Journal Article

Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial

Ryoo, Baek-Yeol, Yoo, Changhoon, Ryu, Min-Hee, Lee, Jong Jin, Kim, Hyun Jin, Nam, Byung-Ho, Ramaiya, Nikhil, Kang, Yoon-Koo, Jagannathan, Jyothi, Demetri, George D

2013

Overview

Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients. In our prospective, randomised, double-blind trial, we enrolled adults (≥18 years) who had previously benefited from first-line imatinib (initial response or stable disease for ≥6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1:1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01151852. Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5·2 months (IQR 3·4–9·4), median PFS was 1·8 months (95% CI 1·7–3·6) with imatinib compared with 0·9 months (0·9–1·7) with placebo (hazard ratio for progression or death 0·46, 95% CI 0·27–0·78; p=0·005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]). In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression. Novartis Oncology, Ludwig Center at Dana-Farber/Harvard.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Aged / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Benzamides - administration & dosage / Benzamides - adverse effects / Disease Progression / Disease-Free Survival / Double-Blind Method / Drug Administration Schedule / Female / Gastrointestinal Stromal Tumors - drug therapy / Gastrointestinal Stromal Tumors - enzymology / Gastrointestinal Stromal Tumors - mortality / Gastrointestinal Stromal Tumors - secondary / Hematology / Hematology, Oncology and Palliative Medicine / Humans / Imatinib Mesylate / Indoles - administration & dosage / Indoles - adverse effects / Kaplan-Meier Estimate / Male / Medical imaging / Metastasis / Middle Aged / Molecular Targeted Therapy / Oncology / Patients / Piperazines - administration & dosage / Piperazines - adverse effects / Proportional Hazards Models / Prospective Studies / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - adverse effects / Pyrimidines - administration & dosage / Pyrimidines - adverse effects / Pyrroles - administration & dosage / Pyrroles - adverse effects / Radiology / Republic of Korea / Time Factors / Treatment Outcome / Tumors