CHICAGO—Although afatinib has limited single-agent activity in recurrent glioblastoma, potential activity in biomarker-selected patients warrants further evaluation, according to investigators reporting results of a Phase 2 trial at the American Society of Clinical Oncology’s 2011 Annual Meeting.

David E. Eisenstat, MD, of Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada, and colleagues conducted the randomized, multicenter, international trial to determine if afatinib alone or in combination with protracted, low-dose temozolomide was an effective treatment for recurrent glioblastoma. The primary endpoint of the trial was 6-month progression-free survival (PFS-6). Secondary endpoints included objective tumor response according to RANO criteria, PFS, overall survival, molecular markers, and safety. 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.

Of the 119 patients randomized to receive afatinib or temozolomide monotherapy or combination afatinib + temozolomide; the median age was 58 years (range 23–81) and 54% had a Karnofsky Performance Status (KPS) of 70–80. Patients were stratified by age (≤50 years vs. ≥50 years) and KPS (70, 80 vs. 90, 100). Afatinib was dosed at 40mg daily and temozolomide was dosed at 75mg/m2 for 21 days in a 28-day cycle.

PFS-6 by investigator assessment was 0.24 [95% CI 0.10–0.39], 0.11 [95% CI 0.01–0.21], and 0.05 [95% CI 0.00–0.12] afatinib, afatinib + temozolomide, and temozolomide arms, respectively. Afatinib was statistically worse compared to temozolomide (P=0.008); afatinib + temozolomide was comparable to temozolomide (P=0.59). PFS was improved in EGFRvIII status patients who received afatinib + temozolomide vs. afatinib alone. In patients with EGFRvIII status 2+3+ or 3+, PFS was superior in the afatinib + temozolomide arm compared with both monotherapy arms. Best overall response included partial response in one, two and four patients and SD in 14, 14 and 22 patients treated with afatinib, afatinib + temozolomide, and temozolomide, respectively. Preliminary biomarker data in 54 patients suggested durable disease control in EGFRvIII-positive pts treated with afatinib or afatinib + temozolomide.

The most frequent adverse events reported were diarrhea (63.4% and 79.5%) and rash (65.9% and 64.1%) in afatinib and afatinib + temozolomide, respectively. Dr. Eisenstat noted that although the rate was low, lymphopenia occurred more frequently in the temozolomide arm (10.3% vs. 0% for both afatinib arms).

Study investigators concluded that though afatinib has limited single-agent activity in unselected glioblastoma, it confers no improvement in PFS-6 when given in combination with temozolomide. However, patients with glioblastoma that exhibit high levels of EGFRvIII immunoreactivity may have better responses and more durable PFS in response when given afatinib + temozolomide. Further evaluation is required to validate this data.