Gleevec for metastatic GIST has been one of the great success stories in cancer treatment. It is probably the biggest advance in solid tumors made over the last decade. Ten years ago, the response rate of GIST to the standard chemotherapies of the day was less than five percent. With Gleevec, 85 percent of patients experience benefit including shrinkage or significant periods of stable disease. As a result, Gleevec was approved for first-line treatment of metastatic or unresectable GIST in 2002.
With the excellent initial response rate of Gleevec, why would patients want to forgo Gleevec and participate in a frontline trial? Despite the impressive initial response, half of patients will relapse within two years and 75 percent will relapse eventually. So far, Gleevec resistance is proving to be hard to overcome, with gains coming primarily with Sutent for wild-type GIST and for patients with KIT exon 9 mutations.
Nearly all of the current clinical trials for GIST involve either (1) trying to prevent a recurrence using Gleevec or (2) trying to treat the disease after it has become resistant. What has been missing is an attempt to improve upon and lengthen the excellent initial response to Gleevec. This appears to be changing. Within the last 18 months, five new approaches designed to improve initial results have entered into clinical trials.
This drug is commonly spelled as either masitinib or masatinib
Masitinib (Manufactured by AB Science in France) is a c-Kit/ PDGFRa inhibitor similar to imatinib and nilotinib. After promising phase I/II results, masitinib is moving into a phase III trial for first-line therapy in GIST. This trial is open to patients with metastatic or non-resectable GIST and patients treated with adjuvant/neoadjuvant imatinib who relapsed after discontinuing imatinib (not imatinib-resistant).
The trial is open in 14 sites in France, three sites in the United States and four sites in Lebanon, and is expected to enroll 222 patients. Unlike other tyrosine kinase inhibitors used in GIST, masitinib will be dosed based on each patients weight, 7.5 mg/kg/day. The trial is randomized and patients with receive either masitinib or imatinib (400 mg or 600 mg).
Imatinib + bevacizumab
This large phase III trial adds a second drug, bevacizumab (the approved name is Avastin) to the current front-line treatment, imatinib (Gleevec). Charles Blanke, MD, FACP, of the British Columbia Cancer Agency, is the study chair of this trial, which is currently recruiting in over 200 sites in the United States.
Bevacizumab (Avastin™) (Manufactured by Genentech, South San Francisco, Calif) was the first U.S. Food and Drug Administration (FDA)- approved biological therapy designed to inhibit the formation of new blood vessels to tumors. It works by blocking VEGF (vascular endothelial growth factor) signaling. The VEGF signaling pathways are considered to be one of the most important pathways that tumor cells use to promote the growth of new blood vessels. Bevacizumab is currently approved in the United States and is given in combination with chemotherapy for patients with metastatic colorectal cancer, non-small cell lung cancer and metastatic breast cancer.
According to Blanke, “Bevacizumab is one of the most exciting anticancer agents developed recently, and there are strong scientific reasons to think it will work effectively against GISTs. It is our hope that patients on this trial have a higher chance of remission and/or living longer and better with their GISTs.”
This trial is randomized with half of the patients receiving imatinib, and the other half receiving imatinib plus bevacizumab. Bevacizumab is given intravenously every 21 days. Patients will have mutational screening with a priority given to quickly identify patients with a KIT exon 9 mutation. Patients with exon 9 mutations will be placed on a higher dose of Gleevec (800 mg if tolerated) (Please see the LRG Dosage Study in the March 2007 newsletter).
Most Life Raft Group members have heard of nilotinib or AMN107 (Manufactured by Novartis and approved as Tasigna). It is currently in a large phase III trial for third-line therapy after failure of Gleevec and Sutent.
Nilotinib is a more powerful inhibitor of KIT and PDGFRA than Gleevec. In particular, Dr. Cristina Antonescu and her colleagues at Memorial Sloan-Kettering Cancer Center have shown that nilotinib is a very potent inhibitor of wild-type KIT. It is also a strong inhibitor of the most common secondary mutation in GIST, the V654A mutation in exon 13 of KIT. Nilotinib does not depend on the OCT1 protein for uptake into tumor cells (Gleevec is dependent on OCT1) and in test tube experiments reaches much higher concentrations inside tumor cells than Gleevec.
Nilotinib has moved into first-line trials with a small phase II trial in Bad Saarow, Germany and a larger phase III trial that is not yet recruiting, but has an estimated enrollment of 736 patients. At this time there are only two trial sites in Brazil listed on clinicaltrials.gov. We understand that another front-line trial with nilotinib is planned that will include sites in the United States, but it is not yet listed and details are lacking.
In the phase II trial in Brazil, all patients will receive nilotinib. The phase III trial will be randomized with patients receiving either imatinib or nilotinib.
Imatinib + pegylated interferon-a 2B
This front-line trial is being conducted at the Huntsman Cancer Institute at the University of Utah by Dr. Lei Chen. “The two major obstacles of durable remission in cancer patients are acquired drug-resistant clones and tumor stem cells” according to Chen. “Although GIST has initial excellent response, more than half of patients develop Gleevec resistance in less than two years. The responders are committed to Gleevec life-long because of the ‘tumor stem cell’, which will regenerate as soon as Gleevec is discontinued. GIST is a great model to prove the concept of combination targeted therapy and immunotherapy.”
In order to stimulate/optimize an immune response against GIST, this phase II trial adds pegylated interferon α 2b (PEG-intron, Schering Plough) to Gleevec. “If given at the right dose, [with the] right timing, combined with the right drug, interferon α holds the greatest potential in breaking immune tolerance and shifting to immune stimulation against patients’ tumors,” said Chen, “with pegylated interferon α 2b we expect much improved toxicity.”
NOTE: The imatinib + pegylated interferon- a 2B trial is currently ongoing, but not accepting new patients pending an internal review.
This small phase II trial is investigating how well dasatinib works when given as front-line therapy in GIST. Also known as SPRYCEL, Dasatinib (manufactured by Bristol-Myers Squibb) is a potent but less selective inhibitor of KIT, PDGFRA and the SRC kinases. This trial is being sponsored by the Swiss Group of Clinical Cancer Research and is only open at Center Hospitaleir Universitaire Vaudois in Lausanne, Switzerland.
These five different approaches for front-line therapy are a welcome addition to the GIST clinical trial world. Improving therapy while GIST tumor cells are still sensitive to treatment is a significant step towards a “cure”.
Given the limited patient pool, one wonders if this important strategy will be tested in a trial.
Patient accrual may be a concern with front-line trials. The recent FDA approval of Gleevec for adjuvant therapy is likely to reduce the number of GIST patients available for front-line therapy, especially if these patients continue Gleevec indefinitely. Patients that have a recurrence while taking still taking adjuvant Gleevec would typically not be eligible for a front-line trial. Patients taking adjuvant Gleevec for a period of time (for example, a year) but who stop Gleevec before a recurrence and then have a recurrence later, may still be eligible for some front-line trials. In addition, it seems likely that most patients will just forgo a front-line trial and take Gleevec instead. Early indications are that one way pharmaceutical companies are dealing with the problem of a limited patient pool is to spread out the trials.