First-line treatment strategies for BRAF-V600E mutated non-small cell lung cancer: lessons from real-world data and ongoing uncertainties

Introduction

The treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF-V600E mutation represents a complex area in thoracic oncology. Somatic BRAF mutations occur in approximately 2–4% of NSCLC cases, with adenocarcinoma representing the predominant histologic subtype (1,2). About half are V600E mutations (class I), while the remaining cases are non-V600E (class II/III) mutations. BRAF-V600E mutations are more common in women and never-smokers (1,2). Patients with BRAF-V600E mutated NSCLC are associated with elevated programmed death receptor ligand-1 (PD-L1) tumour proportion scores (TPS) and high tumour mutational burden (TMB) (3,4).

To date, two treatment strategies are available for this subgroup of patients: the combination of targeted therapy with BRAF plus MEK inhibitors (dabrafenib plus trametinib or encorafenib plus binimetinib) and immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy. In a phase II trial, the combination of dabrafenib and trametinib demonstrated substantial and durable activity, with objective response rates (ORR) of 64% in treatment-naïve patients and 68% in previously treated patients. Median progression-free survival (PFS) was 10.8 months and median overall survival (OS) reached 17.3 months in the first-line setting, with comparable outcomes observed in pretreated patients (10.2 and 18.2 months, respectively) (5). Similarly, the combination of encorafenib and binimetininb in a more recent phase II trial showed solid benefit, reporting an ORR of 75% in treatment-naïve patients and 46% in pretreated patients. Median PFS was 30.2 and 9.3 months, respectively (6,7).

Given the consistent efficacy proven by BRAF plus MEK inhibitors in clinical trials, international guidelines including European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) guidelines, recommend targeted therapy as the standard first-line treatment for patients with BRAF-V600E mutated NSCLC (8,9).

In contrast to other oncogenic alterations (EGFR, ALK, ROS1), for which targeted therapy has been firmly established as the most effective first-line treatment, patients with BRAF-V600 mutations seem to derive benefit from both BRAF plus MEK inhibitors and ICI with or without chemotherapy. Although data on the efficacy of single-agent immunotherapy in BRAF-V600E mutant NSCLC remain scarce, real-world evidence from Actionable Genomic Alterations (AGA) registries provides valuable insights, as described by the IMMUNOTARGET registry, which reported an ORR of 24%, a median PFS of 3.1 months, and a median OS of 13.6 months (10).

In melanoma, a tumour characterized by a high prevalence of BRAF-V600E mutations, recent studies (the DREAMseq and SECOMBIT trials) have established immunotherapy as the preferred first-line treatment (11,12); however, in NSCLC, the optimal approach remains uncertain.

The multicenter retrospective study by Wiesweg et al. adds to this debate by comparing outcomes of upfront targeted therapy and ICI-based strategies (13). In this editorial commentary, we discuss the real-world findings reported by Wiesweg et al., highlighting their contribution to the ongoing debate on the optimal first-line strategy for BRAF-V600E mutated NSCLC and underscoring both the strengths and the limitations of the study.

Study summary

The study included 205 patients with advanced BRAF-V600E mutated NSCLC enrolled in the German National Network Genomic Medicine (nNGM) Lung Cancer. The median age of the study cohort was 69 years, with 43.9% of patients being female and 70.2% having a documented smoking history. Most tumours were adenocarcinomas (97.1%), harbouring a p.V600E mutation (99%) with a high PD-L1 expression (defined as PD-L1 TPS ≥50%) observed in 40.5% of cases. For the primary analysis, 175 patients were assessable: 55.6% were treated with dabrafenib plus trametinib, while 29.8% received ICI-based regimens as first-line treatment (13.2% chemo-immunotherapy, while 16.6% mono-immunotherapy). A total of 30 patients were excluded as they received chemotherapy only or had no documented systemic therapy.

Overall, 39.4% of patients did not receive any second-line therapy. More than half of patients treated upfront with single-agent immunotherapy (52.9%) and 29.6% of those receiving chemo-immunotherapy did not proceed to targeted therapy. Likewise, 39.5% of patients who started with dabrafenib plus trametinib did not subsequently receive immunotherapy.

Baseline characteristics were overall well-balanced between patients treated with targeted therapy and those receiving ICI-based regimens. Notably, PD-L1 status was unevenly distributed across the cohorts, with a clear predominance of patients with high PD-L1 expression in the immunotherapy group (63%) compared to those receiving targeted therapy (33%) (P<0.001). In addition, patients with liver metastases tended to receive targeted treatment in first line (P=0.04).

The primary objective of the study was to compare OS and TTF by first-line treatment (defined as time interval from the start of the first-line therapy until its discontinuation for any reason) between targeted therapy or ICI-based therapies. The prespecified endpoints included OS, TTF with first-line therapy, and cumulative TTF across first- and second-line treatments with either targeted therapy or ICI-based regimens.

No statistically significant difference in OS was found between patients receiving upfront dabrafenib plus trametinib and immunotherapy alone or in combination with chemotherapy [28.8 vs. 28 months, hazard ratio (HR) =1.1, P=0.68] and cumulative TTF of first- and second-line treatment was identical regardless of sequence (HR =1.18, P=0.64).

In contrast, the sub-analysis revealed a trend towards less favourable outcomes with first-line mono-immunotherapy compared to both chemo-immunotherapy and targeted therapy (median OS 21 vs. 31.8 vs. 38 months, P=0.43; median PFS 7.3 vs. 15.4 vs. 12.3 months, P=0.37).

In both univariate and multivariate analyses of baseline prognostic factors, only two variables demonstrated a significant association with OS: female sex and high PD-L1 expression. Female sex was shown to be favourably prognostic for OS and TTF, although the observed benefit on OS (Kaplan-Meier analysis; multivariate HR =0.61, P=0.046) was driven exclusively by patients receiving first-line dabrafenib plus trametinib. No meaningful sex-related differences were found among those treated with (chemo)-immunotherapy. By contrast, high PD-L1 expression was identified as adversely prognostic for TTF (multivariate HR =1.75, P=0.004) in patients treated with both dabrafenib plus trametinib and ICI-based treatments.

Strengths and limitations

Primary endpoints of the study were OS, which provides robust and objective evidence, and TTF, which reflects real-world practice. Importantly, the study compared two valid first-line strategies (BRAF plus MEK inhibitors and ICI-based treatments) rather than isolated cohorts, offering insights for practical guidance in a field where evidence to guide treatment choice remains limited. However, the observational and retrospective design of the study represents a key limitation for a meaningful comparison between the two therapeutic approaches. Moreover, attrition bias was significant, as many patients never reached second-line therapy (about 40% of the study population). Data on safety and quality of life were also notably absent.

A further interpretative limitation concerns PD-L1 expression. In advanced NSCLC, high PD-L1 is a well-recognised favourable prognostic and predictive biomarker (14-17). In addition, it serves as a key criterion guiding first-line regimen selection as, in most European jurisdictions, mono-immunotherapy is approved almost exclusively for tumours with PD-L1 ≥50%. As a result, PD-L1 did not merely correlate with outcome in this cohort as it actively shaped first-line treatment allocation. This creates a confounding-by-indication scenario: the apparent inferiority of single-agent immunotherapy may in part reflect regulatory-driven patient selection rather than a true treatment effect.

Interestingly, the authors also report that high PD-L1 was associated with shorter TTF even among patients treated with BRAF/MEK inhibition, suggesting that PD-L1 may behave as a surrogate for adverse tumour biology in this molecular subgroup. However, without randomisation, the respective contributions of biology and treatment-selection pressure remain impossible to determine. Consequently, the prognostic relevance of high PD-L1 and its impact on observed TTF and OS should be interpreted with caution.

Overall, while the study performed by Wiesweg et al. provides valuable hypotheses, results are too premature to define a practice-changing standard.

Evidence in context

Despite the potential efficacy of immunotherapy in advanced NSCLC with BRAF V600-E mutations (4,18), the findings by Wiesweg et al. are consistent with and expand upon the real-world analysis reported by Garassino et al. (19). In that study, real-world time on treatment (rwTOT) and real-world time to next treatment (rwTTNT) were longer for chemo-immunotherapy compared to mono-immunotherapy (median rwTOT 17.5 vs. 7.6 months and median rwTTNT 19.7 vs. 10.5 months). The results by Wiesweg et al. further support the superior efficacy of combining chemotherapy and ICI, yielding improved outcomes and prolonged treatment duration compared to immunotherapy alone.

In the sub-analysis of baseline prognostic factors performed by Wiesweg et al., the finding that high PD-L1 TPS was associated with shorter TTF regardless of the treatment received, contrasts with previous evidence. Earlier studies reported that elevated PD-L1 TPS and TMB predict greater benefit from immunotherapy in NSCLC (14-17). Given that BRAF-V600E mutant tumours have been shown to frequently express high PD-L1 TPS (4,18), the current findings, observed across both (chemo)immunotherapy and targeted therapy, are therefore unexpected.

Some of the results reported by Wiesweg et al. contrast with those of the multicentre FRONT-BRAF study by Di Federico et al., which represents the largest cohort of BRAF-V600E mutated NSCLC reported to date. In this analysis, ICI-based regimens were associated with a significant OS advantage compared with BRAF plus MEK inhibitors (40.9 vs. 25.1 months; HR =0.69, P=0.04), confirmed in multivariable and propensity-matched analyses. This benefit was most pronounced among patients with a smoking history, PD-L1 TPS ≥1%, TP53 co-mutations, and in the absence of brain metastases. Conversely, BRAF/MEK combinations achieved higher ORR, with no significant difference in PFS between the two strategies (20). Consistent with the findings of Wiesweg et al., chemo-immunotherapy demonstrated a trend toward improved outcomes compared with single-agent immunotherapy, with higher ORR and longer, although not statistically significant, PFS, likely due to the limited size of the analyzed subgroups. These results reinforce the added value of combination approaches in this setting.

While the German cohort was strongly shaped by European Medicines Agency (EMA) restrictions on immunotherapy alone, resulting in a narrow PD-L1 distribution and treatment allocation largely dictated by PD-L1 status, the FRONT-BRAF study enrolled patients across the United States, Europe and Brazil, where both monotherapy and chemo-immunotherapy were used across the spectrum of PD-L1 expression. In this less regulation-driven setting, immunotherapy was selected on clinical grounds, particularly for tumours with features associated with ICI sensitivity, such as high PD-L1 expression and a smoking-related TMB. Consequently, patients receiving ICI with or without chemotherapy had higher PD-L1 TPS and a higher prevalence of smoking history than those treated with BRAF/MEK inhibitors.

In this more heterogeneous setting, PD-L1 behaved as expected: higher expression correlated with improved outcomes under ICI-based regimens. This is the opposite of the Wiesweg cohort, where high PD-L1 was paradoxically associated with shorter TTF irrespective of treatment strategy.

These divergent associations are plausibly explained by differences in design and population. FRONT-BRAF spanned multiple regulatory environments, reducing the selection pressure that funnelled PD-L1 ≥50% patients almost exclusively toward monotherapy in Wiesweg et al. study, leading to a confounding-by-indication scenario. Moreover, the FRONT-BRAF population was enriched for smoking-related tumours, a context in which PD-L1 and TMB more reliably predict durable benefit from immunotherapy.

Overall, FRONT-BRAF reinforces the established predictive and prognostic significance of PD-L1 in metastatic NSCLC, mirroring evidence from melanoma, where upfront immunotherapy outperforms targeted therapy in BRAF-V600E disease, as shown in DREAMseq and SECOMBIT (11,12).

The counterintuitive findings of Wiesweg et al. should be interpreted with caution and viewed through the lens of treatment-selection bias and cohort heterogeneity rather than as evidence of a true biological inversion of PD-L1 behaviour.

Although evidence on gender differences in response to targeted therapy remains limited, previous studies have not identified gender as a factor influencing OS (21). The exploratory findings of this study may suggest molecular or hormonal differences which may modulate sensitivity to BRAF plus MEK inhibition.

Tailored treatment approach

Collectively, the studies by Wiesweg et al. and Di Federico et al. indicate that treatment selection for BRAF-V600E mutated NSCLC should be individualized based on key clinical and molecular features such as smoking history, PD-L1 expression, sex, and co-mutations. ICI-based regimens appear to confer greater benefit among smokers and patients with PD-L1 ≥1%, features associated with a more immunogenic tumour microenvironment. The presence of TP53 co-mutations should be conversely considered a detrimental factor for BRAF/MEK inhibition, probably due to faster development of resistance alterations in a biological system prone to greater cell cycle dysregulation. Contrariwise, BRAF/MEK inhibition may be more appropriate for never-smokers and women, who more often exhibit a true oncogene-addicted phenotype (22,23).

Taken together, these data support a biologically rational, patient-tailored approach, emphasizing chemo-immunotherapy as a valid first-line option for immunogenic tumours and targeted therapy for oncogene-driven disease. Prospective studies are warranted to refine predictive biomarkers and optimize treatment sequencing.

Conclusions

The optimal first-line treatment for patients with BRAF-V600E mutated NSCLC remains undefined. Current evidence supports both BRAF/MEK inhibitor combinations and ICI-based regimens as reasonable options, each with distinct advantages and limitations. However, the supporting data for both strategies largely derive from phase II trials and observational analyses, as no head-to-head prospective trials have yet been conducted in this setting. The recent study by Wiesweg et al. further contributes to this debate by offering real-world comparative insights into the outcomes of targeted and immunotherapy-based approaches. Consistent with the findings of Di Federico et al., its results also raise the question about the limited efficacy of single-agent immunotherapy in this molecular subset, reinforcing that the prescription of ICI monotherapy should be cautiously recommended, especially in the absence of supporting prospective evidence.

Treatment selection should be individualized according to clinical and biological factors, including PD-L1 expression, smoking history, performance status, co-mutations, brain or liver involvement, disease course and the likelihood of access to subsequent therapy, as well as the toxicity profile of each regimen. Ultimately, no single therapeutic strategy fits all patients. Well-designed prospective randomized trials are critically needed to clarify the optimal treatment sequence for this population, integrating clinical, biological, and molecular predictive factors to tailor therapy and optimize outcomes in this heterogeneous subgroup.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1946/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1946/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-9. [Crossref] [PubMed]
2. Chen D, Zhang LQ, Huang JF, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 2014;9:e101354. [Crossref] [PubMed]
3. Ricciuti B, Wang X, Alessi JV, et al. Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels. JAMA Oncol 2022;8:1160-8. [Crossref] [PubMed]
4. Negrao MV, Skoulidis F, Montesion M, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer 2021;9:e002891. [Crossref] [PubMed]
5. Planchard D, Besse B, Groen HJM, et al. Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. J Thorac Oncol 2022;17:103-15. [Crossref] [PubMed]
6. Riely GJ, Smit EF, Ahn MJ, et al. Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAF(V600)-Mutant Metastatic Non-Small-Cell Lung Cancer. J Clin Oncol 2023;41:3700-11. [Crossref] [PubMed]
7. Riely GJ, Ahn MJ, Clarke JM, et al. Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC-A Brief Report. J Thorac Oncol 2025;20:1538-47. [Crossref] [PubMed]
8. Reuss JE, Kuruvilla S, Ismaila N, et al. Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1. J Clin Oncol 2025;43:e31-44. [Crossref] [PubMed]
9. Hendriks LE, Kerr KM, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:339-57. [Crossref] [PubMed]
10. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8. [Crossref] [PubMed]
11. 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;41:186-97. [Crossref] [PubMed]
12. Ascierto PA, Mandalà M, Ferrucci PF, et al. Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial. J Clin Oncol 2023;41:212-21. [Crossref] [PubMed]
13. Wiesweg M, Alaffas A, Rasokat A, et al. Treatment Sequences in BRAF-V600-Mutated NSCLC: First-Line Targeted Therapy Versus First-Line (Chemo-) Immunotherapy. J Thorac Oncol 2025;20:1328-35. [Crossref] [PubMed]
14. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
15. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28. [Crossref] [PubMed]
16. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 2018;378:2093-104. [Crossref] [PubMed]
17. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell 2018;33:843-852.e4. [Crossref] [PubMed]
18. Dudnik E, Peled N, Nechushtan H, et al. BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors. J Thorac Oncol 2018;13:1128-37. [Crossref] [PubMed]
19. Garassino MC, Oskar S, Arunachalam A, et al. Real-World Treatment Patterns and Outcomes of First-Line Immunotherapy Among Patients With Advanced Nonsquamous NSCLC Harboring BRAF, MET, or HER2 Alterations. JTO Clin Res Rep 2023;4:100568. [Crossref] [PubMed]
20. Di Federico A, 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;26:1357-69. [Crossref] [PubMed]
21. Perrone F, Mazzaschi G, Minari R, et al. Multicenter Observational Study on Metastatic Non-Small Cell Lung Cancer Harboring BRAF Mutations: Focus on Clinical Characteristics and Treatment Outcome of V600E and Non-V600E Subgroups. Cancers (Basel) 2022;14:2019. [Crossref] [PubMed]
22. Devarakonda S, Li Y, Martins Rodrigues F, et al. Genomic Profiling of Lung Adenocarcinoma in Never-Smokers. J Clin Oncol 2021;39:3747-58. [Crossref] [PubMed]
23. Ferrara MG, Di Noia V, D'Argento E, et al. Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives. Cancers (Basel) 2020;12:1196. [Crossref] [PubMed]