A phase II trial (N0177) of erlotinib and temozolomide (TMZ) combined with radiation therapy (RT) in glioblastoma multiforme (GBM)

Abstract

2016 Background: EGFR amplification in GBMs is a common occurrence and is associated with treatment resistance. Erlotinib, a selective inhibitor of EGFR, was combined with TMZ and RT in a phase II trial for GBMs. Methods: Adult patients not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) throughout the treatment protocol until progression. Erlotinib alone was delivered for 1 week, then concurrent with TMZ (75 mg mg/m2 daily) and RT (60 Gy), followed by up to 6 cycles of adjuvant TMZ (200 mg/m2, daily x 5d, q28 d). The primary endpoint was survival at 1 year with a planned sample size of 93 patients. Results: 97 eligible patients were accrued with 8 patients over 70 years old. By definition the primary endpoint was successfully met with over half the patients (61%) patients alive at 1 year and a median survival of 15 months. However, there was no sign of benefit when comparing N0177 with the radiation/TMZ arm of EORTC 26981: Recursive partitioning analysis (RPA) III 19 vs. 21 months, RPA IV 15 vs. 16 months, RPA V 8 vs. 10 months respectively (Mirimanoff JCO 2006). Presence of diarrhea and/or rash, EGFRvIII, p53, PTEN, combination EGFR and PTEN, and EGFR amplification status were not significantly (p>.05) predictive of survival. MGMT status was analyzable in only 27% of patients and was not predictive of survival probably due to small sample size. The median survival of patients older than 70 was 4.5 months (p=0.001). Grade 2+ rash (42%) and diarrhea (10%) were frequent adverse events. Conclusions: Although the primary endpoint was successfully met utilizing pre-TMZ era historic controls, there was no sign of benefit compared to TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. Elderly patients did poorly even with combination therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology