Stopping Gleevec

Stopping Gleevec (imantinib)

The question of whether or not a patient can stop imatinib comes up frequently. The answer is highly dependent on the treatment stage that the patient is in.

Neoadjuvant

Imatinib is generally continued until just prior to surgery to remove the primary tumor. For patients with high-risk tumors, it is typically restarted after surgery.

Adjuvant

Imatinib is generally given for at least 3 years if the patient is tolerating it well. Clinical trials are ongoing to determine if longer durations are beneficial. The doctor might consider factors such as risk of recurrence, mutational status (does the patient have a Gleevec-responsive mutation), new trial data, and how well the patient is tolerating imatinib when determining a treatment duration.

Metastatic Disease still responding to imatinib

For metastatic GIST that is still responding to imatinib, the standard treatment would be to continue imatinib as long as possible. The French BFR14 trial investigated the possibility of stopping imatinib for patients with advanced GIST.

One of the conclusions published about this trial was:

“Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity.” http://jco.ascopubs.org/cgi/content/full/25/9/1107

At the 2003 Helsinki and Barcelona conference on the Clinical Management of GIST (before the approval of Sutent for Gleevec-resistant GIST), “Dr. Demetri postulated that signal transduction inhibition with imatinib may result in cell suppression or dormancy but not cell death in some sensitive clones. In essence, these cells “wake up” when the drug is discontinued. Post-imatinib recurrences of GIST have been found to be highly aggressive, placing the patient at risk for marked acceleration of tumor growth and a rapidly fatal course. Therefore, it is advisable not to terminate imatinib therapy as long as the patient is tolerating the drug, especially if there is evidence that only limited progressive disease is present (e.g., 1 focal resistant clone that might be managed by a locoregional measure such as surgical resection or radiofrequency ablation). Chances are good that imatinib will continue to shrink or stabilize most sites of disease for a considerable duration even in a patient who has developed a limited focus of clonal resistance to imatinib.”

The approval of Sutent (sunitinib) and Stivarga (regorafenib) gives patients additional options, but the important point to remember is that some type of kinase inhibition should be maintained in GIST patients as long as they are able to tolerate it.

See Imatinib Discontinuation can result in “PET Flare” for the full story.

Also see:

From the LRG clinical trials database; see the “Trial Results” links for the BFR14 trial near the bottom of this page: https://gisttrials.org/iLRG/details.php?Trial=50

From the JNCCN guidelines (NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)—Update of the NCCN Clinical Practice Guidelines)¹:
“The therapeutic effect (of imatinib) should be monitored using positron emission tomography (PET) or CT. Patients should remain on imatinib or sunitinib as long as possible; however, if the patient is no longer receiving clinical benefit from imatinib or sunitinib, then the drugs should be discontinued and best supportive care used.”

Note: Since the publication of the above quoted guidelines, Stivarga has been approved for 3^rd line treatment for GIST, so it could be used instead of “best supportive care.”

Metastatic Disease resistant to Gleevec

For Gleevec-resistant GIST, the JNCCN guidelines recommend continuing Gleevec or starting Sutent; Stivarga is approved for use after progression on Sutent:

“When patients have experienced progression on imatinib and sunitinib and are not candidates for a clinical trial, the task force believes that discontinuing therapy targeting KIT/PDGFRA may lead to accelerated tumor growth by withdrawing control of sensitive clones of the disease (even if limited sites of disease have been shown to exhibit resistance to therapy and hence to progress more rapidly). Therefore, absent a clinical trial testing a different hypothesis, the task force recommended that patients with limited progression of GIST should continue imatinib or sunitinib at a dose they can tolerate.”

Also see: Managing Progression: Charles D. Blanke, MD discusses Gleevec Resistance

Localized progression

Localized progression is the progression of one or a few (but not all) tumors while on Gleevec. The progressing tumor(s) are treated by surgery, radiofrequency ablation (RFA) or embolization if possible. Gleevec is typically continued at the same dose or an increased dose as tolerated. A change to Sutent or Stivarga can be considered, however continuation of some type of kinase inhibitor is recommended².

Widespread progression

Gleevec is typically continued at an increased dose (800 mg if tolerated) or a change to Sutent or Stivarga can be considered.