Background: In KEYNOTE-555, a model-based approach suggested expected drug exposure with pembro 400 mg Q6W is similar to that observed with approved doses of pembro 200 mg or 2 mg/kg Q3W. The pembro Q6W dose is now approved. We present interim efficacy, safety and PK of 1L pembro 400 mg Q6W for patients (pts) with advanced melanoma in KEYNOTE-555 Cohort B (NCT03665597). Methods: Eligible pts had unresectable stage III or IV melanoma, ECOG PS ≤1, and no prior systemic therapy for advanced disease.Pts received pembro 400 mg Q6W for up to 18 cycles (≈2 years).The primary efficacy endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included PFS by BICR per RECIST v1.1 and safety. PK profile and exposure were evaluated for cycle 1 and steady state (cycle 4). Results: Between May 2019 and Jan 2020, 101 pts were enrolled and received ≥1 dose of pembro. Baseline characteristics were generally similar to pt cohorts of historical pembro studies in advanced melanoma. As of the data cutoff date of August 6, 2020, all pts had ≥6 mo of follow-up and 40.6% of pts had discontinued study treatment. Median (range) duration of treatment and doses administered were 8.2 mo (1 day–13.9 mo) and 6 (1–11) doses, respectively. Observed exposure with pembro 400 mg Q6W had lower variability than model predictions and was within PK parameters from clinical experience with other pembro regimens (Table). ORR was 50.5% (95% CI 40.4–60.6). 12.9% of pts had CR and 37.6% had PR. Median PFS was 13.8 mo (95% CI 3.0–not reached). Estimated PFS rates were 56.5% at 6 mo and 54.3% at 12 mo. Treatment-related AEs of any grade occurred in 79.2% of pts (grade 3–4: 6.9% of pts; no deaths due to a treatment-related AE). The most common immune-mediated AEs were hyperthyroidism (6.9%) and hypothyroidism (6.9%). Conclusions: 1L treatment with pembro 400 mg Q6W yielded a clinically meaningful ORR in pts with advanced melanoma. PK, efficacy and safety results from KEYNOTE-555 Cohort B support prior findings from the model-based assessment and indicate that the benefit-risk profile for the more practical pembro 400 mg Q6W regimen is consistent with that of 200 mg or 2 mg/kg Q3W regimens. Clinical trial information: NCT03665597

^aObserved data. ^bSimulated using a reference population PK model not including KEYNOTE-555 Cohort B. ^cSimulated using a reference population PK model based on dataset of 2993 pts from KEYNOTE-001, 002, 006, 010, and 024.