Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the initial
clinical results on its investigational, tyrosine-kinase inhibitor, AP26113,
in patients with advanced non-small cell lung cancer (NSCLC) from an
ongoing Phase 1/2 trial. The study provides compelling clinical evidence
of the anti-tumor activity of AP26113 at multiple dose levels in
patients with anaplastic lymphoma kinase positive (ALK+) NSCLC and
initial clinical evidence of anti-tumor activity in patients with
epidermal growth factor receptor mutant (EGFR-m) NSCLC. The results are
being presented this morning at the ESMO 2012 Congress of the European
Society for Medical Oncology being held in Vienna, Austria.
Patients enrolled in the trial have advanced solid tumors that were
refractory to available therapies or had no standard or curative
treatment available to them. The primary objectives of the Phase 1
portion of the trial are to determine the maximum tolerated dose (MTD)
and the recommended dose for further study of AP26113 and to
characterize its safety and preliminary anti-tumor activity. The trial
uses an open-label, dose-escalating design. Anti-tumor activity was
determined by serial CT scans using RECIST criteria.
Thirty-four patients have been enrolled to date in the study in six
dose-cohorts (i.e., 30, 60, 90, 120, 180 and 240 mg administered
orally once daily). Nineteen patients currently remain on study, with 16
at the three highest dose levels.
Twenty-nine of the patients enrolled to date in the study have NSCLC: 14
who are ALK+ and 11 who are EGFR-m. More than two-thirds of these
patients failed three or more regimens of prior treatment, including
both targeted therapies and chemotherapy.
"The initial findings from this ongoing study show that AP26113 has
impressive anti-tumor activity in ALK+ NSCLC patients, who are either
naïve or resistant to crizotinib," stated Scott Gettinger, M.D.,
Associate Professor of Medicine at Yale School of Medicine, the study's
presenter at ESMO. "At the same time, it is encouraging to see a partial
response in a patient with EGFR-mutant lung cancer and acquired
resistance to erlotinib in the Phase 1 dose-escalation portion of the
Key data from the study presented at ESMO include:
Safety and Tolerability
Safety data to date show AP26113 to be well tolerated. There was one
patient with a dose-limiting toxicity (DLT) of elevated aspartate
aminotransferase (ALT), a liver enzyme, observed at the 240 mg
dose-level. The enzyme elevation resolved within eight days following
drug interruption; the patient resumed therapy at a lower dose,
remains on study and has achieved a partial response (PR). The 240 mg
cohort has recently been expanded with the enrollment of three
additional patients. The MTD has not yet been identified.
The most common adverse events, all treatment emergent and across all
grades, are nausea (32 percent) and fatigue (26 percent). The only
treatment-related adverse events occurring in at least 10 percent of
study patients are nausea (26 percent), diarrhea (18 percent),
decreased appetite (12 percent), and vomiting (12 percent). There have
been no signs of rash that would be considered typical of EGFR
inhibitors at any doses studied.
Objective responses were observed at the lowest doses which ALK+ NSCLC
patients received (60 mg), and responses were observed in patients who
are either naïve or resistant to crizotinib (Xalkori®)--
the currently available first-generation ALK inhibitor.
Of the 11 ALK+ patients evaluable for response in five dose-levels (i.e.,
60, 90, 120, 180 and 240 mg), eight (73 percent) demonstrated a PR by
RECIST. Six of nine crizotinib-resistant patients (67 percent)
demonstrated a PR, and the two crizotinib-naïve patients treated with
AP26113 also both demonstrated PRs. The longest response durations are
9 months for a crizotinib-naïve patient, and 6 months for a
crizotinib-resistant patient. Both responses are ongoing.
Objective responses were observed in all patients who completed a
first scheduled disease assessment: two patients discontinued prior to
their first scheduled assessment, and one responded by CT but had
progressive disease defined by RECIST due to growth of an unrelated
second tumor type.
Of particular note, one of the ALK+, crizotinib-resistant patients who
achieved a PR also had a response in a pre-existing brain metastasis.
Six EGFR-m patients have received doses of 120 mg or higher and have
been assessed for response. All six patients had failed erlotinib
(Tarceva®), one of the currently available first-generation
EGFR inhibitors, as well as bevacizumab (Avastin®) and at
least one round of chemotherapy. Many had also failed further rounds
of chemotherapy and/or other investigational, targeted agents.
Of these patients, one EGFR-m patient (EGFR exon-19 deletion by
history) achieved a PR and remains on study (duration, 2 months), two
patients had stable disease and remain on study (durations, 2 and 4
months) and three patients had disease progression.
Exposure of AP26113 increases as the dose level is increased. The
pharmacokinetic data indicate that the blood levels achieved are
consistent with the concentrations (IC50 values) predicted
pre-clinically to inhibit ALK, ROS1 and EGFR and their resistance
"This is the first demonstration of anti-tumor activity by AP26113 in
this ALK+ patient population, and the achievement of partial responses
is clear, even at the lower doses and in patients with or without prior
ALK inhibitor treatment and with brain metastasis," stated Frank G.
Haluska, M.D., Ph.D., senior vice president of clinical research and
development and chief medical officer at ARIAD.
"Further, this is the first report of the anti-tumor activity of AP26113
in a patient resistant to EGFR-inhibitor therapy. The EGFR-mutant
patient group is heterogeneous with regard to prior therapy at study
entry and EGFR dependence. We look forward to further characterizing
this activity as the Phase 1 portion of the trial continues and then
transitions into the Phase 2 pre-specified patient cohorts."
ARIAD Pharmaceuticals, Inc.