Abstract
2006 Background: XL184 is an oral, potent inhibitor of MET, VEGFR2 and RET that has demonstrated clinical antitumor activity. In solid tumors, the MTD was 175 mg qd. Elevated levels of VEGFR2 and MET are found in GB, the latter correlated with poor prognosis. Methods: XL184 was studied in two cohorts of previously treated GB pts at 175 and 125 mg qd. The 125 mg cohort was added to further optimize tolerability while maintaining activity. Pts with and without prior antiangiogenic therapy (AAT) were allowed. Primary objectives include independent centrally confirmed (IRF) overall response rate (ORR), 6-month progression-free survival (PFS6) and safety. Secondary objectives include duration of response, survival, and changes in steroid usage. Plasma biomarkers were assessed for evidence of target inhibition. Results: Interim results are presented for 124 pts enrolled with a median age 55 yrs (range: 21-73); 42 (34%) had prior AAT, 42 (34%) were in second relapse, and 48 (39%) required corticosteroids at baseline. In the 175 mg qd cohort (n = 46) PFS6 (all pts) was 21%; ORR in AAT-naïve (n = 34) and AAT-pretreated pts (n = 12) was 21% and 8%, respectively; median duration of response was 5.9 months (range: 1.9-12.8). In the 125 mg qd cohort, ORR in response- evaluable AAT-naïve (n = 25) pts was 32%, with a median duration of response not yet reached. The rate of ≥ 50% decline in size of enhancing lesions at ≥ 1 timepoint, in response-evaluable AAT-naïve pts for the 175 mg and 125 mg qd cohorts was 41% and 60%, respectively. Decrease in size of enhancing lesions has been observed in some AAT-pretreated pts. Most frequent Gr3/4 AEs were fatigue (23%), hypophosphatemia (10%), serum lipase elevation (10%) and ALT, headache, lymphopenia and convulsion (9% each). Dose interruption/reduction, AEs related to TKI/VEGFR-inhibition (hypertension, proteinuria, bleeding, hand-foot syndrome), and modulation of plasma biomarkers for VEGFR and MET inhibition (VEGF-A, PlGF, sVEGFR2, sMET) were observed at both doses. Conclusions: XL184 demonstrates clinical activity and target inhibition of MET and VEGFR2 at 175 mg and 125 mg qd in pts with progressive GB, including pts with prior AAT. Longer follow-up will allow better risk/benefit evaluation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis
Published Version
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