Pei Meng1, Bart Koopman1, Klaas Kok2, Arja Ter Elst1, Ed Schuuring1, Léon C van Kempen1, Wim Timens1, T Jeroen N Hiltermann3, Harry J M Groen3, Anke van den Berg1, Anthonie J van der Wekken4. 1. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, the Netherlands. 2. Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands. 3. Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, the Netherlands. 4. Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address: a.j.van.der.wekken@umcg.nl.
Abstract
INTRODUCTION: Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations. METHODS: Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered. RESULTS: Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy. CONCLUSION: BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.
INTRODUCTION: Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations. METHODS: Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered. RESULTS: Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy. CONCLUSION: BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.
Authors: Diana Schaufler; David F Ast; Hannah L Tumbrink; Nima Abedpour; Lukas Maas; Ayla E Schwäbe; Inga Spille; Stefanie Lennartz; Jana Fassunke; Mihaela Aldea; Benjamin Besse; David Planchard; Lucia Nogova; Sebastian Michels; Carsten Kobe; Thorsten Persigehl; Theresa Westphal; Sophia Koleczko; Rieke Fischer; Jan-Phillip Weber; Janine Altmüller; Roman K Thomas; Sabine Merkelbach-Bruse; Oliver Gautschi; Laura Mezquita; Reinhard Büttner; Jürgen Wolf; Martin Peifer; Johannes Brägelmann; Matthias Scheffler; Martin L Sos Journal: NPJ Precis Oncol Date: 2021-12-17