Pfizer Inc. (NYSE:PFE) today announced that the European Commission has
approved a label update to expand use of XALKORI® (crizotinib) to
first-line treatment of adults with anaplastic lymphoma kinase
(ALK)-positive advanced non-small cell lung cancer (NSCLC). The Summary
of Product Characteristics also has been updated to include efficacy
data from PROFILE 1014, which demonstrated that XALKORI significantly
prolonged progression-free survival (PFS) in previously untreated
patients with ALK-positive advanced nonsquamous NSCLC when compared to
standard platinum-based chemotherapy regimens.1
“The European Commission’s decision to approve XALKORI in the first-line
setting reinforces XALKORI’s role as a standard of care for patients
with ALK-positive advanced NSCLC,” said Andreas Penk, MD, regional
president Oncology Europe, Africa and the Middle East, Head Greater
China and Asia-Pacific Oncology Regions. “This milestone further
underscores the importance of early and routine biomarker testing in
patients with advanced NSCLC so that these patients can be identified
and treated appropriately.”
The European Commission’s approval of XALKORI follows the positive
opinion issued by the Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Agency, and is supported by the results
from PROFILE 1014, a Phase 3 global, randomized, open-label, two-arm
study evaluating the efficacy and safety of XALKORI in patients
previously untreated for ALK-positive advanced nonsquamous NSCLC.1
XALKORI was the first ALK inhibitor approved by regulatory authorities
in the United States (U.S.), EU, China and Japan, and it is now approved
in more than 85 countries. XALKORI is widely recognized as a standard of
care for patients with ALK-positive advanced NSCLC. To date, more than
20,000 patients have been treated with XALKORI worldwide.2
XALKORI is an oral, ALK inhibitor.3 By inhibiting the ALK
fusion protein, XALKORI blocks signaling in a number of cell pathways
that are believed to be critical for the growth and survival of tumor
cells, which may lead to growth inhibition or regression of tumors.4,5
About Non-Small Cell Lung Cancer
Worldwide, lung cancer is the leading cause of cancer death in both men
and women.6 NSCLC accounts for about 85 percent of lung
cancer cases and remains difficult to treat, particularly in the
metastatic setting.7 Approximately 57 percent of NSCLC
patients are diagnosed late with metastatic, or advanced, disease where
the five-year survival rate is only 5 percent.8
XALKORI® (crizotinib) Indication and
Important Safety Information (as per U.S. Prescribing Information)
XALKORI is a kinase inhibitor indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) whose tumors are
anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved
test.
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
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more than 150 years, Pfizer has worked to make a difference for all who
rely on us. For more information, please visit us at www.pfizer.com.
In addition, to learn more, follow us on Twitter at @Pfizer
and @Pfizer_News,
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DISCLOSURE NOTICE: The information contained in this release is as of
November 25, 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 XALKORI,
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, uncertainties regarding the commercial
success of XALKORI; the uncertainties inherent in research and
development, including the ability to meet anticipated clinical trial
commencement and completion dates and regulatory submission dates, as
well as the possibility of unfavorable clinical trial results, including
unfavorable new clinical data and additional analyses of existing
clinical data; whether and when drug applications or supplemental drug
applications may be filed with other jurisdictions for XALKORI for the
first-line treatment of adults with ALK-positive advanced NSCLC; whether
and when any other applications may be approved by other regulatory
authorities, 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; 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 SEC
and available at www.sec.gov and www.pfizer.com.
1 Solomon B, Mok T, Dong-Wan K, et al. First-Line Crizotinib
versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med 2014;
371:2167-2177. DOI: 10.1056/NEJMoa1408440.
2 Pfizer data on file.
3 Kwak E, Bang Y, Camidge R et al. Anaplastic Lymphoma Kinase
Inhibition in Non-Small Cell Lung Cancer. N Engl J Med.
2010;363:1693-1703.
4 Chiarle R, Voena C, Ambrogio C et al. The anaplastic
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2008;8(1):11-23.
5 Zou HY, Li Q, Lee JH, et al. An orally available
small-molecule inhibitor of c-MET, PF-2341066, exhibits cytoreductive
antitumor efficacy through antiproliferative and antiangiogenic
mechanisms. Cancer Res. 2007;67:4408-4417.
6 The International Agency for Research on Cancer, the World
Health Organization, GLOBOCAN 2012, Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Accessed October 15, 2015.
7 Reade CA, Ganti AK. EGFR targeted therapy in non-small cell
lung cancer: potential role of cetuximab. Biologics. 2009; 3: 215 224.
8 National Cancer Institute. Surveillance, Epidemiology, and
End Results Program. Seer Stat Fact Sheets: Lung and Bronchus Cancer. http://seer.cancer.gov/statfacts/html/lungb.html.
Accessed October 15, 2015.
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