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Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody

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Harding, James J.; Moreno, Victor; Bang, Yung-Jue; Hong, Min Hee; Patnaik, Amita; Trigo, Jose; Szpurka, Anna M.; Yamamoto, Noboru; Doi, Toshihiko; Fu, Siqing; Calderon, Boris; de Mendizabal, Nieves Velez; Calvo, Emiliano; Yu, Danni; Gandhi, Leena; Liu, Zhuqing Tina; Galvao, Violeta Regnier; Leow, Ching Ching; de Miguel, Maria J.

Issue Date
American Association for Cancer Research
Clinical Cancer Research, Vol.27 No.8, pp.2168-2178
Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
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  • Department of Medicine
Research Area Clinical Medicine


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