Background: Second generation ALK tyrosine kinase inhibitors (ALK-TKI), including brigatinib, provide substantial therapeutic benefit in first-line treatment of ALK-positive NSCLC patients (pts) but relapse eventually occurs in all pts due to development of drug resistance, possibly caused by emergence of drug-tolerant cells (DTC). Combining chemotherapy to TKI may prevent DTC emergence in preclinical studies, and results in prolonged progression-free survival (PFS) and overall survival in EGFR-mutant NSCLC. We hypothesize that combination of second generation ALK-TKI with chemotherapy will improve clinical outcomes in advanced ALK-positive NSCLC patients. The IFCT-2101 MASTERPROTOCOL ALK trial will evaluate the efficacy and safety of brigatinib and carboplatin-pemetrexed combination in treatment-naïve metastatic ALK-positive NSCLC. Methods: The IFCT-2101 MASTERPROTOCOL ALK randomized, open-label phase II trial will enrol 110 pts in 30 French centers over 24 months. Eligible pts will have metastatic NSCLC with ALK-fusion according to local testing, be untreated for advanced disease, and have an ECOG Performance Status (PS) of 0-1 and at least one measurable lesion per RECIST 1.1. Pts with asymptomatic and stable brain metastases (BM) will be eligible. Exclusion criteria include leptomeningeal metastases. Patients will be randomized 1:1 to receive brigatinib monotherapy (Arm A) or combination brigatinib and carboplatin-pemetrexed therapy (Arm B), with PS (0 vs 1) and BM (presence vs absence) as stratification factors. Brigatinib will be administered at a dose of 90 mg QD for a 7-day lead-in period followed by 180 mg QD continuously, in 28-day cycles. In Arm B, 4 cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m²) therapy every 3 weeks will be added at Day 8 of brigatinib treatment. Treatment will continue until progression, intolerable toxicity or discontinuation. The first 26 pts enrolled in Arm B will represent the population of a safety phase, during which adverse events (AE) will be closely monitored by an independent data monitoring committee. The primary endpoint is investigator-assessed 12-month PFS rate. Secondary endpoints include independently-reviewed 12-month PFS rate, overall response rate (ORR), 12-month intracranial PFS and ORR, incidence, nature and severity of AEs, and impact of ALK-fusion detection, co-mutations and clearance of circulating tumor (ct) DNA (Guardant360) on outcome. Exploratory objectives include the evaluation of early blood ctDNA decrease on patient outcome. The study is enrolling and primary completion date is March 2025. Clinical trial information: NCT05200481.