An international, multi-center study found that patients with advanced non-small cell lung cancer (NSCLC) whose tumors carry a rare change in the BRAF gene, called BRAFV600E, lived longer when they received immunotherapy as their first treatment, with or without chemotherapy (PD-1 or PD-L1 inhibitors with or without platinum-based chemotherapy), compared with those who first received targeted drugs known as BRAF/MEK inhibitors (dabrafenib and trametinib or encorafenib and binimetinib).
The study, published in The Lancet Oncology and funded by NextGenerationEU, reviewed patients treated at cancer centers across several countries and compared two common first-line treatment options: immunotherapy versus BRAF/MEK-targeted therapy.[1]
The study enrolled 284 patients: 88 (31%) received immune checkpoint inhibitors with or without chemotherapy, and 196 (69%) received BRAF and MEK inhibitors. The median age of participants was 68 years (IQR 61–74), and 148 (52%) participants were female and 136 (48%) male.
Participating patients receiving immune checkpoint inhibitors with or without chemotherapy group had a higher history of smoking (73 [83%] vs 118 [60%]; p=0·0002) and a higher PD-L1 expression (≥50% in 58 [66%] vs 76 [39%], 1–49% in 16 [18%] vs 67 [34%], and <1% in eight [9%] vs 31 [16%]; p=0·0003) compared to patients included in the BRAF and MEK inhibitor group.
Outcome
Patients who started with immunotherapy lived a median of 41 months, compared with 25 months for those who started with BRAF/MEK inhibitors. The benefit from immunotherapy was especially clear in patients whose tumors had PD-L1 levels of 1% or higher, in people with a history of smoking, and in patients who did not have cancer that had spread to the brain.
Although targeted therapy led to more frequent and often faster tumor shrinkage, patients treated first with immunotherapy tended to have better long-term outcomes. The study also found that patients whose tumors had an additional TP53 mutation did much worse on BRAF/MEK inhibitors but not on immunotherapy, suggesting that the broader genetic makeup of the tumor should be considered when choosing treatment.
Finally, the researchers showed that it was safe to give BRAF/MEK inhibitors after immunotherapy, easing earlier concerns about side effects when using these treatments in sequence.
Why important
Patients with BRAFV600E(ie, Val600Glu)-mutated non-small-cell lung cancer (NSCLC) have often been treated with approaches similar to those used for other gene-driven lung cancers, in which targeted therapies are usually given first. These new findings suggest that this may not be the best strategy for many people with BRAFV600E-mutations.
The results support using immunotherapy-based treatment as a first option for many patients, particularly those with PD-L1–positive tumors, a smoking history, and no brain metastases.
More research, including prospective, randomized clinical trials, is needed to confirm these results, determine the optimal sequence for administering immunotherapy and targeted therapy, and identify additional markers to help match each patient to the most effective treatment.
Reference
[1] Di Federico A, Wang K, Chen MF, Barsouk AA, Pagliaro A, Chen LN, Ogliari FR, Stockhammer P, Thawani R, Raslan S, Gariazzo E, Fusco F, Hambelton GM, Citarella F, Meyer D, Aldea M, De Giglio A, Alessi JV, Pecci F, Gelsomino F, Corassa M, Vokes NI, Wang X, de Biase D, Abu Rous F, Areesawangkit P, Elghawy O, Cortellini A, Metro G, Ferrara R, Awad MM, Pabani A, Murray JC, Cappuzzo F, Garassino MC, Dagogo-Jack I, Riely G, Grant M, Herzberg BO, Ardizzoni A, Planchard D, Johnson BE, Langer CJ, Offin M, Negrao MV, Ricciuti B. First-line immunotherapy with or without chemotherapy versus BRAF plus MEK inhibitors in BRAFV600E-mutated metastatic non-small-cell lung cancer (FRONT-BRAF): a multicentre, retrospective cohort study. Lancet Oncol. 2025 Oct;26(10):1357-1369. doi: 10.1016/S1470-2045(25)00409-7. PMID: 41038185.
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