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.

Autor:	Hollebecque A; Drug Development Department (DITEP), Gustave Roussy, Villejuif, France. antoine.hollebecque@gustaveroussy.fr., Chung HC; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of South Korea., de Miguel MJ; START Madrid, HM Sanchinarro Centro Integral Oncológico Clara Campal, Madrid, Spain., Italiano A; Institut Bergonié, Bordeaux, France., Machiels JP; Department of Medical Oncology, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Institut Roi Albert II, Université catholique de Louvain, Brussels, Belgium., Lin CC; National Taiwan University Hospital, Taipei, Taiwan., Dhani NC; Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Toronto, Ontario, Canada., Peeters M; Department of Oncology, Antwerp University Hospital, Edegem, Belgium., Moreno V; START Madrid FJD, Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain., Su WC; National Cheng Kung University Hospital, Taiwan., Chow KH; Eli Lilly and Company, Windlesham, Surrey, United Kingdom., Galvao VR; Eli Lilly and Company, Indianapolis, Indiana., Carlsen M; Eli Lilly and Company, Indianapolis, Indiana., Yu D; Eli Lilly and Company, Indianapolis, Indiana., Szpurka AM; Eli Lilly and Company, Indianapolis, Indiana., Zhao Y; Eli Lilly and Company, Indianapolis, Indiana., Schmidt SL; Eli Lilly and Company, Indianapolis, Indiana., Gandhi L; Eli Lilly and Company, New York, New York., Xu X; Eli Lilly and Company, New York, New York., Bang YJ; Seoul National University College of Medicine, Seoul, Republic of South Korea.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Dec 01; Vol. 27 (23), pp. 6393-6404. Date of Electronic Publication: 2021 Aug 31.
DOI:	10.1158/1078-0432.CCR-21-0261
Abstrakt:	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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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