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Exposure–response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients

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Abstract

Introduction

Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib.

Patients and methods

An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration–time Curve and trametinib trough concentrations (Cmin), univariable and multivariable exposure–response analyses were performed.

Results

In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with Cmin ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib Cmin ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36–0.85, P = 0.007). Median PFS in patients with trametinib Cmin levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with Cmin below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47–1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities.

Conclusions

Overall survival of metastasized melanoma patients with trametinib Cmin levels ≥ 15.6 ng/mL is ten months longer compared to patients with Cmin below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.

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Data availability

Data are available upon reasonable request by contacting the corresponding author.

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Funding

No funding has been received for this research.

Author information

Authors and Affiliations

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

    Stefanie L. Groenland & N. Steeghs

  2. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J. M. Janssen, C. M. Nijenhuis, N. de Vries, H. Rosing, J. H. Beijnen & A. D. R. Huitema

  3. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    S. Wilgenhof, J. V. van Thienen, J. B. A. G. Haanen & C. U. Blank

  4. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    J. H. Beijnen

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

    A. D. R. Huitema

  6. Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    A. D. R. Huitema

Authors
  1. Stefanie L. Groenland
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  2. J. M. Janssen
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  3. C. M. Nijenhuis
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  4. N. de Vries
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  8. J. B. A. G. Haanen
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  11. A. D. R. Huitema
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Corresponding author

Correspondence to Stefanie L. Groenland.

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Conflict of interest

No author has received support for the work in this manuscript. JBAGH served as a consultant advisor for Achilles Therapeutics, AIMM, Amgen, BioNTech, BMS, Bayer, Celsius Therapeutics, Gadeta, GSK, Ipsen, Immunocore, MSD, Merck Serono, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures and Vaximm, and received research funding from BMS, BioNTech, Novartis and MSD. CUB served as a consultant advisor for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre and Third Rock Ventures, received research funding from BMS, Novartis and Nanostring, reports stock ownership of Uniti Cars and is cofounder of Immagene B.V. JHB is a part-time employee, shareholder and patent holder of Modra Pharmaceuticals (a spin-out company developing oral taxane formulations, not related to this work). NS served as a consultant advisor for AIMM Therapeutics, Boehringer Ingelheim, Ellipses Pharma, and received research funding for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, Lilly, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, Takeda (outside the submitted work). All remaining authors have declared no conflict of interest.

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Groenland, S.L., Janssen, J.M., Nijenhuis, C.M. et al. Exposure–response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients. Cancer Chemother Pharmacol 91, 447–456 (2023). https://doi.org/10.1007/s00280-023-04517-8

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