Non-small-cell lung cancer: how to manage BRAF-mutated disease

Abstract

BRAF mutations are reported in about 3–5% of non-small-cell lung cancer (NSCLC), almost exclusively in adenocarcinoma histology, and are classified into three different classes. The segmentation of BRAF mutations into V600 (class 1) and non-V600 (classes 2 and 3) relies on their biological characteristics and is of interest for predicting the therapeutic benefit of targeted therapies and immunotherapy. Given the relative rarity of this molecular subset of disease, evidence supporting treatment choices is limited. This review aims to offer a comprehensive update about available therapeutic options for patients with NSCLC harbouring BRAF mutations to guide the physician in the choice of treatment strategies. We collected the most relevant available data, from single-arm phase II studies and retrospective analyses conducted in advanced NSCLC, regarding the efficacy of BRAF and MEK inhibitors in both V600 and non-V600 BRAF mutations. We included case reports and smaller experiences that could provide information on specific alterations. With respect to immunotherapy, we reviewed retrospective evidence on immune-checkpoint inhibitors in this molecular subset, whereas data about chemo-immunotherapy in this molecular subgroup are lacking. Moreover, we included the available, though limited, retrospective evidence of immunotherapy as consolidation after chemo-radiation for unresectable stage III BRAF -mutant NSCLC, and an overview of ongoing clinical trials in the peri-operative setting that could open new perspectives in the future.

Successful dabrafenib and trametinib combination therapy in a patient with recurrent BRAFV600E‐mutant non‐small‐cell lung cancer and coexisting radiation pneumonitis

“…Mitogen‐activated protein kinase inhibitors, such as trametinib, have been shown to cause pneumonitis induced by targeted molecular therapy. 4 Among targeted therapies for non‐small cell lung cancer, pneumonitis has been reported in 5% of patients with gefitinib, 4.5% with erlotinib, 0.7% with ALK inhibitors, such as crizotinib, ceritinib, and 6.5% with osimertinib therapy. 1 , 5 It has been also reported that 1.1% of patients using dabrafenib plus trametinib developed pneumonitis.…”

“…Given that the combination of radiotherapy and BRAF inhibitors for brain metastases of melanoma may increase cutaneous radiation‐induced reactions, 7 and the exclusion from a clinical trial of patients who had been treated with radiotherapy within 14 days, 3 BRAF inhibitors were started at least 2 weeks after SRT. Trametinib has been reported to cause interstitial lung disease in real‐world clinical practice, 4 accordingly, dabrafenib and trametinib combination therapy was initiated under PSL therapy, which did not worsen the interstitial pneumonitis. When the PSL dose was reduced to 8 mg, there was a worsening of symptoms.…”

Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers

“…BRAFV600E mutations in NSCLC are more common in micropapillary patterns and females with no smoking history, while non- V600E BRAF mutations are more likely associated with mucinous patterns and males with a smoking history [ 2 ]. BRAF mutations are associated with metastasis to the central nervous system (CNS), especially with class II and III mutations [ 65 ]. In an analysis of BRAF -altered samples by Negrao et al, the most common BRAF mutations were missense mutations (90%, with 45% of which were variants of unknown significance), followed by nonsense and splice-site mutations (5% each) [ 64 ].…”

Advancements in NSCLC

“…BRAF, located on chromosome 7, encodes a serine/threonine protein kinase 40 . In the context of NSCLC, BRAF mutations occur in ~1.5% to 3.5% of cases 41 .…”