A retrospective study shows that patients with stage IV non-small cell lung cancer (NSCLC) and class III BRAF alterations who received immunotherapy have shorter survival than those with class II BRAF alterations.

These findings were presented by Alessandro Di Federico, MD, a physician-scientist at the University of Bologna, Italy, during the 2026 World Conference on Lung Cancer (WCLC), in the session titled Novel Immunotherapeutic Strategies in mNSCLC.

Novel Immunotherapeutic Strategies in mNSCLC

Characteristics and Outcomes to Immunotherapy in Patients With NSCLC Harboring Class II and III BRAF Alterations

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Approximately 4% of patients with NSCLC harbor BRAF alterations, which can be classified into three functional groups based on their impact on the kinase. Two-thirds of these BRAF alterations in NSCLC can be categorized as either class II or class III, for which no targeted therapies currently exist. Additionally, the clinical features and responses to immune checkpoint inhibitors (ICIs) in these patients remain poorly understood.

A retrospective, multicenter study was conducted to determine whether patients with NSCLC harboring BRAF class II and III alterations exhibit distinct clinicopathologic and genomic features, as well as responses to immunotherapy. Outcomes were analyzed for patients with stage IV disease who received first-line ICI therapy, with or without chemotherapy. Complementary clinicopathologic and genomic analyses were also performed in a broader cohort of patients with BRAF-altered NSCLC, regardless of stage and treatment status, who were treated at Dana-Farber Cancer Institute or Memorial Sloan Kettering Cancer Center.

Of 15,212 patients with NSCLC, 1.6% had BRAF class II alterations and 1.5% had BRAF class III alterations. Compared to patients with BRAF class II alterations, patients with BRAF class III alterations were more likely to have a history of tobacco use (89.6% vs. 81.6%, p=0.02) and high tumor mutational burden (≥ 10 mutations/megabase: 52.3% vs. 39.5%, p=0.01)

The most common oncogenic driver was KRAS, particularly in patients with class III alterations, occurring in nearly 18%. Additionally, BRAF class III mutations more frequently co-occurred with STK11, KEAP1, and SMARCA4 mutations.

“Then we looked at outcomes to first-line immunotherapy plus or minus chemotherapy among cases where the BRAF alteration was the only oncogenic driver,” said Dr. Di Federico. “Despite not seeing differences in terms of objective response rate (ORR) and progression-free survival (PFS), we did see a significantly shorter median overall survival (OS) in patients with BRAF class III alterations compared to those with BRAF class II alterations.”

Among 256 patients with stage IV disease who received first-line ICI therapy with or without chemotherapy, patients harboring BRAF class II and III alterations achieved similar ORR (47% vs. 52%, p=0.45) and median PFS (5.8 vs. 10 months; hazard ratio [HR] 1.26, p=0.10). However, patients with BRAF class III alterations had a significantly shorter median OS compared to those with class II alterations (12.7 vs. 20.5 months; HR 1.47, p=0.01).

The study also found that concurrent STK11, KEAP1, and SMARCA4 mutations—but not KRAS mutations—were associated with worse outcomes in patients with BRAF class II/III alterations.

These results suggest that patients with BRAF class II and III alterations have distinct clinicopathologic features and co-mutation patterns, with BRAF class III alterations potentially associated with a worse prognosis.