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
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Abstract
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.
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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 [159]
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“One clinical trial reported that a combination of LY3300054 (anti-PDL1) and LY3321367 (anti-TIM-3) showed antitumor activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR solid tumors.(69) Another clinical trial also showed preliminary efficacy of sabatolimab(anti-TIM-3) plus spartalizumab(anti-PD-1) for advanced soli…”
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“[8] The second study was a phase 1b trial as monotherapy or combination with LY3300054 (anti-PD-L1 inhibitor), for patients with micro-satellite instability-high/deficient DNA mismatch repair (MSI-H/dMMR) tumors.”
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“The combination of LY3321367 with LY3300054 (an anti-PD-L1 antibody) did not change the frequencies or types of TRAEs compared with LY3300054 mono ‐ therapy, but led to higher response rates (Hollebecque et al., 2021).”
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“290 Of note, responses were always more favorable if patients initially responded to anti-PD-(L)1 therapy, highlighting the potential use of alternative ICI therapy in acquired ICI resistance.”
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“There are only two studies prospectively exploring the efficacy of anti-PD1/PD-L1 plus inhibitors of some emerging targets, including TGF (15 patients) [16] and TIM3 (22 patients) [17], and a retrospective study analyzing the efficacy of conventional chemotherapy with or without targeted therapy (31 patients) [18].”
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“Therefore, anti-TIM-3 antibodies, mainly in combination with anti-PD-1/PD-L1 immune checkpoint inhibition, are currently being evaluated in clinical trials for the treatment of advanced cancers, including CRC [10,33].”
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“The LY3300054 monotherapy resulted in 32.5% ORR (13/40) and a 60.0% (24/40) disease control rate (DCR) [55].”
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High-Grade Endometrial Cancer: Molecular Subtypes, Current Challenges, and Treatment Options
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“Other ICIs, such as avelumab [132, 133], spartali-zumab [134], LY3300054 [134], durvalumab [135–137], and nivolumab [138], are being studied in phases I and II with combinations with other drugs or radiation therapy to enhance the therapeutic effect.”
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“Prospective studies have shown limited clinical benefit when combining anti-PD-L1 with TGF-β bifunctional fusion protein inhibitor (0% ORR) and anti-TIM3 (4.5% ORR) in patients with ICI-resistant MSI-H CRC 21,22 .”
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“More recently, Tim-3 monoclonal antibodies alone or in combination with PD-1/PD-L1 monoclonal antibodies are being explored as a possible immunotherapy strategy for solid tumours [45 – 47].”
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“In order to prevent resistance to anti-PD-1/PD-L1 treatment, it is recommended to consider using new immune checkpoints such as Tim-3 in combination therapy for CRC [53].”
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Other Immune Checkpoint Targets of Interest
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- Authors
- 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.
- Affiliations
- Institut Gustave Roussy (FR)
- Yonsei University (KR)
- 3START Madrid, HM Sanchinarro Centro Integral Oncológico Clara Campal, Madrid, Spain.
- 4Institut Bergonié, Bordeaux, France.
- Cliniques Universitaires Saint-Luc (BE)
- National Taiwan University Hospital (TW)
- Princess Margaret Cancer Centre (CA)
- Antwerp University Hospital (BE)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- National Cheng Kung University Hospital (TW)
- 11Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
- Eli Lilly (United States) (US)
- 13Eli Lilly and Company, New York, New York.
- Seoul National University (KR)
- Corresponding author
- Hollebecque, Antoine
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-12-01
- Volume
- 27
- Issue
- 23
- Pages
- 6393-6404
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W3197498721
- Cited by
- 65
- References
- 37
- Citations by year
- 2026: 3 · 2025: 15 · 2024: 19 · 2023: 15 · 2022: 11 · 2021: 2
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Eli Lilly and Company (NCT02791334)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- PD-L1 inhibitors, anti-TIM-3 antibody, microsatellite instability-high, immune checkpoint inhibitors, combination immunotherapy, PD-1/PD-L1 inhibitor resistance, treatment-related adverse events, objective response rate, advanced solid tumors, safety and tolerability
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasms, Microsatellite Instability, DNA Mismatch Repair, B7-H1 Antigen
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