Sutent is a tyrosine kinase inhibitor that has anti-cancer and anti-angiogenesis effects. It was previously known as SU-11248, and its chemical name is sunitinib malate. The cellular targets of this drug include KIT, PDGRFA, PDGFRB, all three VEGF receptors, FLT-3, and RET. In terms of GIST, sunitinib (Sutent) acts not only by inhibiting KIT and PDGFRA (like imatinib or Gleevec) but also by inhibiting blood vessel growth (angiogenesis) to the tumor. Sunitinib is thought to block more mutant forms of KIT than does imatinib. Recently Prenen et al (2006) reported activity of sunitinib against several specific mutations. It has been tested against gastrointestinal stromal tumor (GIST) and several other types of cancer in clinical trials. Results of the Phase III GIST trial were published by Demetri et al (2006).
Sutent was approved by the FDA for imatinib-resistant and imatinib-intolerant GIST and for renal cell carcinoma on January 26, 2006. This approval means that in the USA patients can get Sutent outside of a clinical trial; physicians can now prescribe it. Here is the link to the FDA approval notice.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at this FDA link.
Pfizer, the manufacturer of Sutent, has established a website for the drug at www.sutent.com. Pfizer has a downloadable brochure for patients taking Sutent, including advice about side effects. For financial assistance with Sutent, see another brochure (downloadable pdf) from First Resource.
Patients in countries where Sutent has not yet been approved can obtain access to the drug through a clinical trial process. Access this trial link and look for a site in the country of interest to you. You may also call the international phone number for Emerging Med trial matching service at 646-277-4065. In late April 2006 the European Medicines Agency issed a positive opinion that advances sunitinib toward approval in the European Union (see story in GIST in the News).
Trials of sunitinib against GIST
Sunitinib has been tested against GIST in a Phase I-II dose-finding and continuation trial, and later in a Phase III trial. The drug has been tested only in patients who either:
did not respond to imatinib (Gleevec), or
developed resistance to imatinib (Gleevec) and subsequently showed progression, or
were intolerant of imatinib due to severe side effects.
In a Phase I dose-finding study summarized by Dr. Robert Maki at the 2005 ASCO meeting (abstract 9011) three dose schedules were evaluated, and the highest frequency of responses was shown on a 4-weeks-on/2-weeks-off schedule. Patients took 50 mg/day of sunitinib for 4 weeks, followed by 2 weeks without the drug ("washout period"). This schedule was then selected for use in the Phase II continuation study and in the Phase III study.
Patients who achieved partial response or stable disease for over 6 months in the Phase I study were eligible to continue into the Phase II study, also reported by Dr. Maki. The 32 patients Dr. Maki described in the continuation study comprise over half of the 55 patients in the Phase II study referred to as "Study B" in the sunitinib prescribing information and in the slides shown at www.sutent.com . The primary endoint of the Phase II study was objective response rate, as defined by RECIST. To meet the RECIST definition of "partial response" requires a decrease of 30% or more in the longest dimension of a single tumor or in the sum of the longest dimensions of a group of target lesions. Only 9.1% of all 55 patients in the Phase II trial demonstrated partial response. However, a greater proportion of patients achieved stable disease. Among the 32 Phase II patients described by Dr. Maki, about 20% of patients remained on treatment for over one year.
Mutation status and response. Dr. Maki's presentation illustrated that the response of patients to sunitinib was related to the type of mutation shown in their GISTs. As shown in Figure 1, patients whose original (pre-imatinib) mutation status was exon-9-mutant or wild-type (no mutations in the KIT and PDGFRA genes) had a significantly longer duration of response than patients with exon-11 mutations. The median time to progression was 14.3 months for patints with original exon 9 mutations, 13.8 months for patients with wild-type KIT and PDGFRA, and 5.1 months for patients whose original mutation was in exon 11.
Figure 1. Time to Tumor Progression by original mutation status (slide graciously provided by Robert Maki, M.D., from presentation at ASCO 2005, abstract 9011).
As shown below in Figure 2, this difference in response yielded a longer median overall survival time on treatment with sunitinib for patients whose original mutation status was wild-type (29.2 months) versus those with exon-11 mutations (12.7 months), and the median overall survival time had not yet been reached for the exon-9-mutant group at the time of the 2005 presentation.
Figure 2. Overall Survival by original mutation status (slide graciously provided by Robert Maki, M.D., from presentation at ASCO 2005, abstract 9011).
Latest sunitinib effectiveness and side effect data. Dr. George Demetri, principal investigator for the Phase III trial of sunitinib for GIST, presented the latest update on sunitinib (Sutent) effectiveness January 26, 2006 at the ASCO Gastrointestinal Cancer Symposium (link to watch video). The primary endoint of this study was time to progession (by RECIST). Because few patients had shown an objective response (partial response by RECIST) in the Phase II study, the Phase III study was structured to include a placebo arm in which patients received substitute capsules rather than sunitinib. Patients were randomized into the treatment arm (207 patients receiving sunitinib) and the placebo arm (105 patients receiving dummy capsules). Individual patients in the placebo arm were able to cross over to the treatment arm when they showed progression by RECIST (>20% increase in tumor size). Patients were accrued from December 2003 until January 2005, when the first planned interim analysis showed a significant difference between arms in Time to Progression. The study was unblinded, and all patients then in the placebo arm were able to cross over to the treatment arm. As shown in Figure 3, the Time to Progression was significantly longer in the sunitinib arm (median = 27.3 weeks) than in the placebo arm (median = 6.4 weeks).
Figure 3. Time to Tumor Progression by treatment arm: sunitinib group versus placebo group (slide graciously provided by George Demetri, M.D., from presentation at ASCO 2006 GI symposium).
Though the partial response rate for sunitinib in the Phase III trial was only 7%, an additional 19% of patients showed durable stable disease for over 6 months. The benefits of sunitinib were shown in all patient subsets (no response to imatinib, resistance to imatinib after a response, or intolerance of imatinib) and were independent of the dose of imatinib previously taken. The overall survival data for patients in the Phase III trial is shown as Figure 4.
Figure 4. Overall Survival by treatment arm: sunitinib group versus placebo group (slide graciously provided by George Demetri, M.D., from presentation at ASCO 2006 GI symposium).
The formal publication of the Phase III clinical trial data for sunitinib against GIST appeared in October 2006 (Demetri et al, 2006). This important paper briefly alludes to information about the effectiveness of sunitinib for patients whose tumors show different mutation types. The analysis of sunitinib effectiveness by mutation type was presented at ASCO 2006 by Heinrich (abstract 9502), and you can listen to this talk as a webcast (or view the slides without hearing the speech) at the ASCO site after clicking the above abstract link, then clicking the icon for "video" or for "slides" shown below the abstract. Clinical benefit (partial response or stable disease) was significantly more common in patients with exon 9 mutations and patients without mutations of KIT or PDGRFA (wild-type KIT and PDGFRA) than in patients who originally had exon 11 KIT mutations. The occurrence of secondary mutations in the exon-11 group contributed to this difference.
Additional results from the Phase III sunitinib trial were reported by Judson et al at the 2006 European Society of Medical Oncology meeting, and you can link to read abstract 506PD online.
More patients received sunitinib on a "treatment-use" protocol during the time between closing of the Phase III trial and approval of the drug so that it could be prescribed. Dileo et al reported on this group of about 800 patients at the 2006 European Society of Medical Oncology meeting, and you can link to read abstract 507PD online. Side effects and preliminary results of clinical benefit were reported.
In ESMO 2006 abstract 508P (link to read) Blay et al reported an investigation of daily dosing of sunitinib in contrast to the cycled schedule of 4 weeks on-drug followed by 2 weeks off-drug. The purpose is to determine whether the clinical benefit will be greater using 37.5 mg continuous daily dosing versus 50 mg in the cycled dosing schedule. Results are still preliminary at this point.
Side Effects of Sunitinib (Sutent)
Adverse effects experienced by over 10% patients in the Phase III study of sunitinib are shown on page 14 of the Prescribing Information, and abnormalities in lab test results are shown on page 15. Sutent is not as well tolerated as imatinib, but the side effects are manageable for most people without dose reductions. The more common side effects experienced by 20% or more of subjects are shown in Figure 5.
Thyroid function decrease (hypothyroidism) is an additional side effect of sunitinib that has been recognized only recently. According to data for patients in the Phase I/II trial of sunitinib (Sutent), 36% developed hypothyroidism during treatment with sunitinib, and the incidence of hypothyroidism increased with duration of treatment. These findings were published in November 2006 by Desai et al in the Annals of Internal Medicine (click for abstract). A free-access patient information summary is available at the journal site to read online or to print as a pdf. Desai et al report that "15 of 42 patients (36%) developed hypothyroidism after an average of 50 weeks of therapy (range 12 to 94 weeks)" and an additional 7 patients (17%) had an abnormal serum thyroid stimulating hormone (TSH) test result at at least one point during treatment. Two patients' thyroid glands atrophied, becoming undetectable on imaging. All patients responded to treatment with L-thyroxine. Hypothyroidism has also been reported in a separate study of renal cell carcinoma patients treated with sunitinib (AJ Martorella et al, abstract 593 presented at 88th annual meeting o the Endocrine Society, Boston, June 2006). Desai et al recommended that patients on sunitinib therapy be "screened for the development of hypothyroidism with frequent measurements of TSH, perhaps at 2- to 3-month intervals." They recommended L-thyroxine treatment if indicated, as well as consultation with an endocrinologist. The authors stated that "hypothyroidism is easily treated and is not in itself an indication for the discontinuation of sunitinib therapy given its effectiveness in treating life-threatening conditions."
More Sunitinib Research
Here are titles and links to abstracts for several papers on Sutent presented at the European Cancer Conference held in Paris on October 30-November 3, 2005. These abstracts summarize recent clinical-trial-based information on Sutent.
In May 2005 the results of a Phase III trial assessing the efficacy and safety of Sutent against gastrointestinal stromal tumor (GIST) were reported at the ASCO meeting (abstract 4000). SUTENT showed benefit to about 60% of imatinib-resistant patients in the trial. The following link takes you to the abstract of this presentation and allows you to click “video” to hear the presentation and see the slides shown.
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