Study Identifies Distinct Outcomes and Genomic Features in NSCLC With Class II and III BRAF Alterations

(SEOUL, Republic of Korea —Tuesday, September 15th, 9:45 a.m. Korea Standard Time) — 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,” said Alessandro Di Federico, M.D., of Memorial Sloan Kettering Cancer Center in 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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About the IASLC:

The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated solely to the study of lung cancer and other thoracic malignancies. Founded in 1974, the association's membership includes more than 10,000 lung cancer specialists across all disciplines in over 100 countries, forming a global network working together to conquer lung and thoracic cancers worldwide. The association also publishes the Journal of Thoracic Oncology, the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies. Visit www.iaslc.org for more information.

About the WCLC:

The WCLC is the world’s largest meeting dedicated to lung cancer and other thoracic malignancies, attracting nearly 7,000 researchers, physicians, and specialists from more than 100 countries. The goal is to increase awareness, collaboration, and understanding of lung cancer, and to help participants implement the latest developments across the globe. The conference will cover a wide range of disciplines and unveil several research studies and clinical trial results. For more information, visit https://wclc.iaslc.org/.