The Life Raft Group has received two recent reports of patients that had failed multiple therapies and then apparently responded to Nexavar (also known as sorafenib or BAY 43-9006). In both cases, the patients had failed Gleevec, Sutent and AMN107.
Anecdotal reports like this should be viewed with considerable caution. Carefully designed clinical trials are ultimately the only way to prove drug efficacy. We do, however, occasionally report on interesting or unusual cases.
In the most striking case, an Israeli patient had failed six therapies, including Gleevec, Sutent and AMN107. After failing all of these, he managed to obtain Nexavar. After 70 days on Nexavar, a CT scan showed shrinkage in everyone of his 15 metastases ranging from 15 percent to 50 percent. Shrinkage of GIST after initial treatment with Gleevec is a rare event. This patient was known to have a primary exon 11 mutation with at least one secondary exon 17 mutation (resistant patients often have many undetectable secondary mutations).
In the second case, the patient was able to leave hospice and had dramatic symptomatic improvement. A CT scan is needed to verify his response. In both cases patients reported that unwanted weight loss was a problem.
Nexavar was approved in December 2005 for kidney cancer and is in phase II trials for GIST. Patients wishing to try Nexavar or other new agents are encouraged to enter clinical trials if they are eligible. Some patients, however, may not be eligible for or may not be physically able to get to the clinical trials. For these patients, off-label prescription of Nexavar may represent another option after failure of Gleevec and Sutent. Offlabel treatments such as this have many challenges, including unproven efficacy, unknown toxicity (for combinations) and possibly denial of coverage by insurance but they may represent a last hope for some patients.
Nexavar is in some ways similar to Sutent. It inhibits KIT and the VEGF receptors (like Sutent) and also adds RAF inhibition. KIT inhibitors have different activity profiles however. Mutations occur at many different places in KIT and almost all KIT inhibitors inhibit some mutations but not others. Both Nexavar and Sutent have recently been shown to inhibit the KIT “gatekeeper” mutation in exon 14 (T670I). This is a common secondary mutation in GIST and is not inhibited by Gleevec. Nexavar also inhibits several other kinases including VEGFR-2, VEGFR-3, PDGRF- β, FLT3, and RET.
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.
The trial sites are:
University of Chicago- Chicago, Ill.
Decatur Memorial Hospital- Decatur, Ill.
Oncology/Hematology Associates of Central Illinois- Peoria, Ill.
Memorial Sloan-Kettering Cancer Center- New York, N.Y.
City of Hope – Duarte, Calif.