In the RIGHT trial, reported in The Lancet Oncology, Yoon-Koo Kang, MD, of University of Ulsan College of Medicine in Seoul, and colleagues assessed the effects of imatinib (Gleevec) rechallenge in patients with metastatic or unresectable gastrointestinal stromal tumors (GIST) after objective progression on first-line imatinib and second-line sunitinib (Sutent). They found that rechallenge provided progression-free survival benefit compared with placebo.
In this small double-blind phase III trial, 81 South Korean patients 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 first-line imatinib and second-line sunitinib were randomly assigned to receive best supportive care with imatinib at 400 mg per day (n = 41) or matched placebo (n = 40). Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. Patients were stratified by previous treatment and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival determined by a masked external radiologic review.
Patients in the imatinib and placebo groups were generally well matched for age (median, 57 and 61 years), ECOG performance status (0 or 1 in 68% and 70%), primary site (small bowel in 49% and 63%), previous third-line or later treatment (nilotinib [Tasigna] in 17% and 23%, regorafenib [Stivarga] or sorafenib [Nexavar] in 12% and 25%, and divotinib in 17% and 8%), duration of prior first-line imatinib (≥ 24 months in 59% and 62%), and primary genotype (KIT exon 11 mutation in 82% and 77%).
Superior Progression-Free Survival
After median follow-up of 5.2 months, median progression-free survival was 1.8 months (95% confidence interval [CI] = 1.7–3.6 months) in the imatinib group vs 0.9 months (95% CI = 0.9–1.7 months in the placebo group (hazard ratio [HR] = 0.46, P = .005). On investigator assessment, median progression-free survival was 1.8 months (95% CI = 1.7–2.7 months) in the imatinib group and 1.7 months (95% CI = 0.9–1.8 months) in the placebo group (HR = 0.56, P = .019). There were no objective responses in either group. A total of 37 patients (93%) in the placebo group crossed over to open-label imatinib after progression. Estimated median overall survival was 8.2 months (95% CI = 5.5–12.8 months) in the imatinib group and 7.5 months (95% CI = 4.4–12.4 months) in the placebo group (HR = 1.00, P = .92).
The most common adverse events of any grade were anemia (66% of imatinib patients vs 45% of placebo patients) and edema (44% vs 13%, P = .0027). Grade 3 or 4 adverse events were more common in imatinib patients (49% vs 18%, P = .0043), with the most common being anemia (29% vs 8%, P = .020), fatigue (10% vs 0%), and hyperbilirubinemia (7% vs 3%). No patients had dose modification or discontinuation of study treatment due to treatment-related adverse events.
The investigators concluded, “In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to [harbor] many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression.”
The study was funded by Novartis Oncology and the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School.
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