ARIAD Presents Updated Phase 1/2 Data on AP26113 in Patients with Non-Small Cell Lung Cancer
The updated Phase 1/2 results are being presented this morning at the European Cancer Congress (the 38th ESMO, 32nd ESTRO, 17th ECCO conference) being held in Amsterdam.
Phase 1/2 Study Design
Patients enrolled in the Phase 1 portion of the trial had advanced solid tumors that were refractory to available therapies or had no standard or curative treatment available. The objectives of the Phase 1 portion of the trial were to characterize the safety and tolerability of AP26113, pharmacokinetics, and preliminary anti-tumor activity and to determine the recommended dose for further study of AP26113. The trial used an open-label, dose-escalating design. Anti-tumor activity was determined by serial CT scans using RECIST criteria. The study identified a recommended Phase 2 dose of 180 mg administered orally once daily.
The Phase 2 portion of the trial began in June 2013 and has enrolled 26 patients in the United States and Europe. This portion of the trial consists of five expansion cohorts: (1) ALK+ NSCLC treatment-naïve, (2) ALK+ NSCLC resistant to crizotinib, (3) epidermal growth factor receptor mutant (EGFRm) NSCLC resistant to one prior EGFR TKI with documented T790M secondary mutation, (4) cancers with AP26113 targets (including ALK, ROS1, and EGFR ineligible for Cohort 3), and (5) ALK+ NSCLC, either naïve or resistant to crizotinib, with active brain metastases.
Ninety-one patients have been enrolled in the study at seven dose levels (i.e., 30, 60, 90, 120, 180, 240 and 300 mg per day, administered orally). Fifty-four patients currently remain on study.
The updated results from the on-going Phase 1/2 trial show that AP26113 continues to exhibit anti-tumor activity in patients with TKI-naïve and crizotinib-resistant ALK-positive NSCLC, stated D. Ross Camidge, M.D., Ph.D. Associate Professor of Medicine at University of Colorado School of Medicine, the studys presenter at ESMO. Importantly, AP26113 is active in ALK-positive brain metastases, demonstrating responses of clinically meaningful duration.
Key data from the study presented at ESMO include:
Safety and Tolerability
Safety assessments show AP26113 to be generally well tolerated. The most common adverse events (AEs), regardless of treatment relationship and including all grades, were nausea (38%), fatigue (34%), and diarrhea (32%).
Adverse events grade 3 or higher were uncommon. Treatment-related events occurring in two or more patients were dyspnea (4%), fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%).
In 3 out of 26 patients receiving 180 mg per day of AP26113 in the Phase 2 portion of the trial, early-onset pulmonary symptoms were observed after the first dose of AP26113. Similar events were observed at lower doses but less frequently and have not been observed at 90 mg per day or lower.
To lessen the infrequent early pulmonary symptoms observed, the recommended Phase 2 dose of 180 mg per day is now preceded by dosing for 1 week at 90 mg per day, for all patients receiving AP26113.
ALK+ Patients
Objective responses were observed in ALK+ NSCLC patients at the lowest dose tested (60 mg), and responses were observed in patients who were either naïve or resistant to crizotinib.
Of the 34 ALK+ NSCLC patients evaluable for response, 22 (65%) demonstrated an objective response, including 21 partial responses (PR) and one complete response (CR). Of the three TKI-naïve NSCLC patients treated with AP26113, all demonstrated an objective response, including one CR.
Objective response durations ranged from 8+ weeks to 40+ weeks. Of the 15 ALK+ NSCLC patients receiving treatment for at least 6 months, 12 (80%) remain on study. The waterfall plot analysis demonstrated tumor shrinkage in nearly all ALK+ patients.
Of particular note, eight out of ten (80%) ALK+ NSCLC patients with pre-existing brain metastases had evidence of radiographic improvement in those metastases, and seven of these patients remain on study, with duration of central nervous system (CNS) benefit ranging from 8+ to 40+ weeks.
EGFR T790M Patients
Of the 18 patients who had a history of a T790M secondary mutation, 12 were evaluable for response. Three T790M patients have been enrolled since June who met the rigorous eligibility criteria of having failed one prior EGFR TKI, documented T790M secondary mutation following disease progression on most recent EGFR TKI, and administration of AP26113 within 30 days of stopping the prior EGFR TKI. These three patients received 240 mg per day, and one patient was evaluable for response.
Of the 12 evaluable patients with a history of a T790M secondary mutation, no objective responses have been observed to date; 5 (42%) demonstrated stable disease. |