AT-35INTERMITTENT HIGH DOSE (PULSATILE) ERLOTINIB FOR EGFRvIII MUTANT RECURRENT MALIGNANT GLIOMAS: A PILOT CLINICAL TRIAL

Abstract

BACKGROUND: Kinase inhibitors targeting driver mutations are active in several cancers, but have shown only minimal activity against malignant gliomas (MGs). Inadequate drug delivery when administered at the maximum tolerated daily dose may contribute to limited efficacy. Transient inhibition of oncogenic kinases has been shown in experimental models to irreversibly commit cancer cells to death. Therefore, we explored the feasibility of high-dose intermittent (“pulsatile”) kinase inhibitor therapy in a molecularly defined population of patients with recurrent MGs. METHODS: Eligible patients had a recurrent MG harboring EGFRvIII mutation (PCR), age ≥18, KPS ≥ 60, and prior temozolomide and radiotherapy. Prior EGFR inhibitors or bevacizumab were exclusionary. A surgical arm treated patients pre- and post-operatively. All received 2000 mg once weekly of the oral EGFR TKI erlotinib. RESULTS: We enrolled 22 patients (7 women), median age 58 (range 41-81); 18 (82%) had GBMs and 4 anaplastic gliomas. Serum pharmacokinetic (PK) analysis from the first 8 patients demonstrated median Cmax of approximately 7500ng/ml, ten-fold higher than reported for routine daily erlotinib dosing (150 mg). Treatment was well tolerated: no one discontinued for toxicity, and there were no grade ≥4 agent-related adverse events (AEs). Grade 3 AEs were rash (n = 3), fatigue (2), lymphopenia (1), and hyper-bilirubinemia (1). Among those with GBM, one patient has an ongoing complete response (>31 months); two others had less durable improvement of EGFRvIII mutant disease; median survival was 10 months and progression-free survival 1.4 months. CONCLUSION: Pulsatile dosing of kinase inhibitor therapy is feasible and safe, and represents a promising new approach to enhance drug delivery for patients with MG. Full PK results and molecular correlations will be presented.