: ROS1 rearrangement is a rare and distinct molecular subset of non-small cell lung cancer (NSCLC), sensitive to tyrosine kinase inhibitors (TKI) targeting the ROS1 kinase domain. We describe the prevalence, clinicopathological characteristics and clinical outcomes of advanced ROS1 positive NSCLC patients (pts), including concomitant mutations and brain metastases. Methods: We reviewed 1733 consecutive NSCLC pts from the Lung Cancer Consortium Singapore database, reflex tested for ROS1 rearrangement using breakapart fluorescence in situ hybridization. Clinical data including pts characteristics, concomitant mutations, incidence of brain metastasis, response to chemotherapy or TKIs, were retrospectively analyzed. Results: We identified 34 pts (2.0%) with ROS1 positive NSCLC; median age 52 years (range 28-76), 19 males (55.9%), 26 pts (76.5%) never smoked. A patient with stage I was excluded from outcome analysis. All had adenocarcinoma histology. 8 pts (23.5%) had brain metastases at diagnosis and 6 developed brain metastases during treatment. 6 pts (17.6%) harbored concomitant EGFR mutations; 2 (9.1%) had cMET mutations; 1 had EGFR L858R, cMET and ROS1 alterations simultaneously. 8 of 13 pts (61.5%) had PD-L1>1%. Median overall survival (OS) for all pts was 29.3 months (mths). In the first line, 13 pts received chemotherapy; 11 pemetrexed-based with a response rate (RR) of 78% and 2 gemcitabine-based with a RR of 50%. Progression free survival (PFS) was 9.8 mths and OS was 30.6 mths. Ten pts received ROS1 TKIs (9 crizotinib, 1 entrectinib) as first line with RR 80%, PFS 9.9 mths, and OS 23.7 mths. For second line, 7 pts received chemotherapy, 4 were pemetrexed-based (RR 100%) and 3 were gemcitabine-based (RR 0%), 8 pts received ROS1 TKIs (6 crizotinib, 2 ceritinib) (RR 57%). 3 pts with PD-L1>1% received pembrolizumab without objective response. Conclusions: ROS1-positive NSCLC has unique clinicopathological characteristics, high rate of brain metastases and concomitant mutations. Despite effective and durable responses to ROS1 TKI and pemetrexed chemotherapy, optimal treatment sequence remains to be explored and the role of immune checkpoint inhibitors is uncertain.