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.

Hollebecque, Antoine;Chung, Hyun C;de Miguel, Maria J;Italiano, Antoine;Bang, Yung-Jue;et.al.
(2021) Clinical cancer research — Vol. 27, n° 23, p. 6393-6404 (2021)

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  • Hollebecque, Antoineorcid-logo
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  • Chung, Hyun C
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  • de Miguel, Maria Jorcid-logo
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  • Italiano, Antoine
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  • Machiels, Jean-PascalUCLouvain
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  • Bang, Yung-Jueorcid-logo
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Abstract
(en) 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%-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. PATIENTS AND METHODS: 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. RESULTS: 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. 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-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. TRIAL REGISTRATION: ClinicalTrials.gov NCT02791334.
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Hollebecque, A., Chung, H. C., de Miguel, M. J., Italiano, A., Machiels, J.-P., Lin, C.-C., Dhani, N. C., Peeters, M., Moreno, V., Su, W.-C., Chow, K. H., Galvao, V. R., Carlsen, M., Yu, D., Szpurka, A. M., Zhao, Y., Schmidt, S. L., Gandhi, L., Xu, X., & Bang, Y.-J. (2021). 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. Clinical cancer research, 27(23), 6393-6404. https://doi.org/10.1158/1078-0432.CCR-21-0261 (Original work published 2021)