Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors.

Purpose Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI‑H/dMMR) tumors. However, 50 to 60% do not respond to single-agent anti-PD‑1/PD-L1 antibodies, and approximately 50% of responders relapse within 6 to12 months. This phase 1b 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. Experimental design Eligible patients {greater than or equal to}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: 1200mg, Cycle 3 onwards: 600mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. Results Eighty-two patients were enrolled. Most had colorectal (n=39, 47.6%) or endometrial (n=14, 17.1%) tumors. >70% of patients in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort had received {greater than or equal to}3 treatment lines. Treatment-related adverse events (TRAEs) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD‑1/PD-L1 inhibitor-naive combination cohort, and 6 (27.3%) in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort. 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade {greater than or equal to}3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD‑1/PD-L1 inhibitor-naive combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. Conclusions LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naive MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI‑H/dMMR tumors.