Strong, durable responses seen against lung
tumors and brain metastases across multiple lines of therapy
Pfizer Inc. (NYSE:PFE) today announced full results from the
Phase 2 clinical trial of the investigational, next-generation
tyrosine kinase inhibitor lorlatinib that exhibited clinically
meaningful activity against lung tumors and brain metastases in a
range of patients with ALK-positive and ROS1-positive advanced
non-small cell lung cancer (NSCLC), including those who were
heavily pretreated. Further, side effects were generally manageable
and primarily mild to moderate in severity. The results [Abstract
#OA 05.06] were presented by Professor Benjamin Solomon, lead
investigator and medical oncologist at Peter MacCallum Cancer
Centre, Melbourne, Australia, today during an oral session at the
International Association for the Study of Lung Cancer (IASLC) 18th
World Conference on Lung Cancer (WCLC) in Yokohama, Japan. Pfizer
will also present data from several other lung cancer clinical
programs.
“The findings presented today suggest that lorlatinib, if
approved, may represent an effective treatment option for patients
with ALK-positive advanced non-small cell lung cancer across
multiple lines of therapy. These are comprehensive data in
non-small cell lung cancer patients previously treated with
second-generation ALK inhibitors who currently have few available
treatment options,” said Professor Benjamin Solomon, lead
investigator and medical oncologist at Peter MacCallum Cancer
Centre, Melbourne, Australia. “Controlling brain metastases is very
important to these patients and an especially challenging aspect of
treating this disease. We saw excellent intracranial responses in
all patient groups, including those who were heavily
pretreated.”
“Lorlatinib is an extraordinary example of what can be achieved
through translational research and precision medicine development.
Recall that Xalkori (crizotinib) was the first drug approved for
patients with ALK-positive and ROS1-positive NSCLC. By
understanding the mutations that occurred in patients that rendered
their tumors resistant to Xalkori and other ALK inhibitors,
medicinal chemists working at Pfizer were able to design a molecule
with the potential to overcome that resistance and inhibit ALK
despite these mutations. We are very encouraged by the results of
this Phase 2 trial that provide the first clinical evidence of the
activity of lorlatinib in this setting,” said Mace Rothenberg, MD,
chief development officer, Oncology, Pfizer Global Product
Development.
The Phase 2 study examined the antitumor activity and safety of
lorlatinib in 275 patients with or without asymptomatic, untreated
or treated brain metastases. Patients were enrolled in six cohorts
based on biomarker (ALK-positive or ROS1-positive) and prior
therapy. The primary endpoints were objective response rate (ORR)
and intracranial ORR (IC-ORR) confirmed by independent central
review (ICR). Results by clinically relevant groups showed:
- ALK-positive treatment-naïve: ORR was
90% (27/30; 95% CI: 74, 98) and IC-ORR was 75% (6/8; 95% CI: 35,
97).
- ALK-positive previously treated with
crizotinib with or without chemotherapy: ORR was 69% (41/59; 95%
CI: 56, 81) and IC-ORR was 68%(25/37; 95% CI: 50, 82).
- ALK-positive previously treated with a
non-crizotinib ALK inhibitor with or without chemotherapy: ORR was
33% (9/27; 95% CI: 16, 54) and IC-ORR was 42% (5/12; 95% CI: 15,
72).
- ALK-positive previously treated with
two or three prior ALK inhibitors with or without chemotherapy: ORR
was 39% (43/111; 95% CI: 30, 49) and IC-ORR 48% (40/83; 95% CI: 37,
59).
- ROS1-positive regardless of prior
treatment: ORR was 36% (17/47; 95% CI: 23, 52) and IC-ORR was 56%
(14/25; 95% CI: 35, 76).
Lorlatinib was generally tolerable. Most adverse events were
mild to moderate and were managed by dose reductions or delay or
with standard medical therapy. There were no treatment-related
deaths and a low (3%) rate of discontinuation due to drug-related
adverse events. The most common adverse events were:
hypercholesterolemia (81%), hypertriglyceridemia (60%), edema
(43%), peripheral neuropathy (30%), weight increase (18%),
cognitive effects (18%), mood effects (15%), fatigue (13%),
diarrhea (11%), arthralgia (10%), and increased AST (10%).
The Phase 2 data will form the basis of discussions with global
regulatory authorities, including the U.S. Food and Drug
Administration. On April 26, 2017, the FDA granted Breakthrough
Therapy designation for lorlatinib for the treatment of patients
with ALK-positive metastatic NSCLC previously treated with one or
more ALK inhibitors.
Pfizer Oncology continues to build on its heritage in
biomarker-driven therapies by investigating novel targeted
therapies and immunotherapy combination approaches aimed at
addressing significant unmet needs for patients. In addition to the
lorlatinib results, Pfizer will present data at the conference from
studies examining its current and investigational lung cancer
medicines:
- Plasma genomic profiling and outcomes
of patients with MET exon-14 altered NSCLC treated with crizotinib
on PROFILE 1001 (Late-breaker oral presentation: Abstract #OA
12.06)
- First-line dacomitinib versus gefitinib
in advanced non-small cell lung cancer with EGFR mutation subgroups
(Oral presentation: Abstract #OA 05.01)
- Next-generation sequencing shows
mechanisms of intrinsic resistance in ALK-positive NSCLC patients
treated with crizotinib (Poster presentation: Abstract
#P1.01-016)
- Dacomitinib versus gefitinib for
first-line treatment of advanced EGFR NSCLC in Japanese patients
(ARCHER 1050) (Poster presentation: Abstract #P3.01-072)
- Symptom impact of first-line
dacomitinib versus gefitinib in EGFR-positive NSCLC: Results from a
randomized phase 3 study (Poster presentation: Abstract
#P3.01-012)
About Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer death worldwide.1
NSCLC accounts for about 85 percent of lung cancer cases and
remains difficult to treat, particularly in the metastatic
setting.2 Approximately 75 percent of NSCLC patients are diagnosed
late with metastatic or advanced disease where the five-year
survival rate is only five percent.2,3,4
About Lorlatinib
Lorlatinib is an investigational next-generation ALK/ROS1
tyrosine kinase inhibitor that has been shown to be highly active
in preclinical lung cancer models harboring chromosomal
rearrangements of both ALK and ROS1. Lorlatinib was specifically
designed to inhibit tumor mutations that drive resistance to other
ALK inhibitors and to penetrate the blood brain barrier.
The Phase 3 CROWN study (NCT03052608) of lorlatinib began
enrolling patients earlier this year. CROWN is an ongoing, open
label, randomized, two-arm study comparing lorlatinib to crizotinib
in the first-line treatment of patients with metastatic
ALK-positive NSCLC.
Lorlatinib is an investigational agent and has not received
regulatory approval for any indication anywhere in the world.
About Dacomitinib
Dacomitinib is an investigational, second-generation, oral,
once-daily, irreversible epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor. It has not received regulatory approval
anywhere in the world.
About XALKORI® (crizotinib)
XALKORI is a tyrosine kinase inhibitor indicated in the U.S. 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® 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: 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: 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. No starting dose adjustment is needed for
patients with mild and moderate renal impairment.
For more information and full prescribing information, please
visit www.XALKORI.com.
About Pfizer Oncology
Pfizer Oncology is committed to pursuing innovative treatments
that have a meaningful impact on those living with cancer. As a
leader in oncology speeding cures and accessible breakthrough
medicines to patients, Pfizer Oncology is helping to redefine life
with cancer. Our strong pipeline of biologics, small molecules and
immunotherapies, 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 its breakthrough medicines. Because
Pfizer Oncology knows that success in oncology is not measured
solely by the medicines you manufacture, but rather by the
meaningful partnerships you make to have a more positive impact on
people’s lives.
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, we have worked to make a difference for
all who rely on us. We routinely post information that may be
important to investors on our website at www.pfizer.com. In
addition, to learn more, please visit us on www.pfizer.com and
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@Pfizer and @Pfizer_News, LinkedIn, YouTube, and
like us on Facebook at Facebook.com/Pfizer.
About the World Conference on Lung Cancer
The World Conference on Lung Cancer (WCLC) is the world’s
largest meeting dedicated to lung cancer and other thoracic
malignancies, attracting over 6,000 researchers, physicians and
specialists from more than 100 countries. The goal is to
disseminate the latest scientific achievements; increase awareness,
collaboration and understanding of lung cancer; and to help
participants implement the latest developments across the globe.
Organized under the theme of “Synergy to Conquer Lung Cancer,” the
conference will cover a wide range of disciplines and unveil
several research studies and clinical trial results. For more
information, visit http://wclc2017.iaslc.org/.
DISCLOSURE NOTICE: The information contained in this
release is as of October 16, 2017. 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 an
investigational oncology therapy, lorlatinib, 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 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 any new drug applications may be filed in any
jurisdictions for lorlatinib; whether and when any such
applications may be approved by 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 lorlatinib; 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, 2016 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 The International Agency for Research on Cancer, the World
Health Organization, GLOBOCAN 2008, Available at:
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (select
“Lung” from the drop-down menu). Accessed October 13, 2017.2 Reade
CA, Ganti AK. EGFR targeted therapy in non-small cell lung cancer:
potential role of cetuximab. Biologics. 2009; 3: 215–224.3 Yang P,
Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung
cancer patients: experience at Mayo Clinic from 1997 to 2003.
Chest. 2005;128(1):452–4624 American Cancer Society. Detailed
Guide: Lung Cancer (Non-Small Cell). Available at:
http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates.
Accessed October 13, 2017.
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Pfizer Inc.Media:Sally Beatty,
212-733-6566Sally.beatty@pfizer.comorInvestors:Ryan Crowe,
212-733-8160Ryan.crowe@pfizer.com
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