Class III BRAF alterations linked to shorter survival in metastatic NSCLC

Metastatic non-small cell lung cancer harboring class III BRAF alterations was associated with shorter median overall survival than class II alterations in a retrospective multicenter study presented at the International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer. Patients with class III alterations also had distinct clinical and genomic features, including a higher proportion with tumor mutational burden of at least 10 mutations per megabase and more frequent STK11, KEAP1 and SMARCA4 co-mutations. The findings identify prognostic associations in an observational treatment cohort rather than establishing that BRAF alteration classes or accompanying mutations caused differences in survival.

Researchers at 15 academic centers in Europe and the United States evaluated outcomes among patients with metastatic NSCLC whose tumors carried class II or class III BRAF alterations. The investigators conducted complementary clinicopathologic and genomic analyses in a broader cohort treated at Dana-Farber Cancer Institute or Memorial Sloan Kettering Cancer Center. That cohort included 15,212 patients, of whom 247, or 1.6%, had class II BRAF alterations and 225, or 1.5%, had class III alterations. These less well-defined BRAF categories differ from class I BRAF V600 alterations, for which BRAF- and MEK-targeted therapies are approved. At the time of the report, patients with class II and class III alterations had no approved targeted treatment options.

The broader analysis found several differences between the alteration groups. A history of tobacco use was more common among patients with class III alterations, reported in 89.6% of cases compared with 81.6% among those with class II alterations. The proportion with tumor mutational burden of at least 10 mutations per megabase was also higher for class III disease, at 52.3% versus 39.5%. Concurrent oncogenic alterations also had different distributions. STK11 co-mutations occurred in 27.6% of class III tumors and 19.4% of class II tumors; KEAP1 co-mutations occurred in 24.0% and 15.8%, respectively; and SMARCA4 co-mutations occurred in 28.0% and 16.2%. The investigators observed no significant differences between the groups in age, sex, PD-L1 expression, NSCLC histology or tumor aneuploidy levels.

The treatment analysis included 256 patients whose only oncogenic driver was a class II or class III BRAF alteration and who received first-line immune checkpoint inhibitors with or without chemotherapy. This cohort included 132 patients with class III alterations and 124 with class II alterations. Objective response rates were similar, at 47% for class III disease and 52% for class II disease, with the difference not statistically significant. Median progression-free survival was 5.8 months for class III alterations and 10.0 months for class II alterations; the reported hazard ratio of 1.26 did not reach statistical significance. Median overall survival, however, was significantly shorter for class III disease at 12.7 months, compared with 20.5 months for class II disease, with a hazard ratio of 1.47 and p-value of 0.01.

Within the analyzed population, co-mutation status was also associated with outcome measures. Patients with STK11 co-mutations had an objective response rate of 31%, compared with 57% among those without STK11 co-mutations. Their median progression-free survival was 4.4 months rather than 10.7 months, while median overall survival was 11.5 months rather than 25.3 months. KEAP1 co-mutations were 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 said these patterns resembled observations previously reported in KRAS-mutated NSCLC. Because the study was retrospective and observational, its findings describe measured associations and do not demonstrate that the alteration classes or co-mutations caused the observed differences in treatment response or survival.

Subject of Research: Clinicopathologic features and first-line immunotherapy outcomes in metastatic NSCLC with class II and III BRAF alterations

Article Title: Study identifies distinct outcomes and genomic features in NSCLC with class II and III BRAF alterations

Article References: Study identifies distinct outcomes and genomic features in NSCLC with class II and III BRAF alterations. Original publication (Bibliographic details unavailable.)

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Keywords: NSCLC, BRAF alterations, immunotherapy, overall survival, progression-free survival, STK11, KEAP1, SMARCA4, tumor mutational burden, retrospective study, identifies, distinct