Francesco Facchinetti1, Ludovic Lacroix2, Laura Mezquita3, Jean-Yves Scoazec4, Yohann Loriot3, Lambros Tselikas5, Anas Gazzah6, Etienne Rouleau2, Julien Adam7, Stefan Michiels8, Christophe Massard6, Fabrice André9, Ken A Olaussen1, Gilles Vassal10, Karen Howarth11, Benjamin Besse9, Jean-Charles Soria12, Luc Friboulet13, David Planchard3. 1. Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800, Villejuif, France. 2. Department of Medical Biology and Pathology, Gustave Roussy Cancer Centre, Villejuif, France. 3. Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France. 4. Department of Pathology, Gustave Roussy Cancer Centre, Villejuif, France; Université Paris-Saclay, Institut Gustave Roussy, Inserm US23, CNRS UMS3655, AMMICa, Villejuif, France. 5. Department of Interventional Radiology, Gustave Roussy Cancer Centre, Villejuif, France. 6. Drug Development Department (DITEP), Gustave Roussy Cancer Centre, Villejuif, France. 7. Department of Pathology, Gustave Roussy Cancer Centre, Villejuif, France. 8. Biostatistics and Epidemiology Service, Gustave Roussy Cancer Centre, Villejuif, France. 9. Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800, Villejuif, France; Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France. 10. Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France. 11. Inivata Ltd, Granta Park, Cambridge, United Kingdom. 12. Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800, Villejuif, France; Drug Development Department (DITEP), Gustave Roussy Cancer Centre, Villejuif, France. 13. Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800, Villejuif, France. Electronic address: luc.friboulet@gustaveroussy.fr.
Abstract
INTRODUCTION: BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAFV600E NSCLC. PATIENTS AND METHODS: Patients with BRAFV600E NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array. RESULTS: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb). CONCLUSIONS: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAFV600E NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
INTRODUCTION:BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAFV600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAFV600ENSCLC. PATIENTS AND METHODS: Patients with BRAFV600ENSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array. RESULTS: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and ratsarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb). CONCLUSIONS: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAFV600ENSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
Authors: Gonzalo Recondo; Linda Mahjoubi; Aline Maillard; Yohann Loriot; Ludovic Bigot; Francesco Facchinetti; Rastislav Bahleda; Anas Gazzah; Antoine Hollebecque; Laura Mezquita; David Planchard; Charles Naltet; Pernelle Lavaud; Ludovic Lacroix; Catherine Richon; Aurelie Abou Lovergne; Thierry De Baere; Lambros Tselikas; Olivier Deas; Claudio Nicotra; Maud Ngo-Camus; Rosa L Frias; Eric Solary; Eric Angevin; Alexander Eggermont; Ken A Olaussen; Gilles Vassal; Stefan Michiels; Fabrice Andre; Jean-Yves Scoazec; Christophe Massard; Jean-Charles Soria; Benjamin Besse; Luc Friboulet Journal: NPJ Precis Oncol Date: 2020-09-08