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A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

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Summary

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1–56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4–65.1), and the median PFS was 7.4 months (95% CI: 6.7–13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

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Acknowledgements

We would like to thank all patients, together with their families and friends, who participated in the study. We would also like to thank the many investigators (along with individuals at the investigational sites who support the investigators), and the global and local study teams for their efforts for this study. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Funding

This work was supported by GlaxoSmithKline, Inc.

Author information

Authors and Affiliations

  1. Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Emilie M. J. van Brummelen

  2. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation

    Evgeny Levchenko

  3. Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain

    Manuel Dómine

  4. University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, UK

    Dean A. Fennell

  5. University of Chicago Medical Center, Chicago, IL, USA

    Hedy L. Kindler

  6. Instituto Oncológico Rosell, Hospital Universitario Dexeus, Grupo Quironsalud, Barcelona, Spain

    Santiago Viteri

  7. Karmanos Cancer Institute, Detroit, MI, USA

    Shirish Gadgeel

  8. Hospital Universitario Ramón y Cajal, Madrid, Spain

    Pilar Garrido López

  9. Leningrad Regional Oncology Dispensary, St. Petersburg, Russian Federation

    Vladimir Kostorov

  10. Washington University School of Medicine, St. Louis, MO, USA

    Daniel Morgensztern

  11. First Pavlov State Medical University, St. Petersburg, Russian Federation

    Sergey Orlov

  12. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Marjorie G. Zauderer

  13. Respiratory Oncology Unit, Department of Pneumology, University Hospitals KU Leuven, Leuven, Belgium

    Johan F. Vansteenkiste

  14. GlaxoSmithKline, Inc., 1250 South Collegeville Road, Collegeville, PA, USA

    Katherine Baker-Neblett, James Vasquez, Xiaowei Wang, Li Yan, Ionel Mitrica & M. Phillip DeYoung

  15. Five Prime Therapeutics, Inc., South San Francisco, CA, USA

    David I. Bellovin

  16. Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens

  17. Phase I Trials Unit, Medical Oncology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Campus Universitario Teatinos, s/n 29010, Málaga, Spain

    José Trigo

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  1. Emilie M. J. van Brummelen
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Corresponding authors

Correspondence to M. Phillip DeYoung or José Trigo.

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Conflict of interest

M. Dómine reports receiving speakers’ bureau honoraria and is a consultant/advisory board member for AstraZeneca (AZ), Bristol-Myers Squibb (BMS), Boehringer Ingelheim (BI), Celgene, MSD, Roche-Genentech, and AbbVie.

D.A. Fennell reports receiving commercial research grants from Astex, Bayer, and BI, speakers’ bureau honoraria from BI and BMS and is a consultant/advisory board member for Roche, Bayer, Aldeyra Therapeutics, AbbVie, and BMS.

H.L. Kindler reports receiving commercial research grants from Aduro Biotech, AZ, Bayer, GlaxoSmithKline (GSK), Merck, MedImmune, Verastem, BMS, Eli Lilly, Polaris, and Deciphera and is a consultant/advisory board member for Aduro Biotech, MedImmune, Bayer, Celgene, GSK, AZ, Merck, BMS, BI, Ipsen, Erytech Pharma, Five Prime Therapeutics, and Paredox Therapeutics.

S. Gadgeel is a consultant/advisory board member for AZ, Roche-Genentech, Takeda, BMS, and AbbVie.

P. Garrido Lopez reports receiving commercial research grants from GSK, Celgene, Sanofi, PharmaMar, Theradex, Roche, BMS, Lilly, Guardant, Sysmex, Takeda, AZ, BI, and Novartis and is a consultant/advisory board member for Roche, MSD, BMS, BI, Pfizer, Abbvie, Guardant,

Novartis, Lilly, AZ, Janssen, Sysmex, Blueprint Medicine, and Takeda.

D. Morgensztern is a consultant/advisory board member for Takeda, AbbVie, BMS, and PharmaMar.

M.G. Zauderer is an employee of MSKCC and MSKCC has an institutional collaboration agreement with IBM for Watson for Oncology and receives royalties from IBM, is the Chair of the Board of Directors of the Mesothelioma Applied Research Foundation, reports receiving commercial research grants from MedImmune, Epizyme, Polaris, Sellas Life Sciences, BMS, and Millenium, and is a consultant/advisory board member for Epizyme and Aldeyra Therapeutics.

J.F. Vansteenkiste reports receiving research funding/honoraria from MSD, AZ, BMS, BI, and Roche and is a consultant/advisory board member for AZ, BMS, BI, MSD, and Roche.

K. Baker-Neblett, X. Wang, L. Yan, I. Mitrica, and M.P. DeYoung are employees of and hold ownership interest in GlaxoSmithKline. J. Vasquez is an employee of GlaxoSmithKline.

D.I. Bellovin is an employee of and holds ownership interest in Five Prime Therapeutics.

J.H.M. Schellens is an employee of and holds ownership interest in Modra Pharmaceuticals and is a consultant/advisory board member for Debiopharm.

J.M. Trigo reports receiving speakers’ bureau honoraria from BMS and BI and is a consultant/advisory board member for BMS, BI, Merck, and Takeda.

No potential conflicts of interest were disclosed by the other authors.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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

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van Brummelen, E.M.J., Levchenko, E., Dómine, M. et al. A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma. Invest New Drugs 38, 457–467 (2020). https://doi.org/10.1007/s10637-019-00783-7

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