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

Clin Cancer Res. 2021 Apr 15;27(8):2168-2178. doi: 10.1158/1078-0432.CCR-20-4405. Epub 2021 Jan 29.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03099109.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacokinetics
  • B7-H1 Antigen / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Female
  • Hepatitis A Virus Cellular Receptor 2* / antagonists & inhibitors
  • Humans
  • Immune Checkpoint Inhibitors* / administration & dosage
  • Immune Checkpoint Inhibitors* / adverse effects
  • Immune Checkpoint Inhibitors* / pharmacokinetics
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms* / diagnosis
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Neoplasms* / mortality
  • Progression-Free Survival
  • Response Evaluation Criteria in Solid Tumors
  • Young Adult

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Immune Checkpoint Inhibitors
  • LY3321367

Associated data

  • ClinicalTrials.gov/NCT03099109