Pfizer Inc. (NYSE:PFE) today announced that the U.S. Food and Drug
Administration (FDA) has accepted and granted Priority Review for a
supplemental New Drug Application (sNDA) for XALKORI®
(crizotinib) for the treatment of patients with metastatic non-small
cell lung cancer (NSCLC) whose tumors are ROS1-positive. In April 2015,
XALKORI received Breakthrough Therapy designation by the FDA for this
potential indication. If approved, XALKORI would be the first
FDA-approved biomarker-driven therapy for the treatment of ROS1-positive
metastatic NSCLC. XALKORI is currently indicated for patients with
metastatic NSCLC whose tumors are anaplastic lymphoma kinase
(ALK)-positive as detected by an FDA-approved test. The projected FDA
action date is April 2016.
Priority Review status accelerates FDA review time from 10 months to a
goal of six months from the day of acceptance of filing and is given to
drugs that may offer major advances in treatment or may provide a
treatment for which no adequate therapy exists.1
“ROS1 represents the second molecular subgroup of NSCLC in which XALKORI
has demonstrated a level of anti-tumor activity that can potentially
make a meaningful difference for patients,” said Dr. Mace Rothenberg,
senior vice president of Clinical Development and Medical Affairs and
chief medical officer for Pfizer Oncology. “The development of XALKORI
in this subgroup of patients is an example of the capability of
precision medicine to identify treatments for patients whose tumors
contain rare genetic mutations, such as ROS1-positive metastatic NSCLC.”
ROS1 rearrangement occurs when the ROS1 gene attaches to another gene
and changes the way each gene normally functions, which can contribute
to cancer-cell growth. Epidemiology data suggest that ROS1
rearrangements occur in approximately one percent of NSCLC cases. Of the
estimated 1.5 million new cases of NSCLC worldwide each year, roughly
15,000 may be driven by oncogenic ROS1 fusions. 2,3
The submission to the FDA is based on data from a multicenter,
single-arm Phase 1 study (Study 1001) that evaluated XALKORI in 53
patients with ROS1-positive metastatic NSCLC.3 Data from 50
of these patients were published in the November 20, 2014 issue of The
New England Journal of Medicine and showed that XALKORI exhibited
marked anti-tumor activity in patients with ROS1-positive metastatic
NSCLC. Additionally, the safety profile of XALKORI in ROS1-positive
metastatic NSCLC was consistent with that observed in patients with
ALK-positive metastatic NSCLC. 4
About XALKORI® (crizotinib)
XALKORI is a kinase inhibitor indicated in the U.S. for the treatment of
patients with metastatic non-small cell lung cancer whose tumors are
anaplastic lymphoma kinase-positive as detected by an FDA-approved test.
XALKORI has received approval in more than 85 countries including
Australia, Canada, China, Japan, South Korea and the European Union.
XALKORI® Important Safety Information
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome
occurred in 0.1% of patients treated with XALKORI across clinical trials
(n=1669). Transaminase elevations generally occurred within the first 2
months. Monitor with liver function tests including ALT and total
bilirubin every 2 weeks during the first 2 months of treatment, then
once a month and as clinically indicated, with more frequent repeat
testing for increased liver transaminases, alkaline phosphatase, or
total bilirubin in patients who develop transaminase elevations.
Permanently discontinue for ALT/AST elevation >3 times ULN with
concurrent total bilirubin elevation >1.5 times ULN (in the absence of
cholestasis or hemolysis); otherwise, temporarily suspend and
dose-reduce XALKORI as indicated.
Interstitial Lung Disease (Pneumonitis): Severe,
life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis
can occur. Across clinical trials (n=1669), 2.9% of XALKORI-treated
patients had any grade ILD, 1.1% had Grade 3/4, and 0.5% had fatal ILD.
These cases generally occurred within 3 months after initiation of
treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis.
Exclude other potential causes and permanently discontinue XALKORI in
patients with drug-related ILD/pneumonitis.
QT Interval Prolongation: QTc prolongation can occur. Across
clinical trials (n=1560), 2.1% of patients had QTcF (corrected QT by the
Fridericia method) ≥500 ms and 5.0% had an increase from baseline QTcF
≥60 ms by automated machine-read evaluation of ECG. Avoid use in
patients with congenital long QT syndrome. Consider periodic monitoring
with ECGs and electrolytes in patients with congestive heart failure,
bradyarrhythmias, electrolyte abnormalities, or who are taking
medications that prolong the QT interval. Permanently discontinue
XALKORI in patients who develop QTc >500 ms or ≥60 ms change from
baseline with Torsade de pointes, polymorphic ventricular tachycardia,
or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients
who develop QTc >500 ms on at least 2 separate ECGs until recovery to a
QTc ≤480 ms, then resume at a reduced dose.
Bradycardia: Symptomatic bradycardia can occur. Across clinical
trials, bradycardia occurred in 12.3% of patients treated with XALKORI
(N=1669). Avoid use in combination with other agents known to cause
bradycardia. Monitor heart rate and blood pressure regularly. In cases
of symptomatic bradycardia that is not life-threatening, hold XALKORI
until recovery to asymptomatic bradycardia or to a heart rate of ≥60
bpm, re-evaluate the use of concomitant medications, and adjust the dose
of XALKORI. Permanently discontinue for life-threatening bradycardia due
to XALKORI; however, if associated with concomitant medications known to
cause bradycardia or hypotension, hold XALKORI until recovery to
asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant
medications can be adjusted or discontinued, restart XALKORI at 250 mg
once daily with frequent monitoring.
Severe Visual Loss: Across clinical trials, the incidence of
Grade 4 visual field defect with vision loss was 0.2% (N=1669).
Discontinue XALKORI in patients with new onset of severe visual loss
(best corrected vision less than 20/200 in one or both eyes). Perform an
ophthalmological evaluation. There is insufficient information to
characterize the risks of resumption of XALKORI in patients with a
severe visual loss; a decision to resume should consider the potential
benefits to the patient.
Vision Disorders: Most commonly visual impairment, photopsia,
blurred vision or vitreous floaters, occurred in 62% of 1669 patients.
The majority (95%) of these patients had Grade 1 visual adverse
reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual
impairment. The majority of patients on the XALKORI arms in Studies 1
and 2 (>50%) reported visual disturbances which occurred at a frequency
of 4-7 days each week, lasted up to 1 minute, and had mild or no impact
on daily activities.
Embryofetal Toxicity: XALKORI can cause fetal harm when
administered to a pregnant woman. Advise of the potential risk to the
fetus. Advise females of reproductive potential and males with female
partners of reproductive potential to use effective contraception during
treatment and for at least 45 days (females) or 90 days (males)
respectively, following the final dose of XALKORI.
Adverse Reactions: Safety was evaluated in a phase 3 study in
previously untreated patients with ALK-positive metastatic NSCLC
randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse
events were reported in 34% of patients treated with XALKORI, the most
frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal
adverse events in XALKORI-treated patients occurred in 2.3% of patients,
consisting of septic shock, acute respiratory failure, and diabetic
ketoacidosis. Common adverse reactions (all grades) occurring in ≥25%
and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy
were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs
12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper
respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal
pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher
incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%),
and constipation (2% vs 0%). In patients treated with XALKORI vs
chemotherapy, the following occurred: elevation of ALT (any grade [79%
vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs
28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or
Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade
3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4
[10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal
cysts occurred (5% vs 1%). Nausea (56%) decreased appetite (30%),
fatigue (29%), and neuropathy (21%) also occurred in patients taking
XALKORI.
Drug Interactions: Exercise caution with concomitant use of
moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which
may increase plasma concentrations of crizotinib. Avoid concomitant use
of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A
substrates with narrow therapeutic range in patients taking XALKORI. If
concomitant use of CYP3A substrates with narrow therapeutic range is
required in patients taking XALKORI, dose reductions of the CYP3A
substrates may be required due to adverse reactions.
Lactation: Because of the potential for adverse reactions in
breastfed infants, advise females not to breast feed during treatment
with XALKORI and for 45 days after the final dose.
Hepatic Impairment: XALKORI has not been studied in patients with
hepatic impairment. As crizotinib is extensively metabolized in the
liver, hepatic impairment is likely to increase plasma crizotinib
concentrations. Use caution in patients with hepatic impairment.
Renal Impairment: Administer XALKORI at a starting dose of 250 mg
taken orally once daily in patients with severe renal impairment (CLcr
<30 mL/min) not requiring dialysis. No starting dose adjustment is
needed for patients with mild and moderate renal impairment.
For more information and full prescribing information visit www.XALKORI.com.
About Pfizer Oncology
Pfizer Oncology is committed to the discovery, investigation and
development of innovative treatment options to improve the outlook for
cancer patients worldwide. Our strong pipeline of biologics and small
molecules, one of the most robust in the industry, is studied with
precise focus on identifying and translating the best scientific
breakthroughs into clinical application for patients across a wide range
of cancers. By working collaboratively with academic institutions,
individual researchers, cooperative research groups, governments, and
licensing partners, Pfizer Oncology strives to cure or control cancer
with breakthrough medicines, to deliver the right drug for each patient
at the right time. For more information, please visit www.pfizer.com.
Pfizer Inc.: Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring therapies
to people that extend and significantly improve their lives. We strive
to set the standard for quality, safety and value in the discovery,
development and manufacture of health care products. Our global
portfolio includes medicines and vaccines as well as many of the world's
best-known consumer health care products. Every day, Pfizer colleagues
work across developed and emerging markets to advance wellness,
prevention, treatments and cures that challenge the most feared diseases
of our time. Consistent with our responsibility as one of the world's
premier innovative biopharmaceutical companies, we collaborate with
health care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world. For
more than 150 years, Pfizer has worked to make a difference for all who
rely on us. To learn more, please visit us at www.pfizer.com.
DISCLOSURE NOTICE: The information contained in this release
is as of December 8, 2015. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result of
new information or future events or developments.
This release contains forward-looking information about a potential
new indication for XALKORI for the treatment of patients with
metastatic non-small cell lung cancer whose tumors are ROS1-positive
(the “Potential Indication”), including its potential benefits, that
involves substantial risks and uncertainties that could cause actual
results to differ materially from those expressed or implied by such
statements. Risks and uncertainties include, among other things, the
uncertainties inherent in research and development, including, without
limitation, the possibility of unfavorable clinical trial
results, including unfavorable new clinical data and additional analyses
of existing clinical data; whether regulatory authorities will be
satisfied with the design of and results from our clinical studies;
whether and when any applications may be filed with other regulatory
authorities for XALKORI for the Potential Indication; whether and when
the FDA may approve the sNDA for the Potential Indication and whether
and when other regulatory authorities may approve any such other
applications, which will depend on the assessment by such regulatory
authorities of the benefit-risk profile suggested by the totality of the
efficacy and safety information submitted; decisions by regulatory
authorities regarding labeling and other matters that could affect the
availability or commercial potential of XALKORI for the Potential
Indication; and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended December
31, 2014 and in its subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward-Looking
Information and Factors That May Affect Future Results”, as well as in
its subsequent reports on Form 8-K, all of which are filed with the U.S.
Securities and Exchange Commission and available at www.sec.gov
and www.pfizer.com.
__________________________
1 U.S. Food and Drug
Administration. Priority Review. Available at: http://www.fda.gov/forpatients/approvals/fast/ucm405405.htm.
Accessed November 5, 2015.
2 Gainor JF, Shaw AT. Novel
targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist
2013;18:865-75.
3 American Cancer Society. Detailed
Guide: What is Lung Cancer – Non-Small Cell? Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer.
Accessed March 16, 2015.
4 Shaw AT, Ou SI, Bang Y, et
al. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. N Engl J
Med 2014; 371:1963-1971.
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