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Cancer Cells Outsmarting Smart Bombs: Gastrointestinal Stromal Tumors (GIST)

Sandra Kear
Published Online: Thursday, May 12, 2011
gastrointestinal stomal tumor scansGleevec (imatinib), a kinase inhibitor used to treat unresectable or metastatic gastrointestinal stromal tumors (GISTs), was once touted as a cancer smart bomb. Like other targeted therapies, however, smart bombs can become “outsmarted” in certain patients whose cancer cells form mutations and build up a resistance to the drug, driving the need for second- and third-line therapies.

Clinical trial data indicated that some disease progression would likely occur in about 75% of patients with metastatic, bulky GIST after about 3 years of therapy on Gleevec.1 A second-line therapy, Sutent (sunitinib), was approved in 2006 by the FDA for the treatment of GIST after disease progression on or intolerance to imatinib.2

Unfortunately, mechanisms of resistance and tumor progression are similar with imatinib and sunitinib failure. In the case of GISTs, secondary mutations in KIT or PDGFR-α, or in alternative signaling cascades such as RAF, have led to resistance and tumor progression.3

This week the FDA has granted fast track designation to the investigational compound regorafenib (BAY 73-4506) for the treatment of patients with metastatic and/or unresectable GIST whose disease has progressed despite prior treatments of at least imatinib and sunitinib.3

Regorafenib is an investigational oral multi-kinase inhibitor of angiogenic, stromal, and tyrosine kinases. It inhibits angiogenic kinases like receptors for VEGF and the TIE2 receptor, which play important roles in angiogenesis.3 Regorafenib also inhibits various oncogenic kinases including RAF, RET, and KIT, which may help to cease cancer cell proliferation.3

Enrollment began in January for a randomized, double-blind, placebo-controlled phase III study of regorafenib as a third-line or greater treatment for GIST. Interventions include regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable GIST whose disease has progressed despite prior treatment with at least imatinib and sunitinib.4 Approximately 170 patients will be randomized in a 2:1 ratio to receive either regorafenib or placebo. Subjects receiving placebo who experience disease progression may be offered a cross-over option of open-label regorafenib.4

The primary endpoint of this trial is progression-free survival, and secondary endpoints include overall survival, time to progression, disease control rate, tumor response rate, duration of response, and safety. All patients will enter a survival follow-up period upon discontinuation of study treatment, during which an assessment of survival status will be performed.4 Primary outcome data is expected early in 2012.

GIST accounts for only 5,000 new cases in the US each year. Prior to these targeted therapies, patients with GIST had no effective systemic treatment and poor prognosis.5 Between 1992 and 2000, the overall relative 5-year survival rate of people diagnosed with a malignant GIST was estimated to be about 45%.6 According to the American Cancer Society, people currently being treated with targeted therapies for GIST will likely have a better outlook.6 Oncologists will need to continue to monitor patients with GIST carefully for disease recurrence, however, to be sure the cancer cells don’t “outsmart” these targeted therapies.

References

  1. GIST Support International: Gleevec Side Effects and Tips. Available at: GIST Support International. Accessed May 11, 2011.
  2. Highlights of Prescribing Information: Sutent (sunitinib malate). Available at: Highlights of Prescribing Information. Accessed May 11, 2011.
  3. Bayer Press Release: FDA Grants Fast Track Designation to Bayer’s Investigational Compound Regorafenib for the Treatment of Gastrointestinal Stromal Tumors. Available at: Bayer Press Release. Accessed May 11, 2011.
  4. ClinicalTrials.gov Identifier:NCT01271712. Available at: ClinicalTrials.gov. Accessed May 11, 2011.
  5. Treatment of Gastrointestinal Stromal Tumors: CancerConnect.com. Available at CancerConnect.com. Accessed May 11, 2011.
  6. American Cancer Society. Gastrointestinal Stromal Tumor (GIST). Survival rates. Available at: American Cancer Society. Accessed May 11, 2011.


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