Marcel Wiesweg1, Cedric Preuß2, Julia Roeper3, Martin Metzenmacher4, Wilfried Eberhardt4, Ursula Stropiep3, Katrin Wedeken3, Henning Reis5, Thomas Herold5, Kaid Darwiche6, Clemens Aigner7, Martin Stuschke8, Hans-Ulrich Schildhaus5, Kurt W Schmid9, Markus Falk10, Lukas Heukamp10, Markus Tiemann10, Frank Griesinger3, Martin Schuler11. 1. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; Division of Thoracic Oncology, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany. Electronic address: marcel.wiesweg@uk-essen.de. 2. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany. 3. Department of Hematology and Oncology, University Department Internal Medicine-Oncology, Pius Hospital, Medical Campus University of Oldenburg, Oldenburg, Germany; Lung Cancer Network NOWEL, Oldenburg, Germany. 4. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; Division of Thoracic Oncology, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany. 5. Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany. 6. Department of Pulmonary Medicine, Section of Interventional Pneumology, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany. 7. Department of Thoracic Surgery and Endoscopy, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 8. Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 9. Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 10. Institute for Hematopathology Hamburg, Hamburg, Germany; Lung Cancer Network NOWEL, Oldenburg, Germany. 11. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany; Division of Thoracic Oncology, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
Abstract
OBJECTIVE: BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non-small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts. METHODS: We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAF V600E-targeting. RESULTS: In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF-mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class. CONCLUSIONS: Patients with BRAF-mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF-mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors.
OBJECTIVE:BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non-small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts. METHODS: We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAFV600E-targeting. RESULTS: In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF-mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class. CONCLUSIONS:Patients with BRAF-mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF-mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors.