Dr Florez on the Role of First-Line IO for BRAF V600E+ Metastatic NSCLC

“The majority of responses [favored first-line] targeted therapy…this is very important, particularly in patients who have BRAF V600E [mutations] without tobacco history. These patients are less likely to benefit from immuno-oncology [treatment] in the first line, so they should go on targeted therapy.”

Narjust Florez, MD, the associate medical director of the Cancer Care Access Program and a thoracic medical oncologist at the Dana-Farber Brigham Cancer Center, a member of faculty at Harvard Medical School, and co-chair of the 2025 Bridging the Gaps in Lung Cancer meeting, addressed clinical decision-making in patients with oncogene-driven non–small cell lung cancer (NSCLC) during a live-streamed session that incorporated audience polling and expert interpretation.

In response to a clinical question regarding optimal first-line treatment for patients with BRAF V600E–mutated metastatic NSCLC, the majority of respondents on X and LinkedIn indicated a preference for targeted therapy over immune checkpoint blockade. Florez supported this approach, particularly in patients with no tobacco exposure, noting that these individuals are less likely to benefit from immune checkpoint inhibitors in the first-line setting.

She emphasized that the newer-generation BRAF-targeted therapies have improved tolerability compared with earlier agents, potentially allowing patients to remain on therapy longer. However, she acknowledged the absence of head-to-head data comparing BRAF-targeted therapy vs chemoimmunotherapy or checkpoint inhibition alone, highlighting this as an ongoing gap in the evidence base. Treatment selection in this setting, according to Florez, should be guided by clinical phenotype and tumor genotype.

However, she noted that in patients with a strong smoking history, high PD-L1 expression, or elevated tumor mutational burden, first-line immunotherapy-based regimens may be reasonable. In contrast, for patients with limited smoking history—particularly women—targeted therapy may offer more consistent clinical benefit. Given the known attrition between treatment lines in advanced NSCLC, Florez emphasized the importance of delivering the most effective therapies early in the disease course.

The discussion also covered cMET overexpression testing in the context of the recent FDA approval of telisotuzumab vedotin-tllv (Emrelis). Survey results indicated variability in clinical practice, with 67% of respondents on LinkedIn and 50% on X indicating that they perform MET immunohistochemistry testing at diagnosis. Florez underscored the dynamic nature of this expression over time, citing emerging evidence suggesting that cMET overexpression can fluctuate between diagnosis and progression. Although current guidance recommends testing at progression, baseline testing may provide valuable insight into treatment options and facilitate future planning. She acknowledged, however, that the optimal timing for MET testing, whether at diagnosis or at progression, remains an area of active investigation.