ARIAD Pharmaceuticals, Inc. (ARIA) today 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).
“The updated data on select doses from the Phase 1/2 trial show robust anti-tumor activity of brigatinib in patients with crizotinib-resistant ALK+ NSCLC, with responses now approaching one year,” stated Rafael Rosell, M.D., Director, Cancer Biology & Precision Medicine Program Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital in Barcelona, Spain. “Importantly, by starting at the 90 mg dose, we have seen a reduction of early-onset pulmonary events observed at the higher starting doses.”
Key data from the study update include:
- 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.
- 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).
Pivotal Phase 2 ALTA Trial Enrolling Patients
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) 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.
“We are on track for full patient enrollment in the ALTA trial in the third quarter of this year,” stated Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD. “We are encouraged by the CNS anti-tumor activity, now exceeding 18 months in the Phase 1/2 brigatinib trial, and look forward to the evaluation of activity on brain metastasis in the ALTA trial.”
ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts and Lausanne, Switzerland, is an integrated global oncology company focused on transforming the lives of cancer patients with breakthrough medicines. ARIAD is working on new medicines to advance the treatment of various forms of chronic and acute leukemia, lung cancer and other difficult-to-treat cancers. ARIAD utilizes computational and structural approaches to design small-molecule drugs that overcome resistance to existing cancer medicines. For additional information, visithttp://www.ariad.com or follow ARIAD on Twitter (@ARIADPharm).
This press release contains forward-looking statements. Any statements contained herein which do not describe historical facts, including, but not limited to, statements regarding: updated clinical data for brigatinib and the estimated timing for completing enrollment in our ALTA clinical trial, are forward-looking statements which are based on management’s expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. These factors, risks and uncertainties include, among others: preclinical data and early-stage clinical data may not be replicated in later-stage clinical studies; the costs associated with our research, development, manufacturing and other activities; the adequacy of our capital resources and the availability of additional funding; our ongoing and additional clinical trials of brigatinib may not be successful or initiated, enrolled or conducted in a timely manner; regulatory developments and safety issues; competitive risks; manufacturing issues and those additional factors detailed in our public filings with the U.S. Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q. Except as otherwise noted, these forward-looking statements speak only as of the date of this press release and we undertake no obligation to update or revise any of these statements to reflect events or circumstances occurring after this press release. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. All forward‐looking statements in this press release are qualified in their entirety by this cautionary statement.