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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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.
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Clinical trials showed that α-TIM-3 plus α-PD-1/PD-L1 was tolerable without unexpected safety signals.
“The results of clinical trials showed that α-TIM-3 plus α-PD-1/PD-L1 was tolerable without unexpected safety signals, but more efforts are needed for patient selection [158–160].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [158]
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- Authors
- Harding, J. J., Moreno, V., Bang, Y.-J., Hong, M. H., Patnaik, A., Trigo, J., Szpurka, A. M., Yamamoto, N., Doi, T., Fu, S., Calderon, B., Velez de Mendizabal, N., Calvo, E., Yu, D., Gandhi, L., Liu, Z. T., Galvao, V. R., Leow, C. C., & de Miguel, M. J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 2START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain.
- Seoul National University (KR)
- Yonsei University (KR)
- South Texas Accelerated Research Therapeutics (US)
- Hospital Clínico Universitario Virgen de la Victoria (ES)
- Eli Lilly (United States) (US)
- National Cancer Centre Japan (JP)
- National Cancer Center Hospital East (JP)
- The University of Texas MD Anderson Cancer Center (US)
- 7Eli Lilly and Company, Indianapolis, Indiana.
- 11START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
- Dana-Farber Cancer Institute (US)
- 13Eli Lilly and Company, New York, New York.
- Corresponding author
- Harding, James J.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-01-29
- Volume
- 27
- Issue
- 8
- Pages
- 2168-2178
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3123341232
- Cited by
- 161
- References
- 31
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 39 · 2023: 37 · 2022: 17 · 2021: 13
- FWCI
- 9.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TIM-3, PD-L1 inhibitors, immune checkpoint blockade, PD-1/PD-L1 inhibitor resistance, non-small cell lung cancer, combination immunotherapy, CD8+ T cell infiltration, pharmacokinetics, pharmacodynamics, target engagement, antidrug antibodies
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Progression-Free Survival, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neoplasm Staging, Neoplasms, Young Adult, B7-H1 Antigen, Antibodies, Monoclonal, Humanized, Response Evaluation Criteria in Solid Tumors
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