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ARIAD Pharmaceuticals, Inc.
today announced updated clinical
results on its investigational tyrosine kinase inhibitor (TKI), AP26113, in
patients with advanced non-small cell lung cancer (NSCLC) from an ongoing
Phase 1/2 trial. These study results show sustained anti-tumor activity of
AP26113 in patients with anaplastic lymphoma kinase (ALK) positive NSCLC,
including patients with active brain metastases. The updated Phase 1/2 trial
now contains more mature data of AP26113, including increasing depth and
durability of response in ALK+ NSCLC patients, as well as additional safety
data.
The updated results were presented on Saturday, September 27 at the 2014
European Cancer Congress (the 39th ESMO, 33rd ESTRO, 18th ECCO conference)
held in Madrid, Spain.
Phase 1/2 Study Design
A total of 137 patients have been enrolled in the ongoing Phase 1/2 trial in
the United States and Europe. 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 in subsequent clinical trials.
The trial used an open-label, dose-escalating design.
The Phase 2 portion of the trial consists of five expansion cohorts. The data
presented at ESMO focus on the 79 patients with a history of ALK+ NSCLC tumors
in the entire trial. Fifty-six of these patients currently remain on study
treatment.
“The updated data from the ongoing trial continue to demonstrate the
anti-tumor activity of AP26113 in patients with crizotinib-resistant ALK
rearranged NSCLC, as well as TKI-naïve ALK rearranged NSCLC,” stated Scott N.
Gettinger, M.D., associate professor of medicine at Yale School of Medicine.
“One of the distinguishing features of the data is the evidence for anti-tumor
activity in the brain, a common site of treatment failure.”
Key data from the study include:
Safety and Tolerability – All Patients Enrolled
* The most common adverse events (AEs), regardless of treatment relationship
and including all grades, were nausea (45%), diarrhea (37%), and fatigue
(37%).
* Adverse events, grade 3 or higher, occurring in three or more patients
were dyspnea (4%), increased lipase (4%), hypoxia (4%), fatigue (3%),
alanine aminotransferase (ALT) increased (2%) and amylase increased (2%).
* Serious AEs, all causality, occurring in three or more patients were
dyspnea (7%), pneumonia (5%), hypoxia (4%), neoplasm progression (4%),
pyrexia (2%) and pulmonary embolism (2%).
* Early onset pulmonary symptoms were observed in 13 of 137 (10%) patients
enrolled in the study and occurred more frequently with starting doses of
180 mg per day and higher compared to the lower starting doses. These
symptoms occurred within 7 days of treatment initiation, and in some
cases, included dyspnea, hypoxia, and new pulmonary opacities on chest
imaging.
* To minimize the early-onset pulmonary symptoms observed, two additional
dosing regimens were examined in the Phase 2 portion of the trial: 90 mg
per day for 1 week followed by 180 mg per day (n=32) and 90 mg per day
continuously (n=18). The incidence of early-onset pulmonary symptoms in
these two dosing regimens was 0 of 32 and 2 of 18 patients, respectively.
Overall, 2 out of 50 patients (4%) who began dosing at 90 mg per day had
early-onset pulmonary symptoms and continued on treatment.
Anti-tumor Activity – ALK+ NSCLC Patients
* Objective responses were observed in ALK+ NSCLC patients at the lowest
dose tested in these patients (60 mg), and responses were observed in
patients who were either TKI-naïve or resistant to crizotinib.
* Of the 72 ALK+ NSCLC patients evaluable for response, 52 (72%)
demonstrated an objective response. The “waterfall plot” analysis
demonstrated tumor shrinkage in nearly all ALK+ NSCLC patients, with 16
patients experiencing 100% shrinkage of the target lesion. The median
duration of response was 49 weeks, and the median progression-free
survival (PFS) was 56 weeks.
* Of the seven evaluable TKI-naïve ALK+ NSCLC patients treated with AP26113,
all demonstrated an objective response, including two complete responses
(CR).
* Of the 65 evaluable ALK+ NSCLC patients with prior crizotinib therapy
treated with AP26113, 45 (69%) demonstrated an objective response. Median
progression-free survival was 47.3 weeks.
* In a subgroup analysis, 10 of 14 (71%) ALK+ NSCLC patients with active,
untreated or progressing, brain metastases had evidence of radiographic
improvement in those metastases. Four of these patients demonstrated a CR
by independent review. Of the 10 patients who responded, six remain on
study, with treatment durations up to 105 weeks. In addition, improvement
in a patient with leptomeningeal metastasis was observed.
Pivotal Phase 2 Trial Enrolling Patients
A separate, pivotal global Phase 2 trial of AP26113 in patients with locally
advanced or metastatic NSCLC who were previously treated with crizotinib is
open and enrolling 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 will be randomized
1:1 to receive either 90 mg of AP26113 once per day continuously or a lead-in
dose of 90 mg per day for 7 days followed by 180 mg once per day continuously.
“We anticipate full patient enrollment in the ALTA trial in the third quarter
of next year,” stated Frank G. Haluska, M.D., Ph.D., senior vice president of
clinical research and development and chief medical officer at ARIAD. “Based
on the continued responses seen in the ongoing Phase 1/2 trial of AP26113, and
in particular, the 100% response rate and durability of response in the
TKI-naïve patients, we are also actively planning a clinical trial to
evaluate the potential of AP26113 in the newly diagnosed ALK+ lung cancer
setting.”
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