(P 096) AN OPEN-LABEL, PHASE 2 EFFICACY STUDY OF TEMOZOLOMIDE IN ADVANCED SUCCINATE DEHYDROGENASE-MUTANT/DEFICIENT GASTROINTESTINAL STROMAL TUMOR

Objective: Most gastrointestinal stromal tumors (GISTs) are caused by gain-of-function somatic mutations in receptor tyrosine kinases. However, up to 10% of GISTs occur due to inherited germline mutations in the succinate dehydrogenase (SDH) A, B, C, and D genes or sporadic SDHC promoter hypermethylation, either of which lead to loss of a functional SDH complex. SDH-deficient GIST has a unique tumor biology that is rarely responsive to tyrosine kinase inhibitor therapies, which are the mainstay of treatment for more common types of GIST harboring activating mutations in driver oncogenes such as KIT or PDGFRA. The oral alkylating agent temozolomide (TMZ) elicits DNA damage, ER stress, and apoptosis in patient-derived SDH-deficient GIST models (Yebra et al., Clin Cancer Res, 2021). Here we report preliminary data from the pre-planned interim futility analysis of a phase II clinical trial of TMZ in patients with advanced SDH-deficient GIST (NCT03556384).

Methods: This single-arm, open-label, multicenter, phase II clinical trial is enrolling patients with unresectable or metastatic pathologically confirmed GIST with loss of SDHB expression by immunohistochemistry and assessment of SDHA/B/C/D gene mutations by next generation sequencing. The primary endpoint is the overall response rate according to RECIST v1.1 at 6 months (ORR6M). A two stage Simon optimal design will be used to test the null hypothesis of a 15% ORR6M, against an alternative hypothesized ORR6M of 35% or greater, at 80% power with 10% type I error. Enrollment began on September 12, 2018, with planned total accrual 23 patients. All patients receive TMZ 85 mg/m2 orally once daily for 21 days followed by 7 days without treatment in 28-day cycles. Patients undergo radiographic imaging (CT or MRI) every 8 weeks to assess tumor response. An interim futility analysis was planned when the first 9 subjects reached 6 months post enrollment; if one or fewer of these 9 achieved ORR6M the study would stop for futility.

Results: As of the data cutoff of December 3, 2021, the first 9 patients were evaluated for the interim futility analysis; ORR6M was attained in 2 of these 9 patients (22.2%). An additional patient achieved partial response at 4 months with eventual disease progression at 6 months. Two patients had disease stabilization on TMZ that made palliative debulking surgery possible. Thus, the study passed the interim futility analysis; enrollment is ongoing. Adverse events (AEs) were noted in 87% of patients, 15% of which were grade 3 or 4; there were no grade 5 AEs.

Conclusion: This trial of TMZ in SDH-deficient GIST patients had an acceptable safety profile and passed the pre-planned interim futility analysis, warranting continuation of the study. Prior studies of tyrosine kinase inhibitors and demethylating agents in this GIST subpopulation have been disappointing, with average response rates of less than 10%. Given the lack of efficacious therapy for treating SDH-deficient GIST, TMZ may provide a new therapeutic option and fulfil an unmet clinical need for these patients. The study will proceed until target accrual is met and the final analysis is completed.