Frontline Immunotherapy Improves OS Vs BRAF/MEK Inhibitors in BRAF+ NSCLC

First-line immune checkpoint inhibitors (ICIs) with or without chemotherapy conferred an improvement in overall survival (OS)—albeit with lower response rates and similar progression-free survival (PFS)—compared with BRAF and MEK inhibitors among patients with non–small cell lung cancer (NSCLC) harboring BRAF V600E mutations, according to findings from a retrospective cohort study published in Lancet Oncology.¹

Among all patients, the median OS was 40.9 months (95% CI, 33.3-not reached [NR]) in the ICIs with or without chemotherapy group and 25.2 months (95% CI, 19.9-31.1) in the BRAF and MEK inhibitor group (HR, 0.69; 95% CI, 0.49-0.98; P = .039; adjusted HR, 0.66; 95% CI, 0.46-0.97; P = .034). In a propensity score-matched population, the median OS was 40.9 months (95% CI, 35.3-NR) and 22.7 months (95% CI, 14.7-27.1), respectively (HR, 0.63; 95% CI, 0.41-0.98; P = .040).

Based on subgroup analyses, factors that correlated with improved OS with ICI-based treatment vs BRAF and MEK inhibitors included a history of smoking (HR, 0.60; 95% CI, 0.40-0.90; P = .013) and a PD-L1 tumor proportion score of 1% or higher (HR, 0.66; 95% CI, 0.45-0.98; P = .039). Additional factors included an age of 70 years or older (HR, 0.54; 95% CI, 0.31-0.94; P = .029), TP53 co-mutations (HR, 0.46; 95% CI, 0.27-0.79; P = .0048), and the absence of brain metastases (HR, 0.66; 95% CI, 0.45-0.99; P = .045).

Across the overall population, the objective response rate (ORR) was 49% among patients who received ICIs with or without chemotherapy vs 63% in those who received BRAF and MEK inhibitors (P = .032). Data revealed a median PFS of 9.6 months (95% CI, 5.3-16.4) and 12.2 months (95% CI, 9.3-15.2) in each respective cohort (HR, 1.13; 95% CI, 0.83-1.53; P =. .45; adjusted HR, 1.18; 95% CI, 0.86-1.64; P = .31). In the propensity score-matched population, the ORR was 49% with ICIs with or without chemotherapy vs 66% with BRAF and MEK inhibitors (P = .068); the median PFS was 9.5 months (95% CI, 4.5-16.4) vs 12.2 months (95% CI, 9.1-18.4), respectively (HR, 1.08; 95% CI, 0.73-1.59; P = .69).

“[I]n individuals with metastatic BRAF V600E-mutated NSCLC, first-line ICIs with or without chemotherapy are associated with lower [ORR] and similar median [PFS] but longer median [OS] compared with first-line BRAF and MEK inhibitors, as previously shown in BRAF V600E-mutated melanoma,” lead study author Alessandro Di Federico, MD, from the Lowe Center for Thoracic Oncology in the Department of Medical Oncology at Dana-Farber Cancer Institute, the Department of Medical and Surgical Sciences at the University of Bologna, and Harvard Medical School, wrote with coauthors in the publication.^1-3 “The [OS] benefit was driven in particular by [patients] with a tobacco smoking history, those with a PD-L1 [tumor proportion score] of 1% or higher, those with TP53 co-mutations, and those without brain metastasis. These factors could help to inform a tailored approach for the upfront treatment of individuals with metastatic BRAF V600E-mutated NSCLC.”

Investigators of the retrospective study assessed outcomes among 284 patients with BRAF V600E-mutated NSCLC who received treatment at 17 centers across the US, Italy, France, and Brazil from January 2, 2015, to July 11, 2024. Overall, 88 patients received frontline ICIs with or without chemotherapy, and 196 received BRAF and MEK inhibitors. The study included a process of propensity score matching patients from each treatment group 1:1 to minimize potential imbalances in key variables and baseline characteristics.

The study’s primary end point was OS. Secondary end points included PFS and OS based on factors such as age, sex, ECOG performance status, smoking status, metastatic sites, PD-L1 tumor proportion sore, and co-mutations.

Patients 18 years and older with histologically or cytologically confirmed stage IV, treatment-naïve disease and an ECOG performance status of 0 to 3 were eligible for inclusion in this analysis. Those with concurrent targetable driver alterations and receipt of BRAF inhibitors without MEK inhibitors were not included in the study.

Before propensity score matching, most patients in the ICI and BRAF/MEK inhibitor populations, respectively, were younger than 70 (59% vs 55%), female (53% vs 52%), and had previously smoked (83% vs 60%). Most patients in each respective group had an ECOG performance status of 0 or 1 (80% vs 81%), no brain metastases (80% vs 85%), no bone metastases (60% vs 64%), and no liver metastases (86% vs 82%). A higher rate of patients in the ICI population had a PD-L1 tumor proportion score of 50% or more (66% vs 39%).

Adverse effects (AEs) of any grade occurred in 71% of patients who received frontline BRAF and MEK inhibitors (n = 196) compared with 74% of those who received second-line BRAF/MEK inhibition after frontline ICIs with or without chemotherapy (n = 43; P = .65). In each respective group, the rates of grade 3 or higher AEs were 22% vs 24% (P = .80). Among patients who initiated second-line BRAF and MEK inhibitors within 12 weeks of finishing frontline ICIs with or without chemotherapy (n = 40), any-grade and grade 3 or higher AEs occurred in 72% and 22%, respectively.

“Prospective studies are needed to confirm these findings,” the study authors concluded.¹

References

1. Federico AD, Wang K, Chen MF, et al. 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;26(10):1357-1369. doi:10.1016/S1470-2045(25)00409-7.
2. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763.
3. Ascierto PA, Casula M, Bulgarelli J, et al. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nat Commun. 2024;15(1):146. doi:10.1038/s41467-023-44475-6.