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A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody–drug conjugate, in patients with advanced or metastatic cancer

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Summary

Background We report a Phase 1 study of LY3076226, an antibody–drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2–5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2–7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov.

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Data availability

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

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Acknowledgements

We thank the patients and their caregivers for participating in this study. We also thank the investigators and their support staff who generously participated in this work. Sambasiva Kolati from Eli Lilly Services India Private Limited and Tiago Campos from Covance Inc provided medical writing support for this article.

Funding

This study was funded by Eli Lilly and Company.

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Authors and Affiliations

  1. British Columbia Cancer Agency, Vancouver, Canada

    Christian Kollmannsberger

  2. Formely With Medical, University of South Carolina, Charleston, SC, USA

    Carolyn D. Britten

  3. Fox Chase Cancer Center, Philadelphia, PA, USA

    Anthony J. Olszanski

  4. Formerly With Eli Lilly and Company, Indianapolis, IN, USA

    Joan Andrews Walker, Daphne L. Farrington & Katherine M. Bell-McGuinn

  5. Eli Lilly and Company, Indianapolis, IN, USA

    Wei Zang, Melinda D. Willard & David B. Radtke

  6. START (South Texas Accelerated Research Therapeutics), San Antonio, USA

    Amita Patnaik

Authors
  1. Christian Kollmannsberger
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Contributions

Conception: DLF; Design: CK, DBR, DLF; Acquisition of the data: CK, CDB, AJO, MDW, DBR, KMBM, AP; Analysis of the data: CK, CDB, WZ, MDW, DBR, DLF, KMBM, AP; Interpretation of the data: CK, CDB, AJO, JAW, WZ, MDW, DBR, DLF, KMBM, AP; Drafting the manuscript: CK, AJO, WZ, MDW, DBR, KMBM; Critical revision or the manuscript for important intellectual content: CK, CDB, AJO, JAW, WZ, MDW, DLF, KMBM, AP. All authors approved the final manuscript to be published.

Corresponding author

Correspondence to Christian Kollmannsberger.

Ethics declarations

Ethics approval

Study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice E6 guidelines, and ethics guidelines that include the Declaration of Helsinki and Council for International Organizations of Medical Sciences. The protocol was approved by the Institutional Review Boards before patient recruitment.

Consent to participate

Written informed consent was obtained from all individual participants included in the study.

Conflicts of interest

CK reports being an ad hoc advisory board member for BMS, Merck, Pfizer, Eisai, Ipsen, Astellas, Janssen, Bayer and receiving speaker honoraria from Pfizer, Ipsen, BMS, Merck. CDB reports receiving research grants from Eli Lilly and Company, AstraZeneca, Celgene, EMD Serono, FivePrime, Genentech, Incyte, Merck, Millennium, Novartis, Regeneron, and Tesaro; being a paid consultant for Five Prime and Pfizer; receiving travel grants from Amgen, Five Prime, and Pfizer; and is an employee and shareholder of Amgen. AJO reports being a paid consultant for Merck, BMS, and Array and a paid instructor for Pfizer. JAW is a former employee of Eli Lilly and Company and a shareholder of Eli Lilly and Company, Pfizer, and Johnson & Johnson. MDW, WZ, and DBR are employees and shareholders of Eli Lilly and Company. DLF is a former employee of Eli Lilly and Company and Verastem Oncology, a current employee of Editas Medicine; and a shareholder of Eli Lilly and Company, Verastem Oncology, and Editas Medicine. KMBM is a former employee of Eli Lilly and Company, a current employee of AbbVie and a shareholder of Eli Lilly and Company. AP reports receiving research grants from Merck, Pfizer, Eli Lilly and Company, Plexxikon, Corvus Pharmaceuticals, Tesaro, Abbvie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus, Fochon, Upsher-Smith, Exelixis, Innovent Biologics (Suzhou), Seattle Genetics.

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Kollmannsberger, C., Britten, C.D., Olszanski, A.J. et al. A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody–drug conjugate, in patients with advanced or metastatic cancer. Invest New Drugs 39, 1613–1623 (2021). https://doi.org/10.1007/s10637-021-01146-x

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