Phase II Trial of Ponatinib in Patients with Metastatic Gastrointestinal Stromal Tumor following Failure or Intolerance of Prior Therapy with Imatinib (POETIG Trial)

PURPOSE: Imatinib resistance is conferred by secondary mutations within the ATP-binding pocket or the activation loop of KIT in gastrointestinal stromal tumors (GIST). Ponatinib is active against KIT secondary activation loop and the gatekeeper mutation T670I in vitro. We evaluated the safety, activity, and inhibitory profile of lower-dose (30 mg) ponatinib in pretreated patients with KIT-mutant GIST. PATIENTS AND METHODS: POETIG was a multicenter phase II trial in patients with advanced, unresectable GIST progressing after imatinib (cohort A, KITV654A-, and cohort B, KITV654A+) or at least imatinib, sunitinib, and regorafenib (cohort C). The primary endpoint was the clinical benefit rate at 16 weeks (modified RECIST 1.1). ctDNA was analyzed for mutations V654A and T670I, and ponatinib was characterized in silico and in vitro using a panel of GIST cell lines. RESULTS: A total of 46 patients were enrolled, and the median follow-up was 1.3 years. The 16-week clinical benefit rate in cohorts A + B was five of 19 (26.3%) and nine of 27 (33.3%) in cohort C, with a median progression-free survival of 2.1 and 3.4 months with four (cohorts A + B) and five (cohort C) patients responding for >6 months. These patients were characterized by exon 11 and/or T670I mutations. Cardiovascular events occurred in four of 46 patients; most common grade 3/4 side effects were hypertension, gamma-glutamyl transferase (GGT)/lipase increase, abdominal pain, and infections. Clinical observations were reproduced by cell line screening and structural modeling. CONCLUSIONS: The trial did not meet its primary endpoint, but lower-dosed ponatinib provided clinical benefit in a subset of patients with expected toxicities. Patients harboring primary exon 11 and/or resistance mutations in T670I and/or exons 17/18 may represent a relevant therapeutic niche for ponatinib.