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Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need.


METHODS
Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG.


RESULTS
Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%).


CONCLUSIONS
This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.