(P 36) CLINICO-GENOMIC ANALYSIS OF KIT/PDGFRA/SDH WILD-TYPE GASTROINTESTINAL STROMAL TUMORS IDENTIFIES POTENTIAL DRIVER MUTATIONS

Objective: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. The vast majority of GISTs (85-90%) are driven by activating mutations in KIT or PDGFRA, and the next most common alterations are in components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and the SDH family. We characterized the clinical and genomic characteristics of these so-called “triple negative” GISTs.

Methods: We searched for patients seen at MD Anderson with diagnosis of GIST and available clinical genomic profiles to identify “triple negative” patients.

Results: Of the 16 patients identified, 9 (56.3%) had gastric and 7 (43.7%) had small intestinal primary sites. Median follow-up from time of diagnosis was 68 months (mean 124.2 months). Fourteen patients (87.5%) eventually developed recurrent or metastatic disease, and 5 of these presented with de novo metastatic disease. For the 9 patients with localized disease initially that later developed recurrent/metastatic disease, the median time to recurrence/metastasis was 29.2 months (range 2.2-509.9 months). For the 11 patients with evaluable response to imatinib (e.g. neoadjuvant treatment or for recurrent/metastatic disease), median PFS with imatinib was 5.2 months (range 0.5-129.4 months). All 16 cases have had clinical genomic sequencing to reveal a potential driver. Four patients were found to have alterations in the RAS/RAF/MAPK pathway: 2 with a BRAF V600E mutation, and 2 with NF1 mutations (1 deletion and 1 splice site mutation). In addition, 2 had PIK3CA mutations (both I391M), 1 had an NTRK3 fusion (ETV6-NTRK3), 1 had a PTEN deletion, 1 had an FGFR1 gain-of-function mutation (K654E), 1 had a CHEK2 loss-of-function mutation (T367fs*), and 1 had an Aurora kinase A fusion (AURKA-CSTF1). The 2 patients with BRAF V600E mutation have both been treated with the combination of BRAF and MEK inhibitors. One patient has been on this therapy for 34.2 months, has had a partial response, and treatment is ongoing; the other patient stopped therapy after 2 months due to toxicity. The patient with ETV6-NTRK3 fusion was treated with larotrectinib for 28.7 months prior to progression, likely due to acquired NTRK3 gatekeeper mutation (F617L) rendering resistance to larotrectinib, then was on a second generation NTRK inhibitor, selitrectinib, for 16.5 months prior to progression.

Conclusion: Triple negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.