CHICAGO – Retreating unresectable gastrointestinal stromal tumors with imatinib after disease progression can improve both progression-free survival and disease control rates, but the benefits of rechallenge are short lived, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Imatinib rechallenge is commonly tried in patients with gastrointestinal stromal tumors (GIST) that have progressed after an initial response to imatinib (Gleevec) in the first line and sunitinib (Sutent) or another tyrosine kinase inhibitor (TKI) in the second line, but without empirical evidence to support the practice, said Dr. Yoon-Koo Kang, professor of oncology at Seoul National University in Seoul, South Korea.
In the phase III RIGHT (Rechallenge of imatinib in GIST having no effective treatment) trial, patients who were randomized to imatinib rechallenge had a small but significant benefit in progression-free survival (PFS), with a median of 1.8 months compared with 0.9 months for patients assigned to placebo (hazard ratio [HR] 0.45, P = .00075).
In addition, significantly more patients retreated with imatinib had stable disease lasting at least 4 weeks (30 vs. 17 patients, P = .005), 8 weeks (17 vs.6, P = .008), or 12 weeks (13 vs. 2, P = .003).
"Rechallenge of imatinib significantly improves progression-free survival and disease-control rate in patients with advanced GIST after failure of at least imatinib and sunitinib, likely by continuous kinase inhibition of the bulk of disease clones which retain imatinib sensitivity. However, TKI-resistant clones continue to progress, leading to relatively brief duration of benefit," said Dr. Kang.
The investigators enrolled patients with metastatic and/or unresectable GIST who had previously had either disease control with first-line imatinib for longer than 6 months, or who experienced disease progression on both first-line imatinib and second-line sunitinib. The patients had Eastern Cooperative Oncology Group (ECOG) performance status scores from 0 to 3.
A total of 41 patients were randomized in a double-blinded fashion to imatinib until disease progression, at which point they could stop or continue on imatinib, and 40 were randomized to placebo until disease progression, after which they could be crossed over to receive imatinib. In each group, 16 patients had previously received treatment with three or more TKIs, including nilotinib (Tasigna), sorafenib (Nexavar), regorafenib (Stivarga), or dovitinib.
Of the 40 patients in the placebo arm, 37 crossed over to imatinib after disease progression. Median PFS after crossover in these patients approached that of patients initially assigned to imatinib at 1.7 months.
Grade 3 or 4 fatigue occurred in four patients on imatinib vs. none on placebo, and grade 3 or 4 hyperbilirubinemia occurred in three patients and one patient, respectively. Grade 3 or 4 anemias were detected in 12 patients on imatinib vs. 3 on placebo.
The trial demonstrates the wisdom of the adage "if at first you don’t succeed, try, try again," said invited discussant Dr. Shreyaskumar Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.
If patients have "run out of all sorts of options, randomizing them to imatinib instead of placebo certainly slows down the rate of progression, even in the absence of a response, and certainly can [have an] impact on their overall quality of life and their natural history," he said.
The results also support the use of a kinase inhibitor rather than placebo in the control arm of future trials for novel anti-GIST agents, he added.
Dr. Kang and Dr. Patel disclosed ties to Novartis. Dr. Kang disclosed ties with Novartis and Bayer Schering Pharma. The RIGHT trial was sponsored in part by Novartis.