Background: Approximately, 95% of patients who have an initial response to ALK-TKIs exhibit an incomplete response resulting in residual disease that enables the emergence of acquired resistance. Eliminating residual disease using LCT may delay resistance emergence and improve clinical outcomes. Methods: This is a single center investigator-initiated trial that assesses the safety, feasibility and efficacy of brigatinib with LCT. Eligible patients have TKI-naïve ALK rearranged advanced NSCLC with any number of metastases. Patients treated with brigatinib for an induction period of 8 weeks followed by LCT with radiation and/or surgery. Results: Between 12/2018 and 01/2020, 17 out of 24 planned patients were enrolled. Median age 55 (range 33-73). At study entry, 15 patients had polymetastatic disease ( > 3 sites) while 2 had oligometastatic disease. As of February 1, 2020, 16 patients were evaluated for response and completed LCT while 1 patient remained on induction brigatinib. The disease control rate was 100% with an objective response rate of 94% (n = 15). Median follow up was 8 months (range 3-13) with no patients with disease progression to date. LCT used was radiation (n = 11), surgery (n = 3), surgery and radiation (n = 2). Among 5 patients who had surgery, 4 had lobectomy and mediastinal lymph node dissection (MLND), 1 had wedge resection with MLND, and 1 had adrenalectomy. Of these, 2 had complete pathological response and 1 had complete pathological response at the primary tumor. There were no grade ≥2 adverse events (AEs) related to LCT, including in 7 patients treated with concurrent brigatinib and radiation, and 6 patients treated with radiation while brigatinib was held. All patients continued brigatinib after LCT. Brigatinib-related severe AEs included grade 3: increased blood levels of creatine kinase, lipase, alanine aminotransferase, amylase (n = 1 each) and nausea (n = 1). One patient had grade 2 pneumonitis after 2 weeks of starting brigatinib, this resolved with steroids and brigatinib was resumed at a lower dose. Conclusions: Brigatinib with LCT is safe and feasible in patients with ALK-rearranged advanced NSCLC irrespective of number of metastatic sites. Brigatinib and LCT may be an effective therapeutic strategy in this subset of NSCLC patients. Clinical trial information: NCT03707938.