3083 Background: MGCD265 targets wild type Met, as well as clinically relevant Met mutants, VEGFR-1,-2 and -3, Ron and Tie-2. MGCD265 combinability with erlotinib is being evaluated in patients (pts) with advanced malignancies. Combining Met and EGFR inhibitors has recently been shown to be synergistic and can overcome resistance to either Met or EGFR inhibitors.
METHODS
Eligible pts in the initial cohort received MGCD265 at 96 mg/m2 once daily (QD) and erlotinib at 100 mg QD. Subsequent cohorts received full dose erlotinib (150 mg QD) with incremental doses of MGCD265, initially on a QD schedule and thereafter twice daily (BID) during a 21-day cycle. The primary objective was to determine the safety profile. Secondary objectives include anti-tumor activity, pharmacodynamics (PD) and pharmacokinetics (PK).
RESULTS
Pt characteristics (n=33): gender: 23 M/10 F; median age: 57 (range 39-76) years; ECOG 0/1: 18/15. Dose limiting toxicities include: diarrhea (1/8 pts at MGCD265 96 mg/m2 QD + erlotinib 100 mg); rash (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg) and fatigue (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg). The BID regimen of MGCD265 has been introduced at 72 mg/m2. One pt with NSCLC experienced a partial response (after 2 cycles of treatment and continuing) and one pt with gastric cancer had resolution of ascites and a decrease in gastric wall thickness (cycle 15 and continuing). Molecular profiling of the archived tumor biopsy from this latter pt showed high levels of Met and phospho-Met protein expression in the absence of MET and EGFR gene amplification or detectable mutations. Prolonged disease stabilization was observed in another pt with gastric cancer (8 cycles and continuing). Ten other pts completed 4-10 cycles. To date, a decrease in HGF plasma levels was observed in Cycle 1 Day 8. Preliminary PK data with MGCD265 in QD dosing indicated no drug-drug interaction and MGCD265 steady state plasma concentrations were multiples above the IC50 for Met and VEGFR2.
CONCLUSIONS
Clinical data to date indicate that MGCD265 can be combined with full dose erlotinib with early signs of clinical activity. This combination merits additional testing in NSCLC and gastric cancer.