Foretinib in Papillary Patients

Phase II Trial of Foretinib in Papillary Patients

Ramaprasad Srinivasan from the National Cancer Institute presented a Phase II study of the investigational drug Foretinib (GSK1363089) in patients with papillary renal cell carcinoma (PRC), both Type I and Type II. Foretinib is a dual inhibitor of c-Met and VEGFR2. The hereditary version of Type I PRC is characterized by mutations of the c-Met gene in the patient’s germline.  VEGFR2 is a receptor for the vascular endothelial growth factor, which is important in the development of new blood vessels. (Note that Foretinib is the same drug that was produced by Exelixis and was called XL880 before being sold to GlaxoSmithKline). 

37 patients entered the trial separated into two arms related to dosing strategies: the first a 14-day intermittent cycle of 240 mg/day for five days on then nine days off and the second of 80 mg daily dosage. The major grade 3/4 adverse events for the intermittent dose patients were hypertension (27%), liver enzyme increase (22%), and diarrhea (11%).  The daily dose patients fared better. 

For the intermittent group of 36 evaluable patients, there were 4 confirmed partial responses (PR) and 2 unconfirmed PR, 28 stable disease (SD), and 2 progressive disease (PD). For the 14 evaluable daily dose patients there were 3 confirmed PR, 11 SD, and 0 PD.  Two-thirds of the patients had some shrinkage. For the intermittent group the median progression-free survival (PFS) was 7.6 mos. The PFS was not yet available for the daily dose group. 

The trial data have not yet matured and the analysis is not complete, but it is clear that at least for some PRC patients, Foretinib is a successful drug. The question is does it only work where the c-MET pathway is activated, since for the vast majority of PRC Type I patients (80-90%), there is no known mutation in the c-MET gene. Further analysis of the trial data by the investigators will help determine what type of patients responded and will set the framework for a Phase III trial for Foretinib. 

Unfortunately, there aren’t too many other choices now for PRC patients. At last year’s ASCO Conference, Elizabeth Plimack presented  prospective trial results from MD Anderson testing Sutent in 20 patients, 13 of whom were papillary. Of the 17 evaluable patients, 9 patients progressed and 8 remained stable with no partial responses. However, at this year’s ASCO, a French group led by Alain Ravaud from Hopital Saint Andre CHU in Bordeaux, presented a poster summarizing the early results of a Phase II study of Sutent for Type I and Type II PRC patients. For Type I, of 6 patients, 1 had a PR and 5 had SD. For Type II, of 20 patients, 3 had a PR, 12 had SD, and 5 had PD. The median progression-free survival was 5.7 mos. These responses are less than half the standard clear cell overall response rate but much better than the MD Anderson study implying that anti-angiogenic therapy is somewhat efficacious against PRC. 

Torisel gave better results in a subset analysis of the Phase III trial that led to Torisel’s FDA approval. Janice Dutcher reported that the “other pathology” patients (on-third of whom were papillary) did as well or better in terms of survival on Torisel than did the clear cell patients.  But we haven’t seen any prospective trials for Torisel (temsirolimus) and PRC except for the one that was also presented at this year’s ASCO, a Phase I trial of Torisel and bryostatin. These are mTOR inhibitors, which work on a different pathway than Sutent. However, of the 23 patients on the trial only 3 have papillary but one is a long-term responder. The trial’s author is again Elizabeth Plimack, who has moved on to Fox Chase. We would still like to see a trial of Torisel in PRC patients.