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DF/HCC-led trials aim to overcome resistance in metastatic GIST

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Each year in the USA, about 20 people per million are newly diagnosed with advanced GIST, representing about 5,000 patients, although many others have earlier stages of the disease. The only two therapeutic drugs approved worldwide for GIST are “kinase inhibitors” that stemmed from academic, clinical, and translational research led by George Demetri, MD (DFCI); Jonathan Fletcher, MD (BWH); and Christopher Fletcher, MD (BWH, DFCI). 

The first approved treatment was imatinib (Gleevec), originally developed to treat chronic myeloid leukemia. Imatinib’s application to GIST emanated from mechanistic studies by Demetri and J. Fletcher showing that nearly 90% of GIST patients have cancer-driving mutations in the KIT oncogene, and that imatinib inhibits GIST cells with those mutations. Translating this work into the clinic led to FDA approval in just two years (2002). This team then discovered the mechanisms of resistance to imatinib and developed the multi-kinase inhibitor sunitinib (Sutent), approved in 2006 for GIST patients following resistance to imatinib. No approved therapy exists for patients resistant to imatinib and sunitinib.

Now, phase II and phase III trials led by DF/HCC investigators are assessing whether a structurally distinct new kinase inhibitor, regorafenib, discovered by Bayer Oncology, can overcome resistance to those two drugs and become an effective third-line therapy for multi-resistant tumors. For the trials, Demetri enlisted a larger team of preclinical and clinical co-investigators from DFCI and BWH to build the research plan from an academic perspective. Both trials are ongoing but fully accrued, so are closed to new patients.

The trials are based on the finding that regorafenib may overcome resistance because it binds in a unique manner to mutant kinase variants and also inhibits signaling pathways not targeted by either imatinib or sunitinib. In becoming resistant to those drugs, GIST develops secondary or tertiary mutations in KIT or PDGFRA, or begins to use other signals such as BRAF and MAP kinases. Regorafenib inhibits those proteins and also members of the FGFR and RAF families of kinases and angiogenic kinases like VEGFR and TIE2 that may contribute to GIST’s resistance.

In the single-arm, multicenter phase II trial, led by Suzanne George, MD (DFCI), preliminary data documented impressive activity of regorafenib in 34 study participants with metastatic GIST whose disease was no longer controlled by standard therapies.

After these promising results, Demetri designed and led a larger international, randomized, placebo-controlled worldwide trial to test whether this agent could overcome life-threatening resistant GIST. With about 200 participants, the trial was conducted at 89 sites in North America, Europe, Australia, and Asia. Bayer Oncology sponsored and helped operationalize the far-flung trial. “This collaboration is a great example of how an academic idea gets translated into reality,” Demetri says.

The phase III trial aims to compare progression-free survival with regorafenib versus placebo for participants with metastatic GIST following failure of both imatinib and sunitinib. All study participants also receive best supportive care. Those in the placebo arm whose disease gets worse can crossover to regorafenib. Secondary objectives include comparisons of overall survival, time to progression, rates of disease control and tumor response, duration of response, correlative science studies (including correlating clinical outcomes with genomic analyses of the patients’ GIST), and safety.

If the phase III trial succeeds, Demetri wants to assess regorafenib as a first-line treatment that hits GIST harder and before tumors have activated resistance mechanisms. Would patients have longer disease control if started on this broad-spectrum therapy earlier in the disease process?

“Right now we can only try to overcome resistance once it’s started,” he says. “Our global goal is to prevent resistance from ever emerging.” He likens the strategy to combination antibiotics that prevent resistant bacteria from evolving, and to the AIDS cocktail that controls HIV long term. “We want to do something similar with kinase-driven tumors like GIST. Then we can apply these lessons to other kinase-driven cancers like lung cancers driven by the EGFR or ALK kinases, breast cancers driven by HER2 or PI-3-kinase, or pediatric tumors such as certain neuroblastomas.”

Phase III Trial


Study of Regorafenib as a 3rd-line or Greater Treatment for Gastrointestinal Stromal Tumors (GIST)[1]

Principal Investigator:

George Demetri, MD (DFCI)


Suzanne George, MD (DFCI)
Jeffrey Morgan, MD (DFCI)
Andrew Wagner, MD PhD (DFCI)
James Butrynski, MD (DFCI)
Kathleen Polson, APRN, bc (DFCI)
Amy Pilotte, APRN, bc (DFCI)

More Information:

The trial is ongoing but no longer recruiting patients. For information on ClinicalTrials.gov, go to NCT01271712

Phase II Trial


Regorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor[2]

Principal Investigator:

Suzanne George, MD (DFCI)

More Information:

The trial is ongoing but no longer recruiting patients. For information on ClinicalTrials.gov, go to NCT01068769

[1] Protocol Name: A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib.


[2] Protocol Name: A multicenter phase II study of regorafenib in patients with advanced gastrointestinal stromal tumor (GIST), following failure of prior therapy with at least imatinib and sunitinib