Background: The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, is a current standard of care for patients (pts) with BRAF^V600E NSCLC. We report efficacy and safety of enco+bini in pts with BRAF^V600E metastatic NSCLC. Methods: PHAROS is an ongoing, open-label, single-arm, phase 2 study that enrolled pts with BRAF^V600E metastatic NSCLC who had measurable disease by RECIST 1.1 and Eastern Cooperative Oncology Group performance status of 0 or 1, and who were either treatment-naive or had received 1 prior therapy (chemotherapy, monotherapy, or combination immunotherapy) for metastatic disease. Exclusion criteria included prior treatment with a BRAF or MEK inhibitor. Pts received enco 450 mg QD + bini 45 mg BID administered orally in 28-day cycles. The primary endpoint was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and time to response (TTR), all by IRR, and safety. Exploratory endpoints included biomarker assessments. Results: At the data cutoff (Sep 22, 2022), 98 pts (59 treatment-naive, 39 previously treated) received enco+bini. The median duration of treatment was 9.2 months with enco and 8.4 months with bini. Treatment is ongoing in 34% of the pts; 38% permanently discontinued due to disease progression and 18% due to adverse events (AEs). The ORR (95% CI) by IRR was 75% (62, 85) in treatment-naive and 46% (30, 63) in previously treated pts. Secondary endpoints are shown in the table. The most frequent (≥30%) treatment-related AEs (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). AEs led to permanent discontinuation of enco+bini in 15% of pts and dose reductions in 24% of pts. One grade 5 TRAE of intracranial hemorrhage was reported. Next-generation sequencing analysis was conducted with archival tumor biopsies from 48 treatment-naive and 32 previously treated pts. The most frequent genomic alterations, in addition to BRAF^V600E, were SETD2 and TP53 (43% each), SMAD4 (21%), ATM, MLL2, CSF1R, and SMARCA4 (14% each), and CDKN2A (11%). Conclusions: The combination of enco+bini showed meaningful clinical benefit in treatment-naive and previously treated pts with BRAF^V600E metastatic NSCLC. The safety profile of enco+bini was generally consistent with that established for pts with BRAF^V600E/K melanoma. ClinicalTrials.gov: NCT03915951. Clinical trial information: NCT03915951.