Role of Immunotherapy Across BRAF-Mutant NSCLC Requires Clarification

Non–small-cell lung cancer (NSCLC) with BRAF mutations affects a small but significant portion of patients overall who have NSCLC, and identifying these patients is of increasing importance as the therapeutic landscape expands. A review published in Lung Cancer highlights current treatment strategies and tools to identify patients with BRAF-mutated NSCLC.

Approximately 4% of patients with NSCLC harbor BRAF mutations, and their disease can be stratified into 3 subtypes: class I (V600E), class II, and class III (both non-V600). Each of the subtypes has different prognostic and predictive outcomes. Identifying BRAF mutations in addition to EGFR, ALK, and ROS-1 mutations has become necessary considering the approval of BRAF inhibition in metastatic NSCLC. BRAF mutations are also relevant in melanoma (39.7% of cases), thyroid cancer (33.3% of cases), and small intestinal malignancies (8.9% of cases).

BRAF mutations have been associated with a history of current or former smoking, and the most common histological pattern is adenocarcinoma. Results from one large study also show a higher percentage of men harbor BRAF mutations vs women (61% vs 39%). The prognostic impact of BRAF mutations is still not clear, although the same study reported lower objective response rates in BRAF-mutated NSCLC compared with wild-type NSCLC. Progression-free survival and overall survival were similar in both populations.

Protein chain reaction (PCR) or next-generation sequencing (NGS) are typically used to identify BRAF mutations, with NGS often preferred because it can simultaneously identify multiple mutations, the authors noted. Another potential option, immunohistochemistry using an antibody that is anti–BRAF V600E, has shown promise in detecting BRAF V600E mutations but not non-V600E mutations. Using PCR or NGS to analyze cell-free DNA (cfDNA) via liquid biopsies is another possible alternative. Several studies suggest cfDNA may be a reliable option for mutation detection, and it is a minimally invasive alternative that could be particularly useful when tissue samples are unavailable.

MAPK inhibitors and the combination of BRAF and MEK inhibitors, initially developed in the field of melanoma, are also highly relevant to BRAF-mutant NSCLC. In previously treated patients with BRAF V600E mutations, vemurafenib and dabrafenib have demonstrated clinical activity. Dabrafenib plus trametinib, however, has shown better results both in the first- and second-line settings and was approved by the FDA for patients with BRAF V600E mutations.

Non-V600 mutations in NSCLC do not have any FDA-approved targeted therapies. This represents a significant need, as approximately half of BRAF-mutant NSCLC patients harbor non-V600 aberrations.

“A paradigm shift from the double BRAF/MEK inhibition to combinations with agents with distinct mechanisms of action, such as immune-checkpoint inhibitors, pan-RAF, and selective ERK 1/ 2 inhibitors, is under investigation and may change the therapeutic landscape of BRAF-driven NSCLC,” the authors wrote.

Although MAPK and MEK inhibitors are more effective than anti-BRAF therapy alone, treatment resistance is a significant challenge in this patient population. Treatment resistance in the context of NSCLC is still not fully understood, and research is mainly sourced from studies of advanced melanoma. Early studies are exploring RAF inhibitors or ERK inhibitors to mitigate treatment resistance by preventing the reactivation of the MAPK pathway, which is a main mechanism in secondary resistance to BRAF inhibition.

The role of immunotherapy in NSCLC with BRAF mutations overall is still not entirely defined, and potential combinations of immunotherapy and chemotherapy have not yet been investigated, the authors noted. In general, more research is necessary to clarify and confirm the role of immunotherapy in this patient subset.

“Given the complexity and plasticity of resistance pathways, the future application of tumor and liquid biopsy for molecular profiling at the time of progression will add relevant information regarding tumor biology, opening new horizons for treatment tailoring, taking into account acquired and targetable resistance mechanisms,” the authors concluded. “Available therapeutic approaches and future combinations, in addition to more potent molecules, will improve the management of BRAF-driven NSCLC.”

Reference

Riudavets M, Cascetta P, Planchard D. Targeting BRAF-mutant non-small cell lung cancer: Current status and future directions. Lung Cancer. Published online May 26, 2022. doi:10.1016/j.lungcan.2022.05.014