Background: Ensartinib is an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), which has shown systemic and central nervous system efficacy in ALK-positive non-small cell lung cancer (NSCLC) and superiority over crizotinib in the first-line setting. This single-arm phase-1b study evaluates the efficacy of ensartinib in combination with platinum-based chemotherapy and bevacizumab in ALK-positive advanced NSCLC. Methods: Patients were treated with 4 cycles of induction ensartinib, carboplatin, pemetrexed, and bevacizumab before receiving maintenance ensartinib with or without bevacizumab and/or pemetrexed until disease progression or intolerable toxicity. Prior treatment with ALK-targeting agents and the presence of asymptomatic brain metastases were allowed. The primary endpoints were to determine safety of ensartinib in combination with carboplatin, pemetrexed, and bevacizumab and to determine the recommend phase 2 dose of ensartinib in this combination. Results: Between June 22, 2021, and August 15, 2022, 6 patients were enrolled into the study and treated with at least one dose of ensartinib in combination with platinum-based chemotherapy and bevacizumab. All patients were included in safety and efficacy analyses. The median age was 54.7y, 3/6 were female, 5/6 were never smokers, the median ECOG was 1, and 3/6 had brain metastases at enrollment. Participants received a median of 2 prior lines of therapy (range 0-3) and 4/6 received prior ALK TKI therapy: 2/6 two prior ALK TKIs, 2/6 three prior ALK TKIs. As of 12/1/2022, the maximum severity adverse event (AE) was grade 2 in 1/6 patients, grade 3 in 4/6 patients, and grade 5 in 1/6 - a therapy unrelated bronchopulmonary hemorrhage. Ensartinib-related grade 1, 2, and 3 AEs occurred in 1/6, 3/6, and 2/6 respectively. Dose reductions from 225mg daily to 200mg daily occurred in 1/6 patients secondary to grade 3 transaminitis, which was subsequently well tolerated. 1/6 patients transitioned therapy after a treatment unrelated bowel perforation. The median time on trial was 9.6 months. 2/6 patients remained on treatment at time of censorship with trial durations of 22.6 and 15.8 months. 1/6 patients progressed and 2/6 patients died on treatment. Conclusions: Ensartinib in combination with platinum-based chemotherapy and bevacizumab had an acceptable safety profile and demonstrates clinical activity in treatment naïve and previously treated advanced ALK-positive NSCLC, including in patients treated with prior ALK-targeted therapies. Next phase study designs are currently being considered. Clinical trial information: 2020-0838.