Strong, durable responses seen against lung tumors and brain metastases
across multiple lines of therapy
NEW YORK--(BUSINESS WIRE)--
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
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expand access to reliable, affordable health care around the world. For
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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):452–462
4 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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Source: Pfizer Inc.