Regorafenib overcomes resistance in patients with metastatic GIST
Phase III study shows that regorafenib was able to control disease for nearly four months longer than placebo in patients for whom imatinib and sunitinib were no longer effective
- Date : 26 Nov 2012
- Topic : Gastrointestinal cancers
Regorafenib, a new targeted drug demonstrated its ability to control metastatic gastrointestinal stromal tumour (GIST) after the disease had become resistant to all existing therapies, investigators who led the worldwide clinical trial report in the journal Lancet.
The treatment of GIST, even in its advanced metastatic stage, has been dramatically improved with two oral targeted drugs, imatinib and sunitinib. To date, these have represented the only two approved treatments by medical regulatory agencies with the proven ability to control GIST. However, in more than 85% of patients, GIST becomes resistant to these drugs and the disease worsens with fatal results.
The new study, whose results are being published in the Lancet, demonstrated that the oral drug regorafenib, which inhibits several cancer-promoting kinase enzymes, was able to control GIST for nearly four months longer than placebo in patients for whom imatinib and sunitinib were no longer effective, a result that was highly significant statistically.
According to Dr George Demetri of Dana-Farber, who was a principal investigator of this clinical trial, when added to best supportive care, regorafenib significantly improves disease control, as measured by progression-free survival time in patients with GIST after progression to other therapies.
Demonstrating the aggressive nature of this resistant disease, the study found that tumours objectively grew in less than a month, on average, in GIST patients who were initially randomized to receive a placebo. The study's cross-over design made it possible to treat those patients whose tumours grew, and 85% of the patients initially on placebo were able to receive regorafenib, which then controlled the disease in these patients as well.
Because of the study's cross-over design, it was not expected to prove that the patients initially randomized to receive regorafenib survived longer – the researchers would have had to withhold the drug from the placebo patients to demonstrate that difference. An application to have regorafenib approved for use in resistant GIST is under review by regulatory bodies.
The phase III international trial involved 199 treatment-resistant GIST patients at 57 hospitals in 176 countries. Of the 199 patients, 133 received a regorafenib daily for three weeks followed by a one-week break, while 66 received a matching placebo. The patients were monitored for at least one year after the trial began.
As for other targeted therapies, the drug did not often shrink tumours but controlled the disease for an average of 4.8 months before it progressed, while patients in the placebo group experienced less than one month (0.9 month) before the disease worsened. There was a high rate of adverse effects including high blood pressure, fatigue, diarrhoea, and redness, swelling, numbness and peeling of skin on the hands and feet. These side effects were managed by reducing or interrupting the regorafenib treatment.
A companion report in The Lancet emphasized that the drug had a "modest" benefit in patients with metastatic colon cancer. A commentary by Dr David Cunningham of the Royal Marsden Hospital in the UK, states "in the relatively rare GIST, the case for routine use of this drug in patients following failure of existing treatments is strong."
Regorafenib can inhibit many of the mutated proteins and abnormal signals, and the next step will be to investigate the molecular mechanisms by which this new drug can control GIST after resistance appears to other targeted therapy drugs.
The clinical trial was supported, in part, by Bayer HealthCare Pharmaceuticals, as well as the Ludwig Centre at Dana-Farber/Harvard Cancer Centre.
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