Clinical proof-of-concept

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) has announced the initial clinical results on its investigational, tyrosine-kinase inhibitor, AP26113, in patients with advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial.

The study provides compelling clinical evidence of the anti-tumour activity of AP26113 at multiple dose levels in patients with anaplastic lymphoma kinase positive (ALK+) NSCLC and initial clinical evidence of anti-tumour activity in patients with epidermal growth factor receptor mutant (EGFR-m) NSCLC. The results are being presented this morning at the ESMO 2012 Congress of the European Society for Medical Oncology being held in Vienna, Austria.

Patients enrolled in the trial have advanced solid tumours that were refractory to available therapies or had no standard or curative treatment available to them. The primary objectives of the Phase 1 portion of the trial are to determine the maximum tolerated dose (MTD) and the recommended dose for further study of AP26113 and to characterise its safety and preliminary anti-tumour activity. The trial uses an open-label, dose-escalating design. Anti-tumour activity was determined by serial CT scans using RECIST criteria.

Thirty-four patients have been enrolled to date in the study in six dose-cohorts (i.e., 30, 60, 90, 120, 180 and 240mg administered orally once daily). Nineteen patients currently remain on study, with 16 at the three highest dose levels.

Twenty-nine of the patients enrolled to date in the study have NSCLC: 14 who are ALK+ and 11 who are EGFR-m. More than two-thirds of these patients failed three or more regimens of prior treatment, including both targeted therapies and chemotherapy.

“The initial findings from this ongoing study show that AP26113 has impressive anti-tumour activity in ALK+ NSCLC patients, who are either naïve or resistant to crizotinib,” stated Scott Gettinger, MD, Associate Professor of Medicine at Yale School of Medicine, the study’s presenter at ESMO. “At the same time, it is encouraging to see a partial response in a patient with EGFR-mutant lung cancer and acquired resistance to erlotinib in the Phase 1 dose-escalation portion of the trial.”  

Key data from the study presented at ESMO include:

• Safety data to date show AP26113 to be well tolerated. There was one patient with a dose-limiting toxicity (DLT) of elevated aspartate aminotransferase (ALT), a liver enzyme, observed at the 240mg dose-level. The enzyme elevation resolved within eight days following drug interruption and resumption at a lower dose; the patient remains on study and has achieved a partial response (PR). The 240mg cohort has recently been expanded with the enrolment of three additional patients. The MTD has not yet been identified.
• The most common adverse events, all treatment emergent and across all grades, are nausea (32%) and fatigue (26%).  The only treatment-related adverse events occurring in at least 10% of study patients are nausea (26%), diarrhoea (18%), decreased appetite (12%) and vomiting (12%). There have been no signs of rash that would be considered typical of EGFR inhibitors at any doses studied.

• Objective responses were observed at the lowest doses which ALK+ NSCLC patients received (60mg), and responses were observed in patients who are either naïve or resistant to crizotinib (Xalkori®) – the currently available first-generation ALK inhibitor.
• Of the 11 ALK+ patients evaluable for response in five dose-levels (i.e., 60, 90, 120, 180 and 240mg), eight (73%) demonstrated a PR by RECIST. Six of nine crizotinib-resistant patients (67%) demonstrated a PR, and the two crizotinib-naïve patients treated with AP26113 also both demonstrated PRs. The longest response durations are nine months for a crizotinib-naïve patient, and six months for a crizotinib-resistant patient.  Both responses are ongoing.
• Objective responses were observed in all patients who completed a first scheduled disease assessment:  two patients discontinued prior to their first scheduled assessment, and one responded by CT but had progressive disease defined by RECIST due to growth of an unrelated second tumor type.
• Of particular note, one of the ALK+, crizotinib-resistant patients who achieved a PR also had a response in a pre-existing brain metastasis.

• Six EGFR-m patients have received doses of 120 mg or higher and have been assessed for response. All six patients had failed erlotinib (Tarceva®), one of the currently available first-generation EGFR inhibitors, as well as bevacizumab (Avastin®) and at least one round of chemotherapy. Many had also failed further rounds of chemotherapy and/or other investigational, targeted agents.
• Of these patients, one EGFR-m patient (EGFR exon-19 deletion by history) achieved a PR and remains on study (duration, two months), two patients had stable disease and remain on study (durations, two and four months) and three patients had disease progression.

• Exposure of AP26113 increases as the dose level is increased.  The pharmacokinetic data indicate that the blood levels achieved are consistent with the concentrations (IC50 values) predicted pre-clinically to inhibit ALK, ROS1 and EGFR and their resistance mutations.

“This is the first demonstration of anti-tumour activity by AP26113 in this ALK+ patient population, and the achievement of partial responses is clear, even at the lower doses and in patients with or without prior ALK inhibitor treatment and with brain metastasis,” stated Frank G. Haluska, MD, PhD, senior vice president of clinical research and development and chief medical officer at ARIAD.