BRAF mutations and BRAF mutation functional class have no negative impact on the clinical outcome of advanced NSCLC and associate with susceptibility to immunotherapy.

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. 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. 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. 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.

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Déclaration de conflit d'intérêts

Conflict of interest statement Marcel Wiesweg—Honoraria: Boehringer Ingelheim, Novartis, Roche, Takeda. Research funding: Bristol-Myers Squibb, Takeda. Julia Roeper—Honoraria: Astra-Zeneca, Boehringer Ingelheim, Roche. Henning Reis—Consulting and advisory role: Bristol-Myers Squibb. Honoraria: Roche and Bristol-Myers Squibb. Travel support: Philips, Roche, Bristol-Myers Squibb. Research funding: Bristol-Myers Squibb. Share ownership: Bayer. Martin Metzenmacher—Honoraria: Merck, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Takeda. Wilfried Ernst Erich Eberhardt—Research funding to institution: Bristol-Myers Squibb, Astra Zeneca and Eli Lilly. Honoraria: Astra Zeneca, Bristol-Myers Squibb, Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Bayer, Johnson & Johnson, Amgen, Daichi Sankyo, Eli Lilly, Honoraria for educational lectures from Astra Zeneca, Bristol-Myers Squibb, Merck, Roche, Pfizer, Boehringer Ingelheim, Takeda, Amgen, Eli Lilly. Clemens Aigner—Research funding: Bristol-Myers Squibb. Kaid Darwiche—Consultancy/Advisory role: Boehringer Ingelheim, Novartis. Honoraria: Boehringer Ingelheim. Hans-Ulrich Schildhaus—Research grant: Novartis, Takeda. Honoraria: Pfizer, Novartis, Roche. Markus Tiemann—Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Takeda, Bristol-Myers Squibb, Merck. Frank Griesinger—Research funding to institution: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Siemens. Honoraria for educational lectures: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GlaxoSmithKline, Amgen, Honoraria: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GlaxoSmithKline, Siemens, Amgen. Martin Schuler—Consultant honoraria from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Roche, Takeda. Honoraria for educational lectures: Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis. Research funding to institution: Astra Zeneca, Boehringer Ingelheim, Bristol Myers-Squibb, Novartis. Other: Universität Duisburg-Essen (Patents). All remaining authors declared no conflicts of interest.