Alternating Sutent and Stivarga
ASCO, June 2
Dana Farber Cancer Institute (DFCI) is about to begin recruiting for a new trial that alternates Sutent and Stivarga -- three days on one drug, four on the other, no washout period -- in an effort to suppress KIT secondary resistance mutations at exons 13 and 17. Dr Suzanne George will be the principal investigator. There are no other trial locations at the present time. Eligible patients will have had experience with all three FDA-approved drugs for GIST and may have tried other investigational agents as well.
The trial is designed to take maximum advantage of the strengths of both drugs: Sutent is effective against mutations at KIT exon 13 but far less effective in controlling mutations at exon 17, while the situation with Stivarga is just the reverse. Pfizer, the manufacturer of Sutent, and Bayer, which makes Stivarga, have collaborated extensively to make this happen, DFCI's Dr George Demetri told GSI. He emphasized that patients should NOT attempt to follow a version of the protocol outside the trial setting, as close monitoring will be needed to minimize any toxicities that may develop, as well as to follow the progress of new resistance mutations as they are suppressed by the "one-two punch" of the drugs.
"By using the two drugs in succession," said Dr Demetri, "we hope to create a seesaw effect by which neither mutation will be allowed to fully develop. That effect may be quite subtle, yet still prevent GIST from progressing," he added.
The trial builds on recent work from Dr Jonathan Fletcher's lab, which demonstrated that KIT resistance mutations develop over a period of approximately three days. It also will utilize the new "liquid biopsy" technique of identifying tumor DNA in plasma (along with other technologies) to follow patients' mutational status as non-invasively as possible.
Additional sequential and/or combination trials for GIST are in the planning stage at DFCI and other major centers. The MEK inhibitors will likely be featured in these, as well as newer TK inhibitors such as ponatinib.
In the words of DFCI's Dr Andy Wagner: "It's going to be an exciting year."