Safety and preliminary efficacy data from a phase I study of ABT-414 (AbbVie) – an investigational antibody drug conjugate or ADC for the treatment of patients with epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM) – showed no dose-limiting toxicities and frequent, reversible ocular toxicities. Additionally, an estimated 30% (n=44) of patients treated with ABT-414 as monotherapy were progression free at six months [95% CI=17, 44] (secondary endpoint).
These results, from an expansion cohort of one arm (Arm C) of a three-arm open-label study, were presented in a poster presentation at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Amplified EGFR is the most common genetic mutation associated with malignant GBM, an aggressive brain cancer.
Mutations in EGFR are the most common genetic abnormality associated with glioblastoma, with a frequency of about 50%.  Prior to diagnosis, patients may experience headache, vision problems, nausea/vomiting, personality changes and seizures. 
The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy.
For adults with more aggressive glioblastoma, treated with standard therapy, median survival is about 15 months.  Treatment for glioblastoma remains challenging.  Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. 
The Phase I, open-label trial was designed to evaluate the safety, pharmacokinetics and maximum tolerated dose of ABT-414. Three study arms evaluated ABT-414 with radiotherapy and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) (Arm A), with TMZ in patients with newly diagnosed glioblastoma who have just completed radiation and TMZ or recurrent GBM (Arm B) or as monotherapy in patients with recurrent GBM (Arm C).
Eligible patients in Arm C were adults with a Karnofsky Performance Status (KPS) score ≥70, EGFR amplification (confirmed centrally), recurrent GBM, normal end-organ function and no prior treatment with bevacizumab. Forty-eight EGFR-amplified recurrent GBM patients were treated in this arm. The median age was 59 years (range, 35-80). Most patients had prior therapies: 40% had one, 48% had two, and 10% had three or more prior therapies.
Common adverse events
As of January 7, 2016, the most common serious adverse event (>1 patient) (n=48) was seizure (8%). Additionally, Best Response Assessment in Neuro-Oncology (RANO) Criteria, an assessment of tumor response used in GBM, identified two partial responses, 18 patients with stable disease, and 24 with progressive disease for a total of 44 patients with complete data.
Urgent Unmet need
“With standard of care therapy, patients with GBM, the most common and most aggressive form of brain cancer, have a median survival of 15 months after diagnosis and two-year survival is 30%,” said Martin van den Bent, M.D., Ph.D., head, Neuro-Oncology Unit, Erasmus MC Cancer Institute, The Netherlands, and lead investigator of the study. 
“There remains an urgent unmet need for new treatment options for this devastating brain cancer. These data are important as they demonstrate the potential of ABT-414 and underscore the need for further investigation in glioblastoma,” Van den Bent added.
Additional Safety Findings
Grade 3/4 treatment emergent adverse events (TEAEs) (>1 patient) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis (6%), hyperglycemia (6%), muscular weakness (6%), seizure (6%), blurred vision (4%) and ulcerative keratitis (4%).The most common TEAEs (≥25% patients) in this study arm were blurred vision (60%), headache (29%), photophobia (29%), dry eye (27%), eye pain (27%), and fatigue (27%). The most common serious adverse event (>1 patient) (n=48) was seizure (8%).
“These results suggest that ABT-414 may have important activity for certain groups of patients with glioblastoma and support the continuation of the ongoing randomized studies,” noted Gary Gordon, M.D., vice president, oncology clinical development, AbbVie.
“AbbVie is committed to continuing to invest in technologies and approaches, including antibody drug conjugates like ABT-414, with the goal of delivering a remarkable impact on cancer treatment,” Gordon further added.
Based on these results, together with previously presented data from this study, AbbVie advanced ABT-414 to a randomized Phase II clinical trial in patients with EGFR-amplified GBM.
ABT-414 is being developed by researchers at AbbVie with components in-licensed from Life Science Pharmaceuticals, Inc. and Seattle Genetics.  In 2014, the FDA and the European Medicines Agency granted orphan drug designation for the treatment of glioblastoma and glioma, respectively.