Date: 2015-04-17
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 2015 European Lung Cancer Conference (ELCC) being held in Geneva, Switzerland
Company: Ariad Pharmaceuticals (USA - MA)
Product: brigatinib (AP26113)
Action mechanism: kinase inhibitor/tyrosine kinase inhibitor
Disease: anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC)
Therapeutic area: Cancer - Oncology
Country: Australia, Austria, Belgium, Canada, Denmark, France, Germany, Hong Kong, Italy, Republic of Korea, The Netherlands, Norway, Singapore, Spain, Sweden, Switzerland, UK, USA
Trial details:
Latest news: • On April 17, 2015, Ariad Pharmaceuticals announced updated clinical data on its investigational tyrosine kinase inhibitor, brigatinib (AP26113), in patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. The new results include an analysis of safety and efficacy for patients treated at select doses of brigatinib and an evaluation of intracranial central nervous system (CNS) antitumor activity. The updated results were presented at the 2015 European Lung Cancer Conference (ELCC) being held in Geneva, Switzerland. Phase 2 Dose Sub-Analysis: The data presented at ELCC focused on the 98 patients treated at doses of 90 mg/day (n=18), 90 mg/day for 1 week followed by escalation to 180 mg/day (n=32), and 180 mg/day (n=48) in the Phase 2 portion of the trial. All patients receiving these doses were evaluated for safety, and patients with ALK+ NSCLC (n=65) were evaluated for efficacy. The presentation at ELCC is based on patient data as of January 19, 2015 with a median follow-up of 40 weeks (range, 0.1 - 150+ weeks). Key data from the study update include: Safety Summary: The most common adverse events (AEs) of any grade, regardless of treatment relationship, were nausea, diarrhea, and fatigue and were similar in incidence across all three dose-cohorts, as follows: At 90 mg/day (n=18): nausea (44%), headache (44%), diarrhea (39%), fatigue (39%), cough (39%), and increased amylase (33%) At 90 mg to 180 mg/day (n=32): diarrhea (44%), nausea (41%), fatigue (38%), headache (28%), cough (28%), and increased amylase (28%) At 180 mg/day (n=48): nausea (63%), diarrhea (38%), fatigue (31%), headache (31%), cough (25%), and increased amylase (15%) Serious AEs, regardless of treatment relationship, occurring in 4% or more patients, were dyspnea, hypoxia, and pneumonia, as follows: At 90 mg/day (n=18): dyspnea (1 patient, 6%), hypoxia (2 patients, 11%), and pneumonia (2 patients, 11%) At 90 mg to 180 mg/day (n=32): dyspnea (2 patients, 6%), hypoxia (1 patient, 3%), and pneumonia (1 patient, 3%) At 180 mg/day (n=48): dyspnea (2 patients, 4%), hypoxia (2 patients, 4%), and pneumonia (2 patients, 4%) As previously observed and reported, fewer early-onset pulmonary events, including dyspnea, hypoxia, and new pulmonary opacities, were reported with a starting dose of 90 mg (2/50 patients, 4%) vs. 180 mg (6/44 patients, 14%). Importantly, no early-onset pulmonary events were observed in the 32 patients started at 90 mg and escalated to 180 mg after 7 days. Response Summary: The median time on study for patients dosed at 90 mg/day was 33.5 weeks (range, 0.7-150+ weeks), 50.3 weeks (range, 0.1-70+ weeks) for the 90 mg to 180 mg/day cohort, and 31.4 weeks (range, 0.1-135+ weeks) for the 180 mg/day cohort. Brigatinib was active at each of the three dosing regimens with similar efficacy among the cohorts: Objective response rate (ORR) among the 14 evaluable ALK+ NSCLC patients dosed at 90 mg/day was 79% (11 patients, 7 confirmed). Among the 26 evaluable ALK+ NSCLC patients dosed at 90 mg/day for 1 week followed by 180 mg/day, ORR was 81% (21 patients, 19 confirmed), including 3 patients (12%) with a complete response (CR). Among the 25 evaluable ALK+ NSCLC patients dosed at 180 mg/day, ORR was 68% (17 patients, 16 confirmed), including 2 patients (8%) with a CR. Median duration of response was 11.2 months for the 90 mg/day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 9.2 months for the 180 mg/day cohort. Median progression-free survival (PFS) was 12.9 months for the 90 mg /day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 11.1 months for the 180 mg/day cohort. Phase 1/2 Analysis of CNS Antitumor Activity A separate evaluation of the efficacy and safety of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also presented at the ELCC meeting. In an independent central radiological review of brain Magnetic Resonance Imaging (MRI) scans, 49 of 79 ALK+ NSCLC patients in the Phase 1/2 trial were identified to have intracranial CNS metastases at baseline. Of these 49 patients, 16 had measurable intracranial CNS metastases (15 evaluable) and 33 patients had only non-measurable intracranial CNS metastases (30 evaluable). AEs in patients with CNS metastases occurred at a similar incidence as in the broader study population. In this post-hoc analysis of centrally reviewed brain MRI, brigatinib demonstrated intracranial CNS antitumor activity with responses in ALK+ NSCLC patients with intracranial CNS metastases at baseline. Objective response rate (ORR) was 53% in evaluable patients with measurable lesions (n=15), including 1 (7%) CR. In evaluable patients with non-measurable lesions (n=30), ORR defined as disappearance of all lesions was 30% (9 patients). For patients with a response and at least one follow-up MRI scan (n=16), median (Kaplan-Meier [KM] estimate) duration of intracranial response was 18.9 months. For patients with a follow-up MRI scan (n=45), median (KM estimate) intracranial PFS was 22.3 months. Median time on study for ALK+ NSCLC patients with intracranial CNS metastases at baseline was 56.1 weeks (range, 0.1-150+ weeks). A separate, pivotal global Phase 2 trial of brigatinib (AP26113) in patients with locally advanced or metastatic ALK+ NSCLC who have progressed on crizotinib continues to enroll patients. The ALTA (ALK in Lung Cancer Trial of AP26113 - NCT02094573) trial is designed to determine the safety and efficacy of AP26113 in refractory ALK+ NSCLC patients. The trial will enroll approximately 220 patients including those with brain metastasis. Patients are randomized 1:1 to receive either 90 mg of brigatinib once per day continuously or a lead-in dose of 90 mg/day for 7 days followed by 180 mg/day continuously.
