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A phase II study of daily afatinib (BIBW 2992) with or without temozolomide (21/28 days) in the treatment of patients with recurrent glioblastoma.

2010 Background: Epidermal growth factor receptor (EGFR) is over-expressed in ~50% of glioblastoma (GBM); approximately half express the constitutively active mutant receptor EGFRvIII. Afatinib (A), an irreversible erbB family blocker (including EGFRvIII), has high levels of in vitro activity in tumor cell lines resistant to reversible EGFR inhibitors.Temozolomide (T) can overcome O6-methylguanine methyltransferase (MGMT) resistance. We hypothesized that daily A or daily A+T (AT, 21/28 days) may be an effective treatment for recurrent GBM.


METHODS
The trial's primary objectives were to evaluate efficacy and safety of A and AT compared to T in recurrent GBM, and to assess molecular determinants of response to A. Patients (pts) with histologically-confirmed GBM at first recurrence after prior combined chemoradiotherapy were randomized 1:1:1 to receive A, AT or T. Randomization was stratified by age (≤50 vs. >50 years) and Karnofsky Performance Status (KPS; 70, 80 vs. 90, 100). A was dosed daily at 40 mg; T was dosed at 75 mg/m2 for 21/28 days. The primary endpoint was 6-month progression-free survival rate (PFS-6). Independent imaging and pharmacokinetic assessments were obtained. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and MGMT. Patients were treated until undue toxicity or disease progression.


RESULTS
Enrolment was completed in June 2010. 119 pts were randomized (median age 58 years [range 22-81]) and 54% had a KPS of 70-80. The most frequent AEs in pts A-treated pts were diarrhea (70% and 68% in A and AT, respectively) and rash (80% and 69%). PFS-6 by investigator assessment was 3%, 17% and 22% in the A, AT and T arms, respectively. A was statistically worse compared to T (p=0.008); AT was comparable to T (p =0.59). Best overall response included partial response in one, five and six pts and SD in 22, 20 and 21 pts in A, AT and T, respectively. Preliminary biomarker data in 54 pts suggested durable disease control in EGFRvIII-positive pts treated with A/AT. Updated biomarker data will be presented.


CONCLUSIONS
Afatinib has limited single-agent activity in recurrent GBM; however, potential activity in biomarker-selected pts warrants further evaluation.