GI Symposium offers interesting abstracts

Thirteen GIST abstracts were presented this year at the 2008 GI Symposium, sponsored by the American Society of Clinical Oncology (ASCO). Space limitations will not permit us to report on all of these abstracts.

The first abstract by Dr. George Demetri is particularly timely as next month (March 2007) the Life Raft Group will report on an update of its 2004 dosage study which adds to the concern that some GIST patients (perhaps most GIST patients) are not receiving an adequate dose of Gleevec.

Correlation of imatinib plasma levels in GIST patients

A higher concentration of Gleevec in the blood correlates with better clinical outcome according to George Demetri, M.D., of the Dana-Farber Cancer Institute. In an interview with Peggy Peck on the medpageTODAY website, Dr. Demetri said that the imatinib plasma level was not associated with age, gender, disease bulk, or body weight. “You really need to do pharmacokinetic testing to determine the level of imatinib because there are no clues,” Demetri reported at the Symposium. The findings suggest that “we may have been under-dosing some people,” he said.

This report is based on analysis of the pharmacokinetic data from the original phase II Gleevec trial for GIST (B2222), which started in July of 2000. Plasma levels (plasma is one component of blood) taken after 29 days of Gleevec, were available for 73 of the 147 patients enrolled in the trial. These plasma levels were grouped into quartiles according to imatinib trough plasma concentrations (the level of drug in the blood at its lowest point during the day, just before taking the daily Gleevec capsule). The plasma levels and response rates of these groups are listed in the table.

The authors concluded that, “Exposure to adequate drug levels of imatinib appears to correlate with clinical benefit; patients with the lowest imatinib levels show lowest objective response and shortest time to progression. These results suggest that monitoring pharmacokinetic/ pharmacodynamic relationships may provide novel predictive markers and that exposure to adequate IM trough plasma concentrations (>1,110 ng/mL) is important for optimal clinical response.”

A video report is available on the medpageTODAY website. In the interview, Dr. Demetri explained that “when you give Gleevec or any other kinase inhibitor to a group of patients, they will handle it very differently, some people will have high levels and some people will have low levels… The important part about that is whether we for years might be underdosing people, and whether we perhaps should develop a blood test to check the levels of this drug in people’s blood and have more certainty that there’s actually therapeutic levels in the blood.” Demetri went on to explain that “it’s possible that we could have done this analysis and found nothing at all, but in fact, we saw something that is a bit worrisome for the patients with the lowest levels of the drug.” The next step according to Demetri will be to “… talk with our colleagues, decide exactly how much this is worth pursuing, (and) decide how to mount a large trial.

Sorafenib (Nexavar)

Preliminary results of the phase II trial for sorafenib in GIST were presented. Sorafenib was approved in the United States in December of 2005 for kidney cancer. Sorafenib is also known as Nexavar or BAY 43-9006.

The sorafenib trial originally required only that GIST patients be resistant to Gleevec. In August of 2006, after FDA approval of Sutent, the trial was amended to require that patients be resistant to both Gleevec and Sutent.

This abstract reports on six Gleevecresistant and 15 Gleevec- and Sutent- resistant GIST patients. Sixteen of these patients were evaluable for response (five too early). Two of the patients (one Gleevec-resistant and one Gleevec- and Sutent- resistant) had partial responses (significant shrinkage of their tumors) while nine patients had stable disease (duration unspecified).

The median progression-free survival for this small group of patients was 13.3 months. Although this trial is small, it should be noted that the reported median progression-free survival exceeds that of any previously reported drug after the failure of Gleevec. However, it should also be noted that median progression free survival is not the only measure of benefit and not necessarily the best measure of benefit.

The phase II trial for BAY 43-9006 is open and recruiting patients. The University of Chicago maintains a central contact point for this trial at the University of Chicago Clinical Trials Office, 773-834-7424.

Adjuvant Gleevec – results of the Z9000 phase II trial

Preliminary results of the phase II Z9000 adjuvant Gleevec trial were presented by Dr. Ronald DeMatteo, a hepatobiliary surgeon at Memorial Sloan- Kettering.

There were 107 evaluable patients enrolled in this trial between September 2001 and September 2003. In contrast to the phase III Z9001 trial, all patients in the Z9000 trial were high risk patients with a primary tumor size of ten cm or more, tumor rupture or less than five peritoneal metastases.

The primary end point of this trial was overall survival. Prior to the availability of Gleevec, patients with a high-risk primary GIST were reported to have a two year overall survival of approximately 50 percent. With a median follow- up of four years, the overall survival rates and recurrence-free survival are:

The authors concluded that, “Imatinib given at a daily oral dose of 400 mg for one year following the resection of a high-risk primary GIST prolongs recurrence- free survival and is associated with improved overall survival compared with historical controls.”