2. Academic Validation
  3. Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis

Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis

  • Cancer Res. 2022 Jul 18;82(14):2552-2564. doi: 10.1158/0008-5472.CAN-21-4152.
Ester Bonfill-Teixidor  # 1,  Raffaella Iurlaro  # 1,  Cornelia Handl  # 2,  Jürgen Wichmann 2,  Alexandra Arias 1,  Isabel Cuartas 1,  Jasmin Emmenegger 2,  Andrea Romagnani 2,  Luca Mangano 2,  Thomas Lorber 2,  Marco Berrera 2,  Christina Godfried Sie 2,  Fabian Köchl 2,  Jan Eckmann 3,  Romi Feddersen 3,  Martin Kornacker 2,  Gabriel Schnetzler 2,  Marta Cicuendez 1,  Esteban Cordero 1,  Thomaz E Topczewski 4,  Abel Ferres-Pijoan 4,  Josep González 4,  Francisco Martínez-Ricarte 1,  Eva Muñoz-Couselo 1,  Josep Tabernero 1,  James R Bischoff 2,  Piergiorgio Pettazzoni 2,  Joan Seoane 1
Affiliations

Affiliations

  • 1 Preclinical and Translational Research Program-Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 2 Roche Pharma Research and Early Development pRED, Roche Innovation Center Basel, Basel, Switzerland.
  • 3 Roche Pharma Research and Early Development pRED, Roche Innovation Center Munich, Penzberg, Germany.
  • 4 Hospital Clinic, University of Barcelona and Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • # Contributed equally.
PMID: 35584009 DOI: 10.1158/0008-5472.CAN-21-4152
Abstract

The therapeutic benefit of approved BRaf and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRaf V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRaf activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRaf V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRaf kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses.

Significance: A brain-penetrant BRaf Inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRaf Inhibitor therapy, supporting further investigation into its clinical utility.

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