Patients with metastatic non-small cell lung cancer (NSCLC) harboring class II and class III BRAF alterations have distinct clinicopathologic and genomic characteristics, with class III alterations potentially associated with worse prognosis, according to research presented today at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).
The study, "Characteristics and outcomes to immunotherapy in patients with NSCLC harboring class II and III BRAF alterations," examined outcomes with first-line immune checkpoint inhibitors (ICI) and genomic features in patients with these less well-defined BRAF alterations. Approximately 4% of patients with NSCLC harbor BRAF alterations. While approved BRAF- and MEK-targeted therapies are available for class I BRAF V600 alterations, patients with class II and III alterations currently lack approved targeted treatment options.
Our group conducted a retrospective, multicenter study across 15 academic centers in Europe and the United States. Complementary clinicopathologic and genomic analyses were also performed in a broader cohort of patients with BRAF-altered NSCLC treated at Dana-Farber Cancer Institute or Memorial Sloan Kettering Cancer Center."
Alessandro Di Federico, M.D., Memorial Sloan Kettering Cancer Center, New York City
Among 15,212 patients in the Dana-Farber/Memorial Sloan Kettering cohort, 247 patients (1.6%) had class II BRAF alterations and 225 (1.5%) had class III alterations. Compared with patients with class II alterations, those with class III alterations more frequently had a history of tobacco use (89.6% vs. 81.6%; p=0.02) and tumor mutational burden of at least 10 mutations per megabase (52.3% vs. 39.5%; p=0.01). The two groups also differed in the distribution of concurrent oncogenic alterations.
Class III tumors more frequently harbored co-mutations in STK11 (27.6% vs. 19.4%; p=0.048), KEAP1 (24.0% vs. 15.8%; p=0.03) and SMARCA4 (28.0% vs. 16.2%; p=0.003) compared with class II tumors. No significant differences were observed in age, sex, PD-L1 expression, NSCLC histology or tumor aneuploidy levels.
In the immunotherapy cohort, 256 patients whose only oncogenic driver was a class II or III BRAF alteration received first-line ICI with or without chemotherapy. Patients with class III alterations (n=132) had a similar objective response rate compared with those with class II alterations (n=124), 47% versus 52% (p=0.45), and median progression-free survival of 5.8 versus 10.0 months (HR 1.26; p=0.10). Median overall survival, however, was significantly shorter for patients with class III alterations: 12.7 months versus 20.5 months (HR 1.47; p=0.01).
The analysis also found that STK11, KEAP1 and SMARCA4 co-mutations were associated with worse outcomes. For example, patients with STK11 co-mutations had an objective response rate of 31% versus 57%, median progression-free survival of 4.4 versus 10.7 months, and median overall survival of 11.5 versus 25.3 months compared with patients without STK11 co-mutations. KEAP1 co-mutations were likewise associated with lower response rates and shorter progression-free and overall survival, while SMARCA4 co-mutations were associated with significantly shorter overall survival.
The investigators concluded that class II and class III BRAF-altered NSCLC show different clinicopathologic characteristics and co-mutation patterns, and that class III disease may be associated with worse prognosis. They also reported that STK11, KEAP1 and SMARCA4 co-mutations were linked to worse outcomes, similar to observations previously reported in KRAS-mutated NSCLC.
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