Activity and safety of cabozantinib in patients with gastrointestinal stromal tumor after failure of imatinib and sunitinib: EORTC phase II trial 1317 CaboGIST.

Abstract

11006 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. Advanced GIST is treated with tyrosine kinase inhibitors (TKIs). Most patients (pts) develop resistance over time. We reported in 2013 (Van Looy CTOS) that cabozantinib (cabo), a TKI targeting KIT/MET/AXL/VEGFR, showed activity in GIST xenograft models through inhibition of tumor growth, proliferation and angiogenesis, both in imatinib-sensitive and -resistant tumors (Gebreyohannes Mol Cancer Ther 2016;15:2845-28). Cohen (Cancer Res 2015;75:2061-70) found that cabo can overcome compensatory MET signaling in GIST in vitro. EORTC 1317 assessed the safety and activity of cabo in pts who had progressed on imatinib and sunitinib. Methods: In this multi-center, open label, single arm Phase 2 study eligible metastatic GIST pts received 60 mg (freebase weight) cabo p.o./d. Primary endpoint was progression-free survival rate at wk 12, assessed by local investigator per RECIST 1.1. If at least 21 of 41 eligible and evaluable pts were progression-free at wk 12, the activity of cabo was sufficient to warrant further exploration (A’Hern one-stage design). Results: A total of 50 consenting pts were eligible and started treatment between 02/2017 and 08/2018, with 16 (32%) still continuing cabo at the database cut-off in 01/2019. The number of 3 wk treatment cycles ranges from 2-28+. Among the first 41 eligible and evaluable pts, 24 were progression-free at wk 12, satisfying the study decision rule. Among all 50 pts, 30 were progression-free at wk 12 (60%, 95% confidence interval (CI) 45-74%). A total of 7 pts achieved a confirmed partial response (PR) (14%, 95%CI 6-27%) and 33 had stable disease (SD) (66%, 95%CI 51-79%). Progression as best response was seen in 9 pts (18%, 95%CI 9-31%), one was not evaluable. Disease control (PR+SD) was achieved in 40 pts (80%, 95%CI 66-90%). Median progression-free survival was 6.0 mo (95%CI 3.6-7.7). The most common cabo-related grade ≥3 adverse events were diarrhea (74%), hand-foot syndrome (58%), fatigue (46%), hypertension (46%), weight loss (38%) and oral mucositis (28%), with 33 (66%) pts requiring dose reductions, 25 (50%) treatment interruptions and no cabo-related deaths. Conclusions: EORTC 1317 met its primary endpoint, with 24/41 pts (58.5%) being progression-free at wk 12. Results of this trial confirm preclinical data and warrant further exploration of cabo in GIST. Clinical trial information: NCT02216578.