A phase II study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC).

5103 Background: XL880 is a potent, orally available small molecule inhibitor of MET and VEGFR2/KDR. Activating mutations and/or amplifications in MET have been described in pts with PRC. In a XL880 Phase 1 study with intermittent dosing, 3 of 4 PRC pts had partial responses (PR), two of which are durable for >2 and 1 year respectively.,This is a phase II study enrolling PRC pts stratified based on presence or absence of MET-pathway dysfunction (activating mutation in MET kinase domain, MET [7q31] amplification, or trisomy 7). Pts with PRC, adequate organ function and ECOG 0-2, receive XL880 at 240 mg/day on Days 1-5 of 14 day treatment cycles. Response is assessed every 8 weeks by RECIST criteria. Plasma markers reflecting effects of anti-angiogenic therapy and potential effects of MET inhibition are analyzed.,As of 21 Dec 2007, 26 subjects were enrolled (17 germ line MET wildtype, 4 hereditary PRC [HPRC] with a germ line MET mutation, 5 with MET pathway dysfunction). Of 20 evaluable pts, all had at least stable disease (SD), 17 had decreases in tumor size (range 1-35%) and for pts with adequate follow up, 12/18 and 10/17 had disease control (SD or PR) at >8 and >10 mos, respectively. Two pts have confirmed PRs and a third has PR pending confirmation. Five pts are too early to evaluate and one subject (following prior sunitinib treatment) developed hypertension and was removed from study. The most frequent adverse events (AEs) associated with XL880 were fatigue, hypertension, nausea, anorexia, and vomiting, primarily grades 1 and 2. In the majority of pts analyzed, administration of XL880 resulted in statistically significant changes in plasma levels of PlGF, VEGF-A, sVEGFR2, EPO, and sMET: effects suggestive of pharmacodynamic inhibition of VEGF and MET signaling by XL880.,XL880 demonstrated antitumor activity in pts with PRC: 3 subjects with PR, all subjects having their first efficacy evaluation with at least stable disease, and all 3 HPRC patients with at least one restaging demonstrate ongoing tumor shrinkage (2 PR). XL880 was generally well tolerated in this pt population. PlGF, VEGF-A, sVEGFR2, EPO, and sMET are promising pharmacodynamic markers to monitor the biological activity of XL880. [Table: see text].