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Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer

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Abstract

Purpose

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).

Methods

Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively.

Results

Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected.

Conclusion

Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.

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Acknowledgements

We thank all patients for participation, the clinical research unit of the Antoni van Leeuwenhoek hospital—Netherlands Cancer Institute Amsterdam for conduct of the trial and Novartis for providing study drugs and an unrestricted grant.

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Author notes

  1. Sanne C. F. A. Huijberts, Robin M. J. M. van Geel and Emilie M. J. van Brummelen have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Sanne C. F. A. Huijberts, Robin M. J. M. van Geel, Emilie M. J. van Brummelen, Frans L. Opdam, Serena Marchetti, Neeltje Steeghs & Saskia Pulleman

  2. Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands

    Robin M. J. M. van Geel

  3. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

    Robin M. J. M. van Geel

  4. Centre for Human Drug Research, Leiden, The Netherlands

    Emilie M. J. van Brummelen

  5. Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Bas Thijssen, Hilde Rosing, Alwin D. R. Huitema & Jos H. Beijnen

  6. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Kim Monkhorst

  7. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands

    Alwin D. R. Huitema

  8. Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

  9. Division of Molecular Carcinogenesis, Oncode Institute and The Netherlands Cancer Institute, Amsterdam, The Netherlands

    René Bernards

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Correspondence to Sanne C. F. A. Huijberts or Frans L. Opdam.

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Conflict of interest

JB and JS (partly) hold a patent on oral taxane formulations, and are shareholders and part-time employees of Modra Pharmaceuticals, a spin out company developing oral taxanes; not related to the manuscript. RB holds a patent on the use of MEK and HER inhibitors in KRAS-mutant cancers. The other authors declare that they do not have a conflict of interest related to this manuscript.

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Huijberts, S.C.F.A., van Geel, R.M.J.M., van Brummelen, E.M.J. et al. Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer. Cancer Chemother Pharmacol 85, 917–930 (2020). https://doi.org/10.1007/s00280-020-04066-4

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