(P 186) BRAF V600E-MUTATED GASTROINTESTINAL STROMAL TUMORS: A CASE SERIES AND ANALYSIS OF IMMUNE TUMOR INFILTRATE

Objective: BRAF V600E-mutated gastrointestinal stromal tumors (GISTs) represent a rare molecular subset, accounting for ~1% of all GISTs. Although BRAF/MEK inhibitors show clinical activity and have received tumor-agnostic regulatory approval, treatments beyond this remain undefined. The immune cell landscape and potential role for immune checkpoint inhibitors (ICIs) in this population are not well characterized.

Methods: We retrospectively identified patients with BRAF V600E mutant GIST at Memorial Sloan Kettering Cancer Center (2009–2024) who underwent next-generation sequencing. Clinical, demographic, genomic, and treatment data were extracted. Immunohistochemistry (IHC) for PD-L1, PD-1, LAG-3, CD3, CD8 and CD20 was performed on available tumor specimens from metastatic patients.

Results: Five patients (median age 48, 4M/1F) were identified; primary tumor locations included small bowel (n=4) and gastric (n=1). Four presented with localized disease (one had metastatic recurrence after 6m [patient A]); one patient (B) presented with metastatic disease at diagnosis. All patients were found to harbor the BRAF V600E mutation, with additional co-alterations identified: EP300, RB1, NF1, and TSC2 in one patient, FLT4 in one patient, and JAK3 in one patient.

Both patients with advanced disease received BRAF+/- MEK inhibition in the first-line setting. Patient A received vemurafenib for 21 months achieving an initial response, followed by gradual progression. He subsequently received dabrafenib/trametinib for 8 months with stable disease initially followed by slow progression. Ipilimumab/nivolumab was initiated and achieved a durable complete response, remaining disease-free for 6.5 years off therapy. Patient B received binimetinib/encorafenib for 26 months showing an initial mixed response with regression of the primary tumor but progression of hepatic metastases. Patient A was managed subsequently by multiple surgical and liver-directed interventional procedures.

IHC in both metastatic cases, on material from metastatic sites obtained prior to ICI treatment, showed infiltration by CD3+ and CD8+ T cells, notably more pronounced in the ICI responding patient. Both were negative for CD20, PD-L1, PD-1, and LAG-3.

Conclusion: BRAF mutant GISTs are rare with variable responses to BRAF/MEK inhibition. A durable complete response to ICI was observed in one patient. Preliminary immune profiling supports further investigation of immunotherapy in selected cases with immune-infiltrated microenvironments.