Pan-cancer landscape and real-world management of BRAF non-V600E and MAP2K1 alterations: Analysis from the WAYFIND-R registry.

3080 Background: While targeted therapies have revolutionized the management of BRAF V600E-mutant tumors, non-V600E BRAF and MAP2K1 alterations remain a clinical "gray zone." These variants represent a functionally diverse group of drivers with no established treatment guidelines, often leading to heterogeneous care and suboptimal outcomes. We used the multinational WAYFIND-R registry to map the prevalence and functional landscape of these rare alterations and to evaluate real-world treatment patterns. Methods: We retrospectively analyzed 4,774 patients with solid tumors from the multinational WAYFIND-R registry (NCT04529122). Patients with BRAF and MAP2K1 alterations identified via Next-Generation Sequencing (NGS) were included. Variants were categorized by functional class (Class I-III). Clinical characteristics, co-mutation profiles, and treatment sequences were analyzed to correlate molecular features with management strategies and outcomes. Results: Rare alterations were identified in 38 (0.8%) patients, predominantly in colorectal (29%), lung (13%), and melanoma (13%) cancers. Genomic analysis revealed a complex landscape. Among BRAF-altered patients (n=30), while Class I (V600E/K) accounted for 63.3% (n=19), the remaining 36.7% comprised non-V600E variants distributed between functional Class II (20.0%) (e.g., G469A, L597S) and Class III (13.3%) (e.g., D594N, G466R). MAP2K1 alterations (n=9) were distributed across RAF-dependent Class I (44.4%), RAF-regulated Class II (44.4%), and RAF-independent Class III (11.1%) variants (e.g., E102_I103del). Treatment patterns were highly inconsistent. While first-line therapy typically consisted of standard chemotherapy or anti-PD-1 monotherapy, there was no consensus for subsequent lines. This lack of targeted approach correlated with poor outcomes in lung and colorectal cohorts. However, in contrast to unselected treatments, we observed durable responses with biology-guided MEK inhibitor plus Immunotherapy combinations in two index cases. A patient with MAP2K1 Class III (E102_I103del) NSCLC achieved a near-complete metabolic response with cobimetinib + nivolumab. Similarly, a BRAF Class II (G469A) NSCLC patient achieved a complete metabolic and molecular response (confirmed by ctDNA clearance) with trametinib + pembrolizumab. Conclusions: This analysis confirms that >35% of BRAF-altered patients (nonV600 mutants) and all MAP2K1-altered patients in real-world settings currently lack standardized treatment protocols. The observed clinical heterogeneity highlights a significant unmet need. Our findings suggest that integrating functional subclassification into clinical decision-making and utilizing targeted combinations is necessary and may offer a viable strategy. Clinical trial information: NCT04529122 .