Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

Abstract

BACKGROUND:

This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST.

PATIENTS AND METHODS:

The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed.

RESULTS:

Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST.

CONCLUSIONS:

Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities.

CLINICAL TRIAL NUMBER:

NCT01068769.

• Authors: E Ben-Ami, C M Barysauskas, M von Mehren, M C Heinrich, C L Corless, J E Butrynski, J A Morgan, A J Wagner, E Choy, J T Yap, A D Van den Abbeele, S M Solomon, J A Fletcher, G D Demetri, S George
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 27 Issue 9 Pg. 1794-9 (09 2016) ISSN: 1569-8041 [Electronic] England
• PMID: 27371698 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Indoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Pyrroles
• regorafenib
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• Sunitinib

Topics

• Adult
• Aged
• Disease-Free Survival
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gastrointestinal Stromal Tumors (drug therapy, genetics, pathology)
• Genotype
• Humans
• Imatinib Mesylate (administration & dosage, adverse effects)
• Indoles (administration & dosage, adverse effects)
• Male
• Middle Aged
• Mutation
• Phenylurea Compounds (administration & dosage, adverse effects)
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Proto-Oncogene Proteins c-kit (genetics)
• Pyridines (administration & dosage, adverse effects)
• Pyrroles (administration & dosage, adverse effects)
• Sunitinib