Lorlatinib in TKI naïve, advanced ROS1-positive non-small-cell lung cancer: A multicenter, open-label, single-arm, phase 2 trial.

8519 Background: ROS1 rearrangement is rare but an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Currently, crizotinib, entrectinib, and reprotrectinib have been approved for ROS1-positive NSCLC. Lorlatinib is a potent, brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) that targets ROS1 as well as ALK. We investigated the antitumor activity and safety of lorlatinib in TKI naïve, advanced ROS1-positive NSCLC. Methods: This is a prospective multi-center, single-arm, phase II study. We enrolled TKI-naïve patients with histologically or cytologically confirmed advanced ROS1-positive NSCLC with an Eastern Cooperative Oncology Group performance status of 2 or less, and who had previously received one or no platinum-based chemotherapy. Lorlatinib 100mg once daily was given orally in continuous 21-day cycles until investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was an objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. For sample size calculation, we used a two-stage design to evaluate the null hypothesis (40%) and the alternative hypothesis (60%), with type I error (α) level of 10% and type II error (β) of 0.20. This study is registered in ClinicalTrials.gov, NCT03612154. Results: Between June 03, 2019, and April 26, 2023, 32 patients with ROS1-positive NSCLC were enrolled. The median age was 60, 63% were female, and all of them (100%) had adenocarcinoma histology. Twenty-one (66%) of 32 patients were treatment-naive, and 11 (34%) had previously received a platinum-based chemotherapy. The estimated median duration of follow-up for response was 15.6 months (Interquartile Range IQR, 10.3–30.4). Twenty-two (69%; 95% confidence interval CI, 52 to 83) patients had objective responses. The median PFS and OS were 35.8 months (95% CI, Not Reached NR to NR) and NR, respectively, for all patients. Regarding the previous therapy, the ORR and PFS of treatment naïve and previously treated patients were 81% vs 46% (p = 0.042) and NR vs 13.9 months (p = 0.25), respectively. The most common 3–4 grade treatment-related adverse events were hypertriglyceridemia (8 25% of 32 patients) and hypercholesterolemia (5 16%). No treatment-related deaths were reported. Conclusions: Lorlatinib showed durable clinical activity in patients with TKI naïve, advanced ROS1-positive NSCLC including those with CNS metastases. Adverse events were mainly of low grade and compatible with long-term administration. Due to its limited treatment options, lorlatinib could be integrated into an earlier stage of treatment for ROS1-positive NSCLC. Clinical trial information: NCT03612154 .