Phase 1 first-in-human study of anti–ILT3 mAb MK-0482 as monotherapy and in combination with pembrolizumab in advanced solid tumors: Dose escalation results.

2505 Background: Immunoglobulin-like transcript 3 (ILT3) is an inhibitory receptor associated with immune tolerance and T-cell suppression within the tumor microenvironment. MK-0482, a novel humanized IgG4 mAb targeting ILT3, is undergoing phase 1 evaluation ± pembrolizumab (pembro) in advanced solid tumors (NCT03918278; MK-0482-001). Dose escalation data are presented. Methods: Eligible patients with advanced solid tumors were enrolled into sequentially escalating dose cohorts of MK-0482 monotherapy (0.2-2250 mg) or MK-0482 (7.5-2250 mg) + pembro 200 mg; both were administered IV Q3W for up to 35 cycles or until progressive disease (PD), unacceptable toxicity, death, or withdrawal. Patients receiving MK-0482 monotherapy could cross over to MK-0482 + pembro after PD. Primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included assessing pharmacokinetics (PK), blood receptor occupancy (RO), anti–drug antibodies (ADA), and objective response rate (ORR) per RECIST v1.1 by investigator assessment. Results: Seventy-five patients were enrolled (n = 29, MK-0482 monotherapy; n = 46, MK-0482 + pembro); 8 patients crossed over to receive the combination. Median age was 63 years (range, 34-86); 73% had ECOG PS 1, 72% received ≥2 lines of prior anticancer therapy, and 32% received prior PD-1/PD-L1 inhibitors. Treatment-related AEs (TRAEs; any-grade/grade 3 or 4) were reported in 34%/7% of patients with MK-0482 monotherapy, 67%/4% with MK-0482 + pembro, and 50%/13% in those who crossed over. The most common TRAEs (≥10% of all patients) were pyrexia (10%) with MK-0482 monotherapy; fatigue (24%) and arthralgia, diarrhea, hyperthyroidism, hypothyroidism, and pruritus (11% each) with MK-0482 + pembro; and arthralgia (25%), hyperthyroidism and hypothyroidism (13% each) for patients who crossed over. Dose-limiting toxicities occurred in 2 patients who received MK-0482 + pembro: 1 grade 5 myositis (MK-0482 750 mg; the only TRAE leading to death) and 1 grade 2 myositis (MK-0482 2250 mg). Preliminary PK and blood RO data suggested that target-mediated drug disposition of MK-0482 was likely saturated in blood mononuclear cells at doses ≥75 mg. ADA to MK-0482 was observed in ̃20% of patients, but no clear impact on MK-0482 PK was observed. A confirmed ORR of 15% (8 PR) was observed in patients who received MK-0482 + pembro, including patients who crossed over; no confirmed responses were observed in patients who received MK-0482 monotherapy. MK-0482 750 mg + pembro was selected as the RP2D based on the totality of data. Conclusions: MK-0482 ± pembro was generally well tolerated, and combination therapy provided modest antitumor activity in patients with heavily pretreated advanced solid tumors. The RP2D of MK-0482 + pembro is under further evaluation in tumor-specific cohorts. Clinical trial information: NCT03918278.