XALKORI is the First Tyrosine Kinase Inhibitor to Receive
Breakthrough Designation for the Treatment of Patients with
Previously-treated Metastatic Non-Small Cell Lung Cancer with MET Exon
14 Alterations
Additional Breakthrough Therapy Designation for the Treatment of
Patients with Relapsed or Refractory Systemic Anaplastic Large Cell
Lymphoma that is ALK-positive
NEW YORK--(BUSINESS WIRE)--
Pfizer Inc. (NYSE:PFE) announced today that the U.S. Food and Drug
Administration (FDA) granted Breakthrough Therapy designation for
XALKORI® (crizotinib) for the treatment of patients with metastatic
non-small cell lung cancer (NSCLC) with MET exon 14 alterations with
disease progression on or after platinum-based chemotherapy. The FDA
also granted Breakthrough Therapy designation for XALKORI for the
treatment of patients with relapsed or refractory systemic anaplastic
large cell lymphoma (ALCL) that is anaplastic lymphoma kinase
(ALK)-positive.
MET is a transmembrane tyrosine receptor kinase which is expressed in
several types of cells. In patients with NSCLC, MET exon 14 alterations
occur in approximately three percent of NSCLC tumors.1
Anaplastic large cell lymphoma is a rare type of non-Hodgkin lymphoma,
divided into ALK-positive or ALK-negative disease.2,3 Despite
the activity of chemotherapy, many patients with ALCL relapse or require
alternative treatment approaches.4
“Biomarker-driven therapies have changed the way we treat cancer,
helping to ensure that patients receive the right medicine for their
disease,” said Mace Rothenberg, M.D., chief development officer,
Oncology, Pfizer Global Product Development. “These Breakthrough Therapy
designations for XALKORI exemplify our commitment to precision medicine
development and delivering medicines that have the potential to
transform the lives of patients whose cancers carry these genomic
alterations.”
XALKORI is currently approved in the U.S. for the treatment of patients
with metastatic NSCLC whose tumors are ALK-positive or ROS1-positive as
detected by an FDA-approved test. XALKORI became a first-line standard
of care for ALK-positive metastatic NSCLC in its first approved
indication and has proven to be a practice-changing treatment for
patients with ALK-positive and ROS1-positive NSCLC, globally. It is the
only FDA-approved treatment indicated for both ALK-positive and
ROS1-positive metastatic NSCLC. If approved in patients with metastatic
NSCLC with MET exon 14 alterations, XALKORI will be the only TKI with
demonstrated efficacy in three separate biomarker-driven indications in
NSCLC.
The Breakthrough Therapy designation for patients with metastatic NSCLC
with MET exon 14 alterations was supported by results from an expansion
cohort of the Phase 1 PROFILE 1001 study, in which XALKORI showed
antitumor activity.5
The designation for patients with relapsed or refractory systemic ALCL
that is ALK-positive was supported by the results from Study ADVL0912
(NCT00939770) and Study A8081013 (NCT01121588). Study ADVL0912 is a
Phase 1/2 study conducted by the Children’s Oncology Group evaluating
the maximum dose that is safe and tolerable, and assessing preliminary
clinical activity in pediatric patients with relapsed or refractory
solid tumors and ALCL. Study A8081013 evaluated XALKORI in pediatric and
adult patients with advanced malignancies known to be ALK-positive other
than NSCLC and included patients with relapsed/refractory ALCL. These
two studies showed compelling antitumor activity in pediatric and adult
patients who received XALKORI.6,7
Please visit clinicaltrials.gov for more information on these studies.
The FDA’s Breakthrough Therapy designation is intended to expedite the
development and review of a medicine if it is intended to treat a
serious or life-threatening disease and preliminary clinical evidence
indicates that the drug may demonstrate substantial improvement over
existing therapies. The Breakthrough Therapy designation is distinct
from the FDA’s other mechanisms to expedite drug development and review.8
About MET Alterations in Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer deaths worldwide.9
NSCLC accounts for about 85 percent of lung cancer cases and remains
difficult to treat, particularly in the metastatic setting.10
Approximately 75 percent of NSCLC patients are diagnosed late with
metastatic or advanced disease where the five-year survival rate is only
five percent.11,12
MET is a transmembrane tyrosine receptor kinase which is expressed in
several types of cells. In patients with NSCLC, MET exon 14 alterations
occur in approximately three percent of NSCLC tumors.1
About Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin
lymphoma (NHL), but one of the more common subtypes of T-cell lymphoma.
ALCL comprises about two percent of all NHLs and approximately 20
percent of all T-cell lymphomas.2,3 Patients with systemic
ALCL are divided into two groups, ALK-positive or ALK-negative. Both of
these lymphomas are treated as aggressive (fast-growing) lymphomas, yet
many patients still relapse or require alternative treatment approaches.
ALK-positive ALCL usually affects children and young adults.4
About XALKORI® (crizotinib)
XALKORI is a tyrosine kinase inhibitor (TKI) indicated for the treatment
of patients with metastatic non-small cell lung cancer (NSCLC) whose
tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected
by an FDA-approved test. XALKORI has received approval for patients with
ALK-positive NSCLC in more than 90 countries including Australia,
Canada, China, Japan, South Korea and the European Union. XALKORI is
also approved for ROS1-positive NSCLC in more than 60 countries.
XALKORI® Important Safety Information
Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome
occurred in 0.1% of patients treated with XALKORI across clinical trials
(n=1719). Transaminase elevations generally occurred within the first 2
months. Monitor liver function tests, including ALT, AST, 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=1719), 2.9% of XALKORI-treated
patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD.
ILD 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=1616), 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 ECGs. Avoid use in
patients with congenital long QT syndrome. Monitor 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 12.7% of patients treated with XALKORI
(n=1719). 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=1719).
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 63.1% of 1719 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.
Embryo-Fetal 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.
ROS1-positive Metastatic NSCLC: Safety was evaluated in 50
patients with ROS1-positive metastatic NSCLC from a single-arm study,
and was generally consistent with the safety profile of XALKORI
evaluated in patients with ALK-positive metastatic NSCLC. Vision
disorders occurred in 92% of patients in the ROS1 study; 90% of patients
had Grade 1 vision disorders and 2% had Grade 2.
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%),
esophagitis (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 breastfeed during treatment
with XALKORI and for 45 days after the final dose.
Hepatic Impairment: Crizotinib concentrations increased in
patients with pre-existing moderate (any AST and total bilirubin >1.5x
ULN and ≤3x ULN) or severe (any AST and total bilirubin >3x ULN) hepatic
impairment. Reduce XALKORI dose in patients with moderate or severe
hepatic impairment. The recommended dose of XALKORI in patients with
pre-existing moderate hepatic impairment is 200 mg orally twice daily or
with pre-existing severe hepatic impairment is 250 mg orally once daily.
Renal Impairment: Decreases in estimated glomerular filtration
rate occurred in patients treated with XALKORI. 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.
For more information and full prescribing information, please visit www.XALKORI.com.
About Pfizer in Lung Cancer
Pfizer Oncology is committed to addressing the unmet needs of patients
with lung cancer, the leading cause of cancer-related deaths worldwide
and a particularly difficult-to-treat disease. Pfizer strives to address
the diverse and evolving needs of patients with non-small cell lung
cancer (NSCLC) by developing efficacious and tolerable therapies,
including biomarker-driven therapies and immuno-oncology (IO) agents and
combinations. By combining leading scientific insights with a
patient-centric approach, Pfizer is continually advancing its work to
match the right patient with the right medicine at the right time.
Through our growing research pipeline and collaboration efforts, we are
committed to delivering renewed hope to patients living with NSCLC.
About Pfizer Oncology
Pfizer Oncology is committed to pursuing innovative treatments that have
a meaningful impact on people living with cancer. Our growing pipeline
of biologics, small molecules, and immunotherapies is focused on
identifying and translating the best scientific breakthroughs into
clinical application for patients across a diverse array of solid tumors
and hematologic cancers. Today, we have 10 approved oncology medicines
and 14 assets currently in clinical development. By maximizing our
internal scientific resources and collaborating with other companies,
government and academic institutions, as well as patients and non-profit
and professional organizations, we are bringing together the brightest
and most enterprising minds to take on the toughest cancers. Together we
can accelerate breakthrough treatments to patients around the world and
work to redefine life with cancer.
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
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DISCLOSURE NOTICE: The information contained in this release
is as of May 29, 2018. 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
(crizotinib) and a potential new indication for the treatment of
patients with relapsed or refractory systemic anaplastic large cell
lymphoma that is ALK-positive (the “Potential Indication”), including
their 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 the ability to meet anticipated [clinical trial
commencement 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; the risk that clinical trial data are subject to
differing interpretations, and, even when we view data as sufficient to
support the safety and/or effectiveness of a product candidate,
regulatory authorities may not share our views and may require
additional data or may deny approval altogether; 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
the FDA or other regulatory authorities for XALKORI for the Potential
Indication; whether and when regulatory authorities may approve any such
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 and, if approved, whether
XALKORI will be commercially successful; decisions by regulatory
authorities regarding labeling and other matters that could affect the
availability or commercial potential of XALKORI, including 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, 2017 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
.
# # # # #
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Accessed May 2018.
9 The International Agency for Research on Cancer, the World
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(select “Lung” from the drop-down menu). Accessed May 2018.
10 Reade CA, Ganti AK. EGFR targeted therapy in non-small
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Accessed May 2018.
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Source: Pfizer Inc.