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ARIAD Pharmaceuticals, Inc.
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:
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).
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."
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