Resumption of Imatinib dosing to control metastatic Gastrointestinal Stromal Tumors (GIST) after failure of Imatinib and Sunitinib: Results of a randomised, placebo-controlled, phase 3 trial (RIGHT)

SUMMARY Background We conducted a prospective, randomised, double-blind trial to evaluate the efficacy of imatinib rechallenge in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) following objective progression of prior approved tyrosine kinase inhibitor (TKI) therapy. Method Between July 2010 and January 2013, 81 patients with prior benefit from first-line imatinib (initial response or stable disease for ≥6 months) and subsequent progression on at least imatinib and sunitinib were randomly assigned in a 1:1 ratio (by computer-generated randomisation list and the central coordinating center using telephone in a double-blind manner; randomised block permutation methods with block size of 2, 4, and 6; stratified by treatment line and performance status) to receive best supportive care with either imatinib 400 mg/day (n=41) or a placebo (n=40). At the time of disease progression, determined by the investigators, crossover to open-label imatinib was allowed. The primary endpoint was progression-free survival (PFS) determined by blinded external radiology review. Secondary endpoints included the disease control rate at 12 weeks, overall survival, and safety. All analyses were based on the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01151852. Findings The median PFS was 1·8 months (95% confidence interval [CI], 1·7–3·6) with imatinib as compared with 0·9 months (95% CI, 0·9–1·7) with placebo (hazard ratio for progression or death, 0·46; 95% confidence interval [CI], 0·27–0·76; p=0·005, two-sided). In the placebo arm, 37 patients (93%) crossed over to open-label imatinib after progression. The most common grade 3 or higher adverse events of imatinib resumption was anemia (12 of 41, 29%), fatigue (four of 41, 10%), and hyperbilirubinemia (three of 41, 7%). Interpretation Despite prior resistance to imatinib, resumption of imatinib significantly improves PFS in GIST patients after disease progression on at least imatinib and sunitinib, demonstrating that residual bulk disease contains clones with continued sensitivity.