A randomized phase 3 study of entrectinib versus crizotinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC with or without baseline CNS metastases (mets).

TPS9141 Background: ROS proto-oncogene 1 ( ROS1) fusions are found in 1–2% of NSCLC cases. As CNS mets are common in pts with ROS1-fp NSCLC and associated with poor prognosis, CNS-active treatments are needed for these pts. Entrectinib and crizotinib are tyrosine kinase inhibitors (TKIs) of ROS1, recommended as first-line treatments for ROS1-fp NSCLC. Both drugs have shown robust systemic efficacy and good tolerability in pts with ROS1-fp NSCLC. While crizotinib may have suboptimal CNS activity, entrectinib has shown intracranial efficacy in pts with baseline CNS mets by blinded independent central review (BICR, PMIDs 30215676; 33646820). We hypothesized that entrectinib may have greater CNS activity than crizotinib, potentially addressing the unmet need for pts with ROS1-fp NSCLC with CNS mets. Methods: This randomized, open-label, multicenter, phase 3 trial (NCT04603807) aims to compare the efficacy and safety of entrectinib vs crizotinib in adult pts with TKI-naïve advanced/metastatic ROS1-fp NSCLC, with or without CNS mets. Key eligibility criteria: advanced/recurrent/metastatic NSCLC with ROS1 fusion determined locally by certified clinical laboratory testing; measurable systemic disease (RECIST 1.1); age ≥18 years; ECOG PS ≤2; no prior ROS1 TKI or systemic treatment for advanced/metastatic disease; adequate hematologic, renal and hepatic functions; prior radiotherapy ≥14 days before randomization and neurologically stable CNS mets per RECIST 1.1 are permitted. Pts will be randomized 1:1 to receive 600 mg entrectinib once a day or 250 mg crizotinib twice a day. Stratification factors are baseline CNS mets (none/measurable/non-measurable) and prior brain radiotherapy ≤2 months (yes/no); to allow sufficient power, ≥30% of randomized pts will have baseline CNS mets. Study treatment will continue until progressive disease, unacceptable toxicity, death or withdrawal from the study. Pts with radiographic disease progression or isolated asymptomatic CNS progression may continue treatment at the investigator’s discretion. Tumor assessments (brain MRI and chest, abdomen and pelvis CT/MRI) will occur at screening, Wk 4, Wk 8 and every 8 wks thereafter. Blood samples will be collected at every visit. Primary endpoint: progression-free survival (PFS) by BICR in pts with baseline CNS mets (CNS population, target HR = 0.57). Secondary endpoints: CNS-PFS by BICR and ORR, duration of response (DoR) and PFS (by BICR and investigator) in the intent-to-treat (ITT) population; overall survival in the CNS and ITT populations; CNS-ORR and CNS-DoR by BICR in the CNS population. Impact on quality of life, functioning and lung cancer-specific symptoms will be evaluated via questionnaires in the ITT population. Safety endpoints and biomarkers will also be evaluated. As of 12 Jan 2022, 8 pts are enrolled (first pt enrolled in Oct 2021). Clinical trial information: NCT04603807.