Limitations of Current Evidence for BRAF V600E-Mutant Metastatic NSCLC and Cross-Trial Comparisons

Segment VIII focuses on the limitations of PHAROS and the broader BRAF-directed therapy evidence base. Dr. Rotow identifies the primary limitation: PHAROS is a non-randomized study. Without a comparator arm, such as chemo-immunotherapy or dabrafenib/trametinib, definitive superiority cannot be demonstrated. Nevertheless, she explains that randomized trials in rare oncogenic subsets are often impractical, making high-quality single-arm data essential for decision-making.

Another challenge is the evolving nature of lung cancer treatment. As second-line therapies become more effective, cross-trial comparisons of survival outcomes become increasingly confounded. Moreover, differences in patient selection, prior treatments, and baseline characteristics across studies complicate interpretation of OS.

The experts also highlight gaps in treatment strategies for non-V600E BRAF mutations, an unmet need that affects a substantial proportion of patients with BRAF-mutant NSCLC. Current therapies demonstrate efficacy primarily in V600E disease, and using them in other mutations could lead to suboptimal outcomes. Dr. Dagogo-Jack expresses concern that clinicians who encounter BRAF infrequently may inadvertently treat non-V600E disease with V600E-specific regimens, potentially diminishing confidence in targeted therapy.

A final discussion point is real-world applicability. Although PHAROS presents exceptional PFS, the modest difference between PFS and OS suggests that resistance remains a major hurdle. As with other MAPK-driven cancers, resistance mechanisms are heterogeneous, making post-progression strategies complex.

Despite these limitations, both speakers agree that the PHAROS data meaningfully shape clinical practice. Clinicians must apply judgment, integrate evolving evidence, and maintain vigilance regarding mutation subtype, patient comorbidities, and individual response patterns.