Background: In a phase 1/2 study, the combination of E, a selective oral inhibitor of the IDO1 enzyme, plus P, a PD-1 inhibitor, suggested promising antitumor activity with minimal additive toxicity. ECHO-301/KEYNOTE-252 (NCT02752074) is a phase 3, randomized, double-blind study evaluating the efficacy and safety of E + P vs placebo + P in pts with untreated unresectable or metastatic melanoma. Methods: Pts had histologically confirmed unresectable stage III or IV melanoma and were treatment naive for advanced or metastatic disease, except for pts with the BRAF V600 mutation who could have received prior BRAF/MEK therapy. Pts were stratified by PD-L1 expression and BRAF mutation status (BRAF mutant with prior BRAF-directed therapy, BRAF mutant without prior BRAF-directed therapy, and BRAF wild type) and randomized 1:1 to E 100 mg BID + P 200 mg Q3W or matched E placebo + P 200 mg Q3W. Response was assessed per RECIST v1.1 and irRECIST (both by central review). The primary endpoints were PFS per RECIST v1.1 and OS. Secondary endpoints were ORR per RECIST v1.1, duration of response, and safety. This is the final analysis for PFS and interim analysis for OS. Results: A total of 706 pts were randomized (354 to E + P and 352 to placebo + P); 72.5% of tumors were PD-L1 positive, 44.5% BRAF mutant (12.2% received prior BRAF/MEK therapy). Median follow-up was ~14 mo. E + P did not result in a significantly longer PFS vs placebo + P (median 4.7 vs 4.9 mo; HR=1.00; CI, 0.83-1.21; P=0.517). PFS rate at 12 mo was 37% in both groups. Findings were consistent across PD-L1 and BRAF subgroups. OS was not expected to reach statistical significance based on the results of this interim analysis (HR=1.13; CI, 0.86-1.49; P=0.807). The OS rate at 12 mo was 74% in both groups. ORR was 34.2% and 31.5% in the E + P and placebo + P groups, respectively. Grade ≥3 treatment-related AEs occurred in 21.8% of patients receiving E + P and 17.0% receiving placebo + P. Conclusions: The addition of E to P did not result in greater clinical benefit over P alone in pts with unresectable or metastatic melanoma. The safety profile was consistent with that observed in previously reported studies of this combination. Clinical trial information: NCT02752074