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Crossover Trial Validates Accelerated Approval of Sunitinib for GIST: Almost Simultaneous Publication with Report at ASCO Annual Meeting about Regorafenib as Third-Line Kinase Inhibitor

Rosenthal, Eric T.

doi: 10.1097/01.COT.0000415891.70630.e6

The crossover trial design implemented in the pivotal Phase III clinical trial of sunitinib (Sutent) for gastrointestinal stromal tumors (GIST) supports the original fast-track approval by the Food and Drug Administration for use in treating tumors resistant to first-line therapy with imatinib (Gleevec), according to a study published in the June 1 issue of Clinical Cancer Research (2012;18;3710–3719).

But so far that's just the middle of the story of successful interventions for GIST, with positive results of a third kinase-inhibitor randomized clinical trial presented at the ASCO Annual Meeting as a late-breaking abstract (LBA10008).

I spoke with George D. Demetri, MD, just before he left for the meeting, about the back-to-back timing of his paper and the presentation.

“It makes a nice story and ties it all together, and frankly it makes the last 12 years of my career look like it was all consciously planned,” he said with a chuckle, admitting that the timing was coincidental as far as he knew.

Although Demetri at that time could not discuss the details of his embargoed presentation (“Randomized Phase III Trial of Regorafenib in Patients with Metastatic and/or Unresectable GIST Progressing Despite Prior Treatment with at Least Imatinib and Sunitinib: GRID trial),” he said the trial's structure was similar to the one in Clinical Cancer Research (“Complete Longitudinal Analyses of the Randomized, Placebo-Controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor following Imatinib Failure”).

That study found that the crossover design—offering patients initially randomized to receive placebo the opportunity to cross over to sunitinib treatment upon disease progression or following unblinding of the trial—benefited patients, and the long-term overall survival benefit was not accompanied with any new adverse effects.

The study also analyzed circulating biomarkers of angiogenesis during treatment and found no clinical associations with outcome, according to the authors.

The original study that led to FDA's 2006 approval found that the median time to tumor progression was 27 weeks for patients in the sunitinib arm and six weeks for those in the placebo arm.

Demetri, Senior Vice President for Experimental Therapeutics at Dana-Farber Cancer Institute and Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, noted that the FDA's approval of sunitinib for this indication was very rapid, with the first GIST patient receiving it in 2002, and approval based on interim results. He was also involved in the imatinib trial.

“I'm really proud of the timeline of this new drug [regorafenib] because we put it into the first patient in February 2010 and by March 2012 we've got data to go to the FDA already,” he said, noting the cooperation of the FDA in recognizing that progression-free survival is clinically meaningful in GIST and does track with survival—“What a great starting point, because very few diseases have that rigorous data,” he said.

The crossover, multicenter, double-blind, placebo-controlled randomized Phase III study involved 361 patients, with 243 receiving sunitinib and 118 placebo, of whom 103 eventually crossed over to the sunitinib arm. Both arms were on a four-weeks-on/two-weeks-off treatment schedule.

Using conventional statistical analysis methods the long-term survival data suggested that the drug had no statistical effect on overall survival, with 72.7 weeks median for those on the sunitinib arm, and 64.9 weeks for those on the placebo arm who switched over to sunitinib.

The authors also used “rank-preserving structural failure time” to analyze the data to model the absence of crossover, and estimated that the median survival for patients receiving placebo would have been 39 weeks—for a substantial overall survival benefit with sunitinib.

Most GISTs are caused by mutations in the KIT proto-oncogene, resulting in the KIT protein constantly transmitting activating signals driving tumor growth. Sunitinib, imatinib, and regorafenib are small-molecule inhibitors of KIT.

Commenting on the use of a crossover design, he said: “I used to tell my patients on these trials, 'Look I don't know what you will get; the computer will decide if you get the sugar pill or the active drug, but trust me we are going to watch you like a hawk and if you have any symptoms even three days after you start the trial, we will do another CAT scan. We will find out the minute the tumor starts to progress and if it is progressing we will do everything we can to cross you over and get you the drug,' and patients really resonated to that idea.”

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Third Agent Effective Against GISTs Resistant to Other Targeted Therapies

CHICAGO—In what he termed “a unique academic-industrial global collaboration with investigators with very fast [two years] timelines,” George D. Demetri, MD, Senior Vice President for Experimental Therapeutics at Dana-Farber Cancer Institute and Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, presented positive data on the results of a randomized, double-blind, placebo-controlled Phase III trial of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib and sunitinib: the GRID trial (LBA10008).

Speaking here at the ASCO Annual Meeting, he noted that GIST had been developed during the last decade from an unknown disease to a very widely known, more adequately treated disease, and said this was an example where basic understanding had truly transformed this form of sarcoma into a revolutionary improvement in patient care.

He said the Phase III trial with 199 patients randomized either to regorafenib (133 patients) or placebo (66 patients) plus best supportive care was developed following positive results from a Phase II study presented at last year's ASCO meeting.

Progression-free survival was significantly longer for patients receiving the oral drug regorafenib (4.8 months) than for those on placebo (0.9 months), and 85% of those on placebo crossed over to regorafenib when their disease progressed.

Although there was no statistical difference in overall survival between the two arms, the study found a non-significant trend in favor of patients who started the drug earlier.

The moderator of a news conference at the meeting that highlighted this and other key studies on “precision medicine,” Sylvia Adams, MD, of New York University, noted that in following the development of imatinib and sunitinib, this study “shows there are effective therapies for patients with rare tumors.”

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.
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