European conferences attract GIST medical professionals

By Norman J. Scherzer with contribution
from Dr. Christopher Corless

Note: Norman Scherzer, Life Raft Group executive director, represented one of the few patient organizations present at the CTOS meeting. Dr. Christopher Corless, member of the Life Raft Group Research Team, attended the EORTC meeting.

While navigating complex meeting agendas, GIST specialists, researchers, pharmaceutical companies and some patient groups made their way to one or both of two major GISTrelated meetings in November. A record turnout of sarcoma specialists and GIST specialists attended the annual meeting of the Connective Tissue Oncology Society (CTOS) in Venice, Italy. Immediately following CTOS, an even larger group of professionals attended the 18th Symposium on Molecular Targets and Cancer Therapeutics in Prague, Czech Republic, cosponsored by the European Organization for Research and Treatment of Cancer (EORTC) along with the National Cancer Institute (NCI) and American Association for Cancer Research (AACR).

There were a series of discussions that took place at these meetings, demonstrating that networking remains a major reason for attending these conferences. The report below combines formal and off the record information from both meetings.

Two GIST trials ended

Robert Benjamin of MD Anderson formally reported on the AMG706 trial. Benjamin concluded that of the 120 protocol eligible patients, 30 had achieved stability for at least 22 weeks and that a total of 28 percent had some clinical benefit, an even more significant achievement considering that these were patients with advanced high-dose resistance to imatinib. Unfortunately, as we reported in our August 2006 newsletter, AMGEN has decided to not pursue a filing with the Food and Drug Administration because the non-randomized design of the phase II study was unlikely to support a filing for GIST. This was because Pfizer had already been granted a full approval for Sutent in the same indication.

RAD001: We were also informally advised that the trial for Gleevec plus RAD001 has also come to an end but we do not know yet what Novartis plans to do in the future. RAD001 is available in many countries, and in some, a similar version of a drug called Rapamune®. In recent days we have received reports of several GIST patients resistant to Gleevec and Sutent receiving a combination of Rapamune plus Sutent. We have no reports regarding efficacy yet.

Ongoing GIST trials

Sutent: Two papers were presented on Sutent (Sunitinib), one with updated results from the treatment-use trial (this is an intermittent dosing regimen) and one on continuous daily dosing. Both treatment regimens had considerable efficacy for imatinib resistant GIST patients, with some demonstrated stability of about 6 months.

Perifosine plus Gleevec: An interesting poster was presented on a randomized, two treatment regimen arm phase II study of imatinib plus perifosine, also for imatinib-resistant GIST patients. The abstract concluded that the treatment was tolerated and might improve efficacy in the treatment of these patients. Early presented data showed that of 16 GIST patients enrolled (and of 12 patients with evaluable disease), two (using Choi criteria) had a partial response. Interestingly, one of these responses was in wild-type kit.

AB1010: Although not on the formal agenda, informal discussions took place regarding an ongoing phase II trial in France with AB1010. This drug, according to several sources, is being given to GIST patients as a first line therapy in lieu of imatinib. We understand that about two dozen patients have demonstrated clinical benefit in excess of 90 percent as the trial enters its second year. We cannot be more specific at this time, but we remain very interested in watching this drug and its parent company, AB Science.

Two new trials presented

Dasatinib (BMS-354825): At CTOS there was a poster about a phase I study of dasatinib. Although this early trial for 18 GIST patients and 30 others reported acceptable side effects, the preliminary data showed only 4 GIST patients still on the drug over 3 months. No objective responses from CT scans have been reported.

IPI-504: At EORTC there was a presentation of the new Infinity drug IPI-504 that was also the subject of a press release sent to us. Preliminary data is encouraging, with 20 GIST patients to date receiving IPI-504. IPI-504 is an intravenous drug and is administered to patients on days 1, 4, 8, and 11, followed by 10 days off treatment (referred to as a “drug holiday”), in a 21-day cycle. Patients included in the study were heavily pretreated and nearly all had failed prior therapy with Sutent as well as Gleevec. A maximum tolerated dose has not yet been identified.

Investigators have observed evidence of biological activity for IPI-504 using positron emission tomography imaging, or PET. In 7 of 17 evaluated patients (41%), PET scans revealed a decrease in tumor uptake of 18-fluorodeoxyglucose, an imaging agent used to measure metabolic activity, in response to IPI-504 administration. In some cases, a rebound in tumor activity was observed during the drug holiday, followed by a decrease in tumor activity upon re-administration of IPI-504 in the next cycle. This pattern of tumor response appears to demonstrate biological activity of IPI-504. In addition to the observed PET responses, 6 of 15 evaluated patients (40%) received five or more cycles of therapy with IPI-504. We understand that a second schedule of treatment without a drug holiday is beginning. Further work on developing an oral version of this drug is underway.

What is particularly noteworthy is the quote in the press release from Dr. George Demetri that the data emerging “is reminiscent of the clinical data seen with other approved therapies such as the kinase inhibitors Gleevec and Sutent.”

Several papers were presented on improving management of GIST patients

Surgery: A group from Poland led by Piotr Rutkowski, M.D., looked at patients treated surgically after responding to imatinib. In the group receiving surgery (n=36) there were no deaths and a progression rate of 11 percent. These patients continued imatinib therapy following surgery. In the group that did not receive surgery (n=130), 17.7 percent died and there was a progression rate of 31.5 percent.

Toxicity: A toxicity risk calculator was introduced for predicting imatinib toxicity for patients with advanced GIST tumors. This calculator was also presented at EORTC and can be seen below.

Patient Advocacy Group Reports: I gave an oral presentation on the changing role of patient groups in cancer research. This presentation discussed the two parallel research tracks of the Life Raft Group, namely conducting our own research using medical updates provided by patients and caregivers and directing a coordinated strategy by the LRG world-class research team to find a cure for GIST that will serve as a model for other cancers.

Report by Dr. Chris Corless at the EORTC meeting

At the Prague meeting there was enthusiasm for recommending mutation testing upfront on all high-risk and metastatic GISTs. This is primarily to determine whether a patient is exon 11 positive (and rule out PDGFRA D842V), but also with regard to dosing of exon 9 cases.

Some data presented suggests that measuring blood levels of imatinib might be helpful in monitoring patients. This is very preliminary and there are no formal recommendations made at this time.

Several cases of imatinibresistant GIST were presented in which responses were observed (somewhat unexpectedly) when patients were switched from sunitinib to AMG706 or nilotinib, and vice-versa. Though strictly anecdotal, these cases illustrate the complexity of resistance and how, at this time, it is not safe to predict what response might be seen in a given patient, irrespective of the original tumor genotype. Several people attending the conference asked about screening for resistance mutations in patients progressing on imatinib. The consensus of the experts was that there is insufficient information at this time to use such testing to guide therapy. Obviously, we need more studies.

The final mutation dataset for the S0033 phase III is now being statistically analyzed. Novartis is funding a meta-analysis of the mutation data from both phase III trials, which is supposed to get underway very soon.