823 Background: Imatinib is a standard first line treatment for advanced gastrointestinal stromal tumor (GIST); however eventually almost all the GISTs become resistant to imatinib. Secondary mutation in KIT is the most relevant cause of imatinib-resistant, as high as 70% of cases. Sunitinib is standard of care for imatinib-resistant GIST with median progression-free survival (PFS) of 24.6 weeks; however, in a preclinical study sunitinib is not active for approximately half of secondary mutations. Regorafenib is active for some secondary mutations resistant to sunitinib in the preclinical study. Therefore, we conducted a phase II study evaluating regorafenib for imatinib-resistant GIST. Methods: Patients with imatinib-resistant advanced GIST were enrolled. Key eligibility criteria were ECOG PS of 0-1 and adequate organ function. Prior exposure of sunitinib was not allowed. The primary endpoint was PFS rate at 24 weeks. ctDNA for KIT was evaluated prior to regorafenib administration. Results: A total of 38 patients were enrolled as planned. Median age was 64.5 (39 - 80). Twenty-five patients were male. Primary site was stomach in 17, small intestine in 16. Median PFS was 36.3 weeks and PFS rate at 24 weeks was 47.4% (primary endpoint was not met). Best overall response was PR for 6 (16 %), SD for 25 (63 %) and PD for 5 (13 %) patients. Grade 3 or more adverse events (AE) were observed in 25 (66 %) patients. Common grade 3 or more AE were hand-foot-skin reaction (n = 9), hypertension (n = 9), hepatotoxicity (n = 4). ctDNA was evaluated in 32 patients and among them secondary mutations were observed in 15 patients (47%). PFS was shorter (15.6 weeks) in patients with exon 13 mutation than that in patients without second mutation (49.3 weeks, not statistically significant). Conclusions: Regorafenib demonstrated favorable activity in patients with imatinib-resistant GIST as second line therapy with acceptable toxicity. Secondary mutation in KIT might be a predictor of the efficacy of regorafenib. Clinical trial information: UMIN000016115.
Regorafenib as second line therapy for imatinib-resistant gastrointestinal stromal tumor (GIST): A phase II study
