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A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment

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Summary

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug–related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29–44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

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Data availability

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

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Acknowledgements

We would like to thank the capmatinib Early Program Team members at Novartis Pharmaceuticals Corporation, in particular Luigi Manenti, for their significant contribution to the study. O. Alejandro Balbin is thanked for assistance with the analysis of next-generation sequencing data and Angela Tam for generating preclinical combination data. Medical writing assistance was provided by Zoe Crossman, PhD of Articulate Science Ltd. and was funded by Novartis Pharmaceuticals Corporation.

Funding

This work was supported by Novartis Pharmaceuticals Corporation.

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Authors and Affiliations

  1. Department of Medical Oncology, Institut Universitaire du Cancer de Toulouse (IUCT) - Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France

    Jean-Pierre Delord

  2. Gastrointestinal Malignancies Division, Vall d’Hebron University Hospital, Barcelona, Spain

    Guillem Argilés

  3. Centre Léon Bérard, Lyon, France

    Jerôme Fayette

  4. Hematology/Oncology Department, Massachusetts General Hospital, Boston, MA, USA

    Lori Wirth

  5. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany

    Stefan Kasper

  6. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy

    Salvatore Siena

  7. Medical Oncology Department, Catalan Institut of Oncology – Hospitalet, IDIBELL, Barcelona, Spain

    Ricard Mesia

  8. Medical Oncology, Università Politecnica delle Marche-Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy

    Rossana Berardi

  9. CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

    Andrés Cervantes

  10. Department of Oncology, University Hospital Leuven, Leuven, Belgium

    Jeroen Dekervel

  11. Novartis Institutes for BioMedical Research, Shanghai, China

    Sylvia Zhao, Yongjian Sun & Andrea Myers

  12. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Huai-Xiang Hao

  13. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Ralph Tiedt & Sergio Vicente

  14. Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Lillian L. Siu

Authors
  1. Jean-Pierre Delord
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  2. Guillem Argilés
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  16. Andrea Myers
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Contributions

Jean-Pierre Delord, Guillem Argilés, Jerôme Fayette, Lori Wirth, Stefan Kasper, Salvatore Siena, Ricard Mesia, Rossana Berardi, Andrés Cervantes, Jeroen Dekervel, and Lillian L. Siu were involved in the acquisition of data; all authors analyzed and interpreted the data; Yongjian Sun undertook the statistical analysis; Huai-Xiang Hao supervised preclinical experiments of cetuximab + capmatinib combination; all authors were involved in the writing, review and/or revision of the manuscript. The final, submitted version was approved by all authors.

Corresponding author

Correspondence to Jean-Pierre Delord.

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Conflict of interest

JP. Delord reports research funding from F. Hoffmann-La Roche, Novartis Pharmaceuticals Corporation, Genentech, Bristol-Myers Squibb, Debiopharm, and Merck Sharpe & Dohme; advisory board participation for Bristol-Myers Squibb, Genentech, Novartis Pharmaceuticals Corporation, Merck Sharpe & Dohme and Takeda; patent holding in the field of molecular signature of cancer drugs effects. G. Argilés reports research funding, travel grants and advisory board participation for F. Hoffmann-La Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono and Menarini; honoraria to his institution from Bayer, Servier, Novartis Pharmaceuticals Corporation, Boehringer Ingelheim, Boston Pharmaceuticals, F. Hoffmann-La Roche, and Genentech. J. Fayette reports honoraria for consultancy or advisory role from AstraZeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme, Merck Serono, Innate Pharma, and Biogen; research funding from AstraZeneca and Bristol-Myers Squibb; travel, accommodation, or expenses from Bristol-Myers Squibb, AstraZeneca and Merck Sharpe & Dohme. L. Wirth reports acting in an advisory role for Eisai, Loxo Oncology, Merck, Ayala, Cue Biopharma and Genentech. S. Kasper reports personal fees, research grants, and advisory board membership from Roche, Merck Serono, Lilly, Amgen, Servier, Sanofi Aventis, Bristol-Myers Squibb, and Merck Sharpe & Dohme. S. Siena reports acting in an advisory role for Amgen, Bayer, Bristol-Myers Squibb, Roche, Merck, Merck Sharpe & Dohme, Novartis Pharmaceuticals Corporation, and Sanofi. R. Mesia reports an advisory role for Merck, Bristol-Myers Squibb, Merck Sharpe & Dohme, AstraZeneca, Roche, and Nanobiotix; speaker bureaus for Merck, Bristol-Myers Squibb, and Merck Sharpe & Dohme. A. Cervantes reports research grants to his institution form Novartis Pharmaceuticals Corporation to develop clinical trials on investigational compounds. J. Dekervel reports speaker fees, consulting fees or travel grants from Amgen, Bayer, Ipsen, Novartis Pharmaceuticals Corporation, Merck and Servier. L. Siu reports research funding for her institution from Novartis Pharmaceuticals Corporation for the conduct of this study. A. Myers, Y. Sun, H.-X. Hao, R. Tiedt, S. Vicente, and S. Zhao are all employed by Novartis Pharmaceuticals Corporation. R. Berardi declares that she has no conflict of interest.

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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 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Delord, JP., Argilés, G., Fayette, J. et al. A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment. Invest New Drugs 38, 1774–1783 (2020). https://doi.org/10.1007/s10637-020-00928-z

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