LY-3321367

Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors.

Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.

Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort.

LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.

T-cell immunoglobulin and mucin-domain–containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.

This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.

No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%–70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non–small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.

LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.