By Will Boggs, MD

NEW YORK (Reuters Health) – Some patients with gastrointestinal stromal tumors (GIST) may benefit from resuming imatinib even after a previous failure of imatinib and sunitinib, according to results from the RIGHT trial.

“Contrary to prior oncology principle, reintroduction of treatment which failed before can be beneficial to patients,” Dr. Yoon-Koo Kang from Asan Medical Center and the University of Ulsan College of Medicine in Seoul, South Korea told Reuters Health.

“It is because it can slow down the overall progression of the disease since there are still tumor cells maintaining sensitivity to the treatment even though it had failed before by response criteria,” Dr. Kang said.

Reintroduction of imatinib dosing has been recommended in many treatment guidelines for patients whose disease progresses despite previous treatment with tyrosine kinase inhibitors, with the goal of delaying disease progression and palliating symptoms by targeting GIST clones that remain sensitive to imatinib inhibition.

Until now, this approach had not been tested in a randomized trial.

The 81 patients in Dr. Kang’s trial all had metastatic or unresectable GIST that initially responded or remained stable on imatinib and subsequently progressed despite treatment with at least imatinib and sunitinib. They were randomly assigned to receive imatinib 400 mg per day or matched placebo, with crossover to open-label imatinib allowed for disease progression.

During a median follow-up of 5.2 months, the median progression-free survival was 1·8 months with imatinib compared with 0.9 months with placebo (hazard ratio for progression or death 0·46, p=0·005), according to a report online October 18th in The Lancet Oncology.

Progression-free survival was better for imatinib patients than for placebo patients at four weeks (73% vs 43%, respectively; p=0.005), eight weeks (42% vs 15%; p=0.008), and 12 weeks (32% vs 5%; p=0.003).

Median overall survival did not differ between the imatinib group (8.2 months) and the placebo group (7.5 months), but this may reflect the fact that 37 of the 40 patients randomly allocated to receive placebo crossed over to open-label imatinib, 35 after experiencing objective tumor progression.

The incidence of grade 3-4 anemia, fatigue, and hyperbilirubinemia was higher with imatinib than with placebo, but none of the patients required dose modification or discontinuation because of treatment-related adverse events, the authors say.

“In US or other countries where resumption of imatinib is reimbursed in this setting, this study results provide rationale to prescribe imatinib after failure of all available treatment,” Dr. Kang said. “In many other countries, including Korea, where reintroduction of imatinib is not reimbursed in this setting, this study result can change the reimbursement policy and consequently practice pattern of the oncologists.”

As for how long to continue imatinib in this setting, Dr. Kang said, “Personally, I would recommend to continue as long as disease is not progressing rapidly and the patient can tolerate the treatment.”

Dr. Kang added, “This study results have implication for the future clinical trials of new agent for advanced GIST. There has been a controversy about the control arm for these trials. With this study results, we have a consensus that any future clinical trial to demonstrate the efficacy of a new agent in advanced GIST should not have placebo (plus best supportive care) alone as the control arm.”

Dr. Heikki Joensuu from Helsinki University Central Hospital in Finland told Reuters Health, “Advanced tyrosine kinase receptor resistant GIST is frequently a heterogeneous disease that may contain cancer cell populations with varying sensitivity to tyrosine kinase inhibitors.”

Dr. Joensuu, who was not involved with Dr. Kang’s study, added, “Imatinib may still inhibit overall cancer growth despite some cell clones progress on it. However, the clinical benefit achieved at his stage is small as compared to patients whose GIST is sensitive to imatinib.”

“Prevention or postponing of emergence of drug resistance is a key goal in the treatment of GIST,” Dr. Joensuu said. “Strategies to achieve this may include treating early enough when the tumor mass is still small (with adjuvant imatinib), using adequate imatinib doses (to prevent underdosing that may allow GIST cell proliferation on imatinib), and promoting patient compliance (by counseling and treating imatinib-related side-effects efficiently).”

Novartis Oncology provided funding for the trial and research support for two of the 10 authors.

SOURCE: 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
Lancet Oncol 2013.