Researchers have identified varying clinicopathologic characteristics and outcomes between patients with non–small cell lung cancer (NSCLC) and class II and III BRAF mutations, according to findings presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC; Abstract MO07.02).
“Patients with BRAF class II and BRAF class III [mutations] show different clinicopathologic characteristics and co-mutation patterns, and BRAF class III may be associated with worse prognosis. STK11, KEAP, and SMARCA4 co-mutations are linked to worse outcomes, similarly to what [was] previously observed in the KRAS-mutated population,” the study authors noted.
Background and Study Methods
BRAF alterations can be classified into three functional groups (classes I–III) according to their effects on BRAF kinase activity. BRAF-targeted therapies are currently only approved for class I alterations, including BRAF V600.
Researchers sought to understand more about the characteristics of class II and III BRAF alterations and outcomes from treatment with immune checkpoint inhibitors in patients with metastatic NSCLC.
“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 [n = 15,212],” explained presenting author Alessandro Di Federico, MD, of Memorial Sloan Kettering Cancer Center in New York City.
Key Findings
Of all included patients, 1.6% (n = 247) had a BRAF class II alteration and 1.5% (n = 225) had a class III BRAF alteration.
Patients with BRAF class III alterations were more likely to have a smoking history (89.6% vs 81.6%; P = .02), a higher tumor mutational burden (≥10 mutations/megabase; 52.3% vs 39.5%; P = .01), and have a different distribution of concurrent alterations (P = .004) compared with class II BRAF alterations. No differences between the two classes were observed in terms of age, sex, PD-L1 expression levels, histology, or tumor aneuploidy levels.
Patients with BRAF class III alterations tended to have more co-mutations in STK11 (27.6% vs 19.4%; P = .048), KEAP1 (24% vs 15.8%; P = .03), and SMARCA4 (28% vs 16.2%; P = .003) compared with class II BRAF alterations.
A cohort of patients received first-line immune checkpoint inhibition, including 256 patients with a BRAF class II (n = 124) or III (n = 132) alteration who also received chemotherapy. Patients with BRAF class II alterations had similar objective response rates (47% vs 52%) and median progression-free survival (5.8 vs 10 months; hazard ratio [HR] = 1.26; P = .10) compared with those with class III alterations. However, patients with class III alterations had significantly worse overall survival outcomes (12.7 vs 20.5 months; HR = 1.47; P = .01) vs class II alterations.
Co-mutations in KRAS were found in 14.2% of patients with BRAF class II alterations and 20.4% of patients with class III alterations. These co-mutations had no impact on outcomes vs KRAS wild-type tumors. However, significantly worse outcomes were seen in patients with co-mutations in STK11 (objective response rate, 31% vs 57%; P = .0008; median progression-free survival, 4.4 vs 10.7 months; HR = 1.73; P = .002; median overall survival, 11.5 vs 25.3 months; HR = 1.77; P = .003), KEAP1 (objective response rate, 25% vs 59%; P < .0001; median progression-free survival, 4.8 vs 10.3 months; HR = 1.82; P = .001; median overall survival, 9.1 vs 25.0 months; HR = 1.78; P = .03), and SMARCA4 (objective response rate, 36% vs 53%; P = .14; median progression-free survival, 4.9 vs 8.5 months; HR = 1.40; P = .17; median overall survival, 9.2 vs 20.8 months; HR = 1.71; P = .03) vs wild-type genes.
After excluding for KRAS co-mutated cases, consistent outcomes were observed.
DISCLOSURES: For full disclosures of the study authors, visit abstractsonline.com.
