Phase I/II trial of the novel Hsp90 inhibitor, IPI-504, in patients with relapsed and/or refractory stage IIIB or stage IV non-small cell lung cancer stratified by EGFR mutation status

B79

Introduction: Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone protein results in selective destruction of the mutated epidermal growth factor receptor (EGFR) kinase in human non-small cell lung cancer (NSCLC) cell lines and significantly reduces tumor growth in in vivo models, including those resistant to tyrosine kinase inhibitors (TKIs). We designed a phase I/II trial of IPI-504, a water-soluble Hsp90 inhibitor, for patients (pts) with advanced NSCLC who had received prior TKI therapy.
 Methods: Patients with Stage IIIB (with malignant effusion) or Stage IV NSCLC who had received prior therapy with an EGFR TKI (e.g., gefitinib or erlotinib) for ≥12 weeks, and had available tissue for EGFR mutation analysis were eligible for treatment. The goal of the Phase I portion was to evaluate the safety and maximum tolerated dose (MTD) of IPI-504 in pts with advanced NSCLC. Once dose-escalation is completed, the Phase II portion will begin with a goal of determining the potential anti-tumor activity of IPI-504 in NSCLC pts, stratified by EGFR mutation status. Pts received IPI-504, IV in 250 cc of normal saline over 30 mins, twice weekly on a four-week cycle. Subjects were evaluated for clinical benefit and radiographic improvement or stabilization by RECIST. Pharmacokinetic profiling of IPI-504 and its major active metabolites (17-AAG and 17-AG) was also performed on all pts.
 Results: 8 NSCLC pts have been entered at 3 dose levels (150 mg/m² IPI-504 [n=3], 225 [3], 300 [2]); 7 females, 1 male; age range 47-83; 7 were positive for EGFR mutation (exon 19del or L858R); avg. # prior therapies 3.7 (range 1-6); All pts completed at least 1 cycle and were evaluated. No objective responses have been observed yet; however, 2 pts had stable disease including 1 pt on therapy for >5 cycles (20 weeks). IPI-504 has been well-tolerated to date; one DLT (grade 3 AST elevation, reversible) was observed at 300 mg/m². This dose level has been expanded. The MTD has not been reached, and dose escalation in the phase I portion of the study is ongoing.
 Conclusions: Targeting Hsp90 represents a novel therapeutic strategy in advanced, metastatic NSCLC patients who have failed prior therapy with TKIs. IPI-504 has been well-tolerated overall, and encouraging preliminary biological activity has been observed with the occurrence of extended stable disease.