BRAF/MEK inhibitor rechallenge in advanced melanoma patients

Olivier J. Van Not, Alfons J.M. van den Eertwegh, John B. Haanen, Rozemarijn S. van Rijn, Maureen J.B. Aarts, Franchette W.P.J. van den Berkmortel, Christian U. Blank, Marye J. Boers-Sonderen, Jan Willem W.B. de Groot, Geke A.P. Hospers, Ellen Kapiteijn, Manja Bloem, Djura Piersma, Marion Stevense-den Boer, Rik J. Verheijden, Astrid A.M. van der Veldt, Michel W.J.M. Wouters, Willeke A.M. Blokx, Karijn P.M. Suijkerbuijk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking. 


Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival. 


The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1–5.2), and median OS was 8.2 months (95% CI, 7.2–9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7–4.0) versus 5.2 months (95% CI, 4.5–5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival. 


This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge.

Original languageEnglish
Pages (from-to)1673-1683
Number of pages11
Issue number9
Early online date10 Jan 2024
Publication statusPublished - 1 May 2024

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Publisher Copyright:
© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.


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