Background: KEYNOTE-022 (NCT02130466) was a phase 1/2 study of pembro + dab + tram or pembro + tram in patients (pts) with unresectable stage III/IV melanoma (parts 1-3) or solid tumors (parts 4 and 5). In previous analyses of pts with BRAF^V600E/K-mutant melanoma, pembro + dab + tram was shown to have manageable safety in parts 1-3, albeit with a higher incidence of TRAEs in part 3, and substantially improved PFS, DOR, and OS vs placebo + dab + tram in part 3, although the primary end point of a statistically significant improvement in PFS was not met. Long-term follow-up of pts with BRAF^V600E/K-mutant melanoma in parts 1-3 are presented. Methods: Eligible pts were ≥18 y with unresectable stage III/IV BRAF^V600E/K-mutant melanoma, ≥1 measurable lesion per RECIST v1.1, ECOG PS 0/1, and no prior systemic therapy for advanced disease. In parts 1 and 2, which involved dose finding and confirmation, pts received pembro 2 mg/kg IV Q3W + dab 150 mg PO BID + tram 2 mg PO QD (MTD). In part 3, pts were randomized 1:1 to pembro + dab + tram at MTD or placebo + dab + tram. Primary end points were safety, tolerability, and MTD (parts 1 and 2); ORR per RECIST v1.1 by investigator review (part 2); and PFS per RECIST v1.1 by investigator review (part 3). Data cutoff was July 14, 2021. Results: Median (range) study follow-up was 72.9 mo (68.4-84.5) in parts 1 and 2 (n = 15) and 61.2 mo (50.7-67.5) for all pts (n = 120; 60 each arm) in part 3. Safety of pembro + dab + tram in parts 1 and 2 was consistent with prior reports; grade 3/4 TRAEs occurred in 11 pts (73%), and no additional DLTs occurred. ORR in parts 1 and 2 was 67% (95% CI, 38-88), which was similar to that reported at an earlier data cut (73% [95% CI, 45-92]); median DOR was 19.4 mo (95% CI, 2.8-NR), median OS was NR (95% CI, 10.3-NR), 48-mo OS rate was 60%, median PFS was 15.2 mo (95% CI, 4.2-NR), and 48-mo PFS rate was 28% (Ribas A et al. Nat Med. 2019;25:936-940). In part 3, median PFS was 17.0 mo (95% CI, 11.3-NR) for pembro + dab + tram vs 9.9 mo (95% CI, 6.7-15.6) for placebo + dab + tram (HR, 0.46; 95% CI, 0.29-0.74) and 24-mo PFS rate was 47% vs 16%, and median OS was 46.3 mo (95% CI, 23.9-NR) vs 26.3 mo (95% CI, 18.2-38.6); and 24-mo OS rate was 63% vs 52%, respectively. ORR was 65% (95% CI, 52-77) for pembro + dab + tram vs 72% (95% CI, 59-83) for placebo + dab + tram; median DOR was 30.2 mo (95% CI, 14.1-NR) vs 12.1 mo (95% CI, 6.0-15.7). Safety in part 3 was similar to prior reports; grade 3-5 TRAEs occurred in 42 pts (70%) in the pembro + dab + tram arm vs 27 pts (45%) in the placebo + dab + tram arm (Ferrucci PF et al. J Immunother Cancer. 2020;8:e001806). No additional grade 5 TRAEs occurred (1 grade 5 pneumonitis had occurred at prior analysis). Conclusions: At long-term follow-up, first-line pembro + dab + tram continued to show improved PFS, DOR, and OS compared with placebo + dab + tram in pts with BRAF^V600E/K-mutant melanoma. TRAEs were more common with pembro + dab + tram but no new safety signals were identified. Clinical trial information: NCT02130466.