Background: INCAGN01876 is a GITR agonist designed to induce antitumor immunity by promoting effector T cells while inhibiting Tregs. Recent clinical studies suggest that combining IO with immune agonists such as INCAGN01876 may extend clinical benefit in pts with cancer. Methods: This global open-label nonrandomized phase 1/2 study assessed the safety, tolerability, recommended phase 2 dose (RP2D), and efficacy of INCAGN01876 + nivolumab (NIVO) and/or ipilimumab (IPI) (NCT03126110). Eligible pts (≥18 y) had locally advanced/metastatic cancer. Phase 1 (dose escalation) consisted of 4 treatment groups: A, INCAGN01876 1, 3, 5, 10 mg/kg Q2W + NIVO 240 mg Q2W; B, INCAGN01876 1, 3, 5, 10 mg/kg for 2 doses then NIVO 240 mg Q2W; C, INCAGN01876 1, 3, 5 mg/kg Q2W + IPI 1 mg/kg Q6W; D, INCAGN01876 1 mg/kg Q2W + NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. INCAGN01876 RP2D was assessed via a 3+3+3 design. Phase 2 (dose expansion) evaluated INCAGN01876 RP2D in combination IO in select tumors; data will be presented elsewhere. Results: As of Nov 9, 2021, 51 pts (A, n=17; B, n=13; C, n=15; D, n=6) were enrolled (most common tumors: breast, gastric, and ovarian [each n=8]; prior PD-(L)1 therapy, n=12). One pt in D had DLTs (nonserious grade [gr] 3 pruritis and rash); MTD was not reached; INCAGN01876 300 mg Q2W was selected as RP2D. All pts in A, B, D, and 93.3% in C had TEAEs. Twenty-six pts had gr ≥3 TEAEs (A, n=10; B, n=5; C, n=7; D, n=4), most commonly, pneumothorax (A [5 mg/kg], n=2) and anemia (B [1, 5 mg/kg], n=2; C [1, 3, 5 mg/kg], n=3). INCAGN01876-related TEAEs occurred in 8, 6, 10, and 5 pts in A, B, C, and D, respectively. Most common immune-related AEs in A: pruritus (gr 1/2, n=2); in B: rash (gr 1, n=2), simultaneous rash and pruritus (gr 1, n=4); in C: pruritus (gr 1/2, n=2), rash (gr 1, n=2), simultaneous rash and pruritus (gr 1, n=2); in D: simultaneous pruritus and rash (gr 3, n=1); 3 pts (A [1 mg/kg], n=1; C [3 mg/kg], n=1; D, n=1) had infusion-related reactions. One pt in A (10 mg/kg Q2W) discontinued treatment due to a pneumonia TEAE. Best unconfirmed overall responses (per RECIST v1.1) were 1 complete response (CR; duration of response [DOR], 1065 days) in renal cancer and 1 partial response (PR; DOR, 573 days) in breast cancer in A; 1 CR (DOR, 876 days) in cervical cancer in B; 1 PR (DOR, 169 days) in ovarian cancer and 1 PR (DOR, 281 days) in lung cancer in C; none in D. The disease control rate was 35.3% in A, 23.1% in B, 33.3% in C, and 0% in D. Conclusions: INCAGN01876 plus NIVO and/or IPI was generally well tolerated in pts with advanced tumors; most common toxicities were mild to moderate pruritus and rash. No novel safety signals were seen. INCAGN01876 300 mg Q2W was selected as RP2D based on safety and preliminary PK/PD data and used for expansion in combination with NIVO or IPI. Clinical trial information: NCT03126110.