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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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References

  1. Yap TA, Aerts JG, Popat S, Fennell DA (2017) Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer 17:475–488

    Article  CAS  Google Scholar 

  2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of Pemetrexed in combination with Cisplatin versus Cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644

    Article  CAS  Google Scholar 

  3. Blackwell C, Sherk C, Fricko M, Ganji G, Barnette M, Hoang B, Tunstead J, Skedzielewski T, Alsaid H, Jucker BM, Minthorn E, Kumar R, DeYoung M (2016) Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230. Oncotarget 7:39861–39871

    Article  Google Scholar 

  4. Stapelberg M, Gellert N, Swettenham E, Tomasetti M, Witting PK, Procopio A, Neuzil J (2005) α-Tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor Autocrine loop. J Biol Chem 280:25369–25376

    Article  CAS  Google Scholar 

  5. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129

    Article  CAS  Google Scholar 

  6. Grose R, Dickson C (2005) Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 16:179–186

    Article  CAS  Google Scholar 

  7. Itoh N (2007) The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull 30:1819–1825

    Article  CAS  Google Scholar 

  8. Dieci MV, Arnedos M, Andre F, Soria JC (2013) Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov 3:264–279

    Article  CAS  Google Scholar 

  9. Nishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T (2018) Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Investig New Drugs 36:424–434

    Article  CAS  Google Scholar 

  10. Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J (2017) Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol 35:157–165

    Article  CAS  Google Scholar 

  11. Michael M, Bang Y-J, Park YS, Kang YK, Kim TM, Hamid O, Thornton D, Tate SC, Raddad E, Tie J (2017) A phase 1 study of LY2874455, an Oral selective pan-FGFR inhibitor, in patients with advanced Cancer. Target Oncol 12:463–474

    Article  Google Scholar 

  12. Harding TC, Long L, Palencia S, Zhang H, Sadra A, Hestir K et al (2013) Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of Cancer. Sci Transl Med 5:178ra39

    Article  Google Scholar 

  13. Tolcher AW, Papadopoulos KP, Patnaik A, Wilson K, Thayer S, Zanghi J, Gemo AT, Kavanaugh WM, Keer HN, LoRusso PM (2016) A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. Ann Oncol 27:526–532

    Article  CAS  Google Scholar 

  14. Pattarozzi A, Carra E, Favoni RE, Würth R, Marubbi D, Filiberti RA, Mutti L, Florio T, Barbieri F, Daga A (2017) The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells. Stem Cell Res Ther 8:119

    Article  Google Scholar 

  15. Schelch K, Hoda MA, Klikovits T, Münzker J, Ghanim B, Wagner C, Garay T, Laszlo V, Setinek U, Dome B, Filipits M, Pirker C, Heffeter P, Selzer E, Tovari J, Torok S, Kenessey I, Holzmann K, Grasl-Kraupp B, Marian B, Klepetko W, Berger W, Hegedus B, Grusch M (2014) Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. Am J Respir Crit Care Med 190:763–772

    Article  CAS  Google Scholar 

  16. Marek LA, Hinz TK, von Massenhausen A, Olszewski KA, Kleczko EK, Boehm D et al (2014) Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma. Mol Cancer Res 12:1460–1469

    Article  CAS  Google Scholar 

  17. U.S. Department of Health and Human Services FaDA, Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM) (2001) Guidance for Industry: Bioanalytical Method Validation

  18. Davidson B, Vintman L, Zcharia E, Bedrossian C, Berner A, Nielsen S, Ilan N, Vlodavsky I, Reich R (2004) Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. Clin Exp Metastasis 21:469–476

    Article  CAS  Google Scholar 

  19. Li Q, Wang W, Yamada T, Matsumoto K, Sakai K, Bando Y, Uehara H, Nishioka Y, Sone S, Iwakiri S, Itoi K, Utsugi T, Yasumoto K, Yano S (2011) Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network. Am J Pathol 179:1483–1493

    Article  CAS  Google Scholar 

  20. Kumar-Singh S, Weyler J, Martin MJ, Vermeulen PB, Van Marck E (1999) Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression. J Pathol 189:72–78

    Article  CAS  Google Scholar 

  21. Hanigan MH, Devarajan P (2003) Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1:47–61

    PubMed  PubMed Central  Google Scholar 

  22. Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A (2016) Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma Avastin Cisplatin Pemetrexed study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387:1405–1414

    Article  CAS  Google Scholar 

  23. Paik PK, Shen R, Berger MF, Ferry D, Soria JC, Mathewson A, Rooney C, Smith NR, Cullberg M, Kilgour E, Landers D, Frewer P, Brooks N, André F (2017) A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers. Clin Cancer Res 23:5366–5373

    Article  CAS  Google Scholar 

  24. Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC (2015) Phase I dose-escalation study of JNJ-42756493, an Oral Pan–fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol 33:3401–3408

    Article  CAS  Google Scholar 

  25. Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, el-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, van Cutsem E, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T (2018) Phase II study of BGJ398 in patients with FGFR-altered advanced Cholangiocarcinoma. J Clin Oncol 36:276–282

    Article  CAS  Google Scholar 

  26. Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, Lennerz JK, Vu P, Deshpande V, Kambadakone A, Mussolin B, Reyes S, Henderson L, Sun JE, van Seventer EE, Gurski JM Jr, Baltschukat S, Schacher-Engstler B, Barys L, Stamm C, Furet P, Ryan DP, Stone JR, Iafrate AJ, Getz G, Porta DG, Tiedt R, Bardelli A, Juric D, Corcoran RB, Bardeesy N, Zhu AX (2017) Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive Cholangiocarcinoma. Cancer Discov 7:252–263

    Article  CAS  Google Scholar 

  27. Quispel-Janssen JM, Badhai J, Schunselaar L, Price S, Brammeld J, Iorio F, Kolluri K, Garnett M, Berns A, Baas P, McDermott U, Neefjes J, Alifrangis C (2018) Comprehensive Pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition. Clin Cancer Res 24:84–94

    Article  CAS  Google Scholar 

  28. Marcq E, Siozopoulou V, De Waele J, van Audenaerde J, Zwaenepoel K, Santermans E et al (2017) Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology 6:e1261241

    Article  Google Scholar 

  29. Alley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, van Brummelen E (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18:623–630

    Article  CAS  Google Scholar 

  30. Zalcman G, Mazieres J, Greillier L, Lantuejoul S, Dô P, Bylicki O et al (2017) LBA58_PR second or 3rd line Nivolumab (Nivo) versus Nivo plus Ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: up-dated results of the IFCT-1501 MAPS2 randomized phase 2 trial. Ann Oncol 28 Issue suppl_5, mdx440.074

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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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