Response to targeted and immune therapy in patients with NSCLC and BRAF non-V600E mutations: A retrospective, multicenter analysis within the national Network Genomic Medicine Lung Cancer (nNGM) in Germany.

person Cornelia Kropf-Sanchen Department of Internal Medicine II, Ulm University Medical Center, DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim,, Ulm/Mannheim, Germany info_outline Cornelia Kropf-Sanchen, Anna Rasokat, Petros Christopoulos, Felix Carl Saalfeld, Thomas Wehler, Maximilian Rost, Jonas Kulhavy, Niels Reinmuth, Christian Schulz, Juergen Wolf, Reinhard Buettner, Sabine Merkelbach-Bruse, Nadine Gaisa, Gerlinde Schmidtke-Schrezenmeier, Maike Collienne, Melanie Janning, Michael Thomas, Matthias Scheffler, Tilman Brummer, Sonja Loges

Authors person Cornelia Kropf-Sanchen Department of Internal Medicine II, Ulm University Medical Center, DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim,, Ulm/Mannheim, Germany info_outline Cornelia Kropf-Sanchen, Anna Rasokat, Petros Christopoulos, Felix Carl Saalfeld, Thomas Wehler, Maximilian Rost, Jonas Kulhavy, Niels Reinmuth, Christian Schulz, Juergen Wolf, Reinhard Buettner, Sabine Merkelbach-Bruse, Nadine Gaisa, Gerlinde Schmidtke-Schrezenmeier, Maike Collienne, Melanie Janning, Michael Thomas, Matthias Scheffler, Tilman Brummer, Sonja Loges Organizations Department of Internal Medicine II, Ulm University Medical Center, DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim,, Ulm/Mannheim, Germany, Network Genomic Medicine, Cologne; University Hospital of Cologne, Cologne, Germany, Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), NCT Heidelberg, and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany, Clinic for Internal Medicine I, University Hospital, TU Dresden, Dresden, Germany, Clinic for Internal Medicine, Justus-Liebig-University, Giessen, Germany, Department of Medicine II, Hematology, Oncology, University Hospital Frankfurt, Frankfurt, Germany, Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken and Bavarian Cancer Research Center (BZKF), University Hospital Wuerzburg, Wuerzburg, Germany, Thoracic Oncology, Asklepios Clinics Munich-Gauting, Gauting, Germany, Universitaetsklinikum Regensburg, Regensburg, Germany, Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany, Institute of Pathology, University Hospital of Cologne, Cologne, Germany, University of Cologne, Institute for Pathology, Faculty of Medicine and University Hospital Cologne, Köln, Germany, Department of Pathology, University of Ulm, Ulm, Germany, Division of Pulmonology, Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany, DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), German Center for Lung Research (DZL), Mannheim/Heidelberg, Germany, Lung Cancer Group Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Dept. I of Internal Medicine, Cologne, Germany, IMMZ, Freiburg, Germany Abstract Disclosures Research Funding Hector Foundation II DKFZ-Hector Cancer Institute Background: Non-small-cell lung cancer (NSCLC) poses a significant global health challenge, with multiple treatment strategies targeting oncogenic drivers. The BRAF V600E mutation, found in 1-3% of NSCLC patients, is effectively targeted by dabrafenib and trametinib, achieving considerable clinical benefits. However, BRAF non-V600E mutations, constituting half of all BRAF mutations, are challenging to treat due to their heterogeneity and lack of information concerning outcome upon targeted and immune therapies. Methods: In order to investigate outcome of patients with BRAF non-V600E mutations upon targeted and (chemo)immune therapy we conducted a retrospective analysis within the national Network Genomic Medicine (nNGM) lung cancer in Germany and. In addition, we evaluated the MEK/ERK activation potential of the BRAF non-V600E mutations from our cohort and their sensitivity to dabrafenib and/or trametinib in vitro. Results: Twenty patients with 11 different BRAF non-V600E mutations were identified. From these patients, 15% achieved partial remission, 40% stable disease, and 40% progressive disease under TKI-therapy. Progression-free survival (PFS) upon targeted therapy ranged from 0.9 to 53.5 months. Notably, patients with MEK/ERK-activating BRAF non-V600E mutations exhibited persistent responses (mPFS 9 months). Specifically, patients with the high-activity mutants p.V600D, p.V600K and p.K601E showed responses to TKI therapy (mPFS 9.2 months). Similar outcome was achieved in patients with activating p.G466V (PFS 4.9 months), p.G469R (PFS 9 months), p.G469V (mPFS 28.2 months) and p.V600_K601delinsE (mPFS 5.6 months) mutations. Interestingly, outcome upon treatment with (chemo)immune therapy for these patients with activating mutations was similar compared to targeted therapy (mPFS 15.0 and 11.7 months). Expectedly, patients with kinase-dead mutants (p.G466R, p.D594E, p.D594G) were not responding to TKIs (mPFS 2.5 months) and had considerably better outcomes under (chemo)immune therapy (mPFS 11.0 and 11 months). Conclusions: Patients with activating BRAF non-V600E mutations can be treated efficiently with BRAF/MEK TKI or (chemo)immune therapy while patients with non-activating mutations do not benefit from targeted therapy but from (chemo)immune therapy. Hence, it is of key importance to apply preclinical activation assays showing good correlations to clinical outcomes in our study prior to applying targeted therapy in patients with unknown BRAF non-V600E mutations. Altogether, our study helps to guide personalized treatment decisions in this patient population.