Approval is based on CROWN trial, which showed
a 72% reduction in risk of progression or death for treatment with
LORBRENA vs. XALKORI®
The U.S. Food and Drug Administration (FDA) approved Pfizer
Inc.’s (NYSE: PFE) supplemental New Drug Application (sNDA) for
LORBRENA® (lorlatinib), expanding the indication to include
first-line treatment of people with anaplastic lymphoma kinase
(ALK)-positive non-small cell lung cancer (NSCLC). LORBRENA is now
indicated for adults with metastatic NSCLC whose tumors are
ALK-positive as detected by an FDA-approved test. The FDA action
also converts the 2018 accelerated approval to full approval. The
application was approved under the FDA’s Real-Time Oncology Review
(RTOR) pilot program.
“For more than a decade, Pfizer has been a pioneer in delivering
biomarker-driven therapies and addressing the diverse and evolving
needs of people with non-small cell lung cancer,” said Andy
Schmeltz, Global President, Pfizer Oncology. “LORBRENA has been a
transformative medicine for people with ALK-positive advanced
NSCLC, and this FDA approval in the first-line setting means that
we can now extend hope to even more people.”
LORBRENA is a third-generation ALK inhibitor specifically
designed to inhibit the most common tumor mutations that drive
resistance to current medications and to address metastases in the
brain, a frequent site for disease progression in ALK-positive
NSCLC. Up to 40% of people with ALK-positive metastatic NSCLC
present with brain metastases at initial diagnosis.1,2,3
The expanded approval of LORBRENA is based on the results from
the pivotal Phase 3 CROWN trial, which showed a 72% reduction in
risk of progression or death vs. XALKORI® (crizotinib) in a
previously untreated patient population (HR 0.28: 95% CI, 0.19 to
0.41; p<0.0001) as assessed by blinded independent central
review (BICR). Central nervous system (CNS) involvement was
assessed in all patients. There were 17 patients in the LORBRENA
arm and 13 in the XALKORI arm with measurable brain metastases
based on baseline brain imaging. A prespecified exploratory
analysis showed that among these patients, the intracranial
objective response rate (IC-ORR), as assessed by BICR, was 82% (95%
CI, 57 to 96) in the LORBRENA arm and 23% (95% CI, 5 to 54) in the
XALKORI arm. The intracranial duration of response (IC-DOR) was 12
months or longer in 79% (n=11) and 0% of patients in the LORBRENA
and XALKORI arms, respectively.
The most common adverse events (AEs) of any Grade and Grade 3-4
worsening laboratory abnormalities occurring in ≥20% of people
treated with LORBRENA were edema (56%), weight gain (38%),
peripheral neuropathy (35%), cognitive effects (21%), diarrhea
(21%), dyspnea (20%), and hypertriglyceridemia (22%). Serious AEs
occurred in 34% of people treated with LORBRENA; the most
frequently reported serious AEs were pneumonia (4.7%), dyspnea
(2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and
pyrexia (2.0%). Fatal AEs occurred in 3.4% of people treated with
LORBRENA and included pneumonia (0.7%), respiratory failure (0.7%),
cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden
death (0.7%). Permanent discontinuation of LORBRENA due to AEs
occurred in 6.7% of people. AEs leading to dose interruptions and
dose reductions occurred in 49% and 21% of people treated with
LORBRENA, respectively. Detailed results from the CROWN study were
published in the November 2020 issue of the New England Journal of Medicine.
“The CROWN data have shown LORBRENA can significantly improve
outcomes in the first-line treatment of ALK-positive non-small cell
lung cancer, including those that present with brain metastases,”
said Benjamin Solomon, M.D., Department of Medical Oncology, Peter
MacCallum Cancer Centre. “This approval is meaningful for my
patients because we now have a highly effective treatment option
that can delay the progression of a typically aggressive
disease.”
In 2018, the FDA approved LORBRENA for the treatment of patients
with ALK-positive metastatic NSCLC whose disease has progressed on
crizotinib and at least one other ALK inhibitor for metastatic
disease; or whose disease has progressed on alectinib or ceritinib
as the first ALK inhibitor therapy for metastatic disease. This
indication was approved under accelerated approval based on tumor
response rate and duration of response. Based on the CROWN data,
the FDA has also converted the accelerated approval to full
approval.
This sNDA was also reviewed by the FDA under Project ORBIS, an
initiative introduced in 2019, which provides a framework for
potential concurrent submissions and collaborative review with
health authorities in Canada, Singapore, Switzerland, Australia,
Brazil and the United Kingdom. Under Project ORBIS, collaboration
among international regulators may allow people with cancer to
receive earlier access to products in other countries. The European
Medicines Agency is also reviewing a Type II variation application
for LORBRENA in the first line indication.
About the CROWN Trial
CROWN is a Phase 3, randomized, open-label, parallel 2-arm trial
in which 296 people with previously untreated advanced ALK-positive
NSCLC were randomized 1:1 to receive LORBRENA monotherapy (n=149)
or XALKORI monotherapy (n=147). Patients were required to have an
ECOG performance status of 0-2 and ALK-positive NSCLC as identified
by the VENTANA ALK (D5F3) CDx assay. The primary endpoint of the
CROWN trial is PFS based on BICR. Secondary endpoints include
overall survival (OS) and tumor assessment related data by BICR,
including ORR, and DOR. In patients with measurable CNS metastases
at baseline, additional outcome measures were IC-ORR and IC-DOR by
BICR.
About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the number one cause of cancer-related death
around the world.4 NSCLC accounts for approximately 80-85% of lung
cancers,5 with ALK-positive tumors occurring in about 3-5% of NSCLC
cases.6 In 2020, an estimated 228,820 new cases of lung cancer were
diagnosed in the U.S.7
About LORBRENA® (lorlatinib)
LORBRENA is a tyrosine kinase inhibitor (TKI) that has been
shown to be highly active in preclinical lung cancer models
harboring chromosomal rearrangements of ALK. LORBRENA was
specifically developed to inhibit tumor mutations that drive
resistance to other ALK inhibitors and to penetrate the blood brain
barrier.
LORBRENA is approved in the U.S. for the treatment of adults
with metastatic NSCLC whose tumors are ALK-positive as detected by
an FDA-approved test.
IMPORTANT LORBRENA® (lorlatinib) SAFETY INFORMATION FROM THE
U.S. PRESCRIBING INFORMATION
Contraindications: LORBRENA is contraindicated in
patients taking strong CYP3A inducers, due to the potential for
serious hepatotoxicity.
Risk of Serious Hepatotoxicity with Concomitant Use of Strong
CYP3A Inducers: Severe hepatotoxicity occurred in 10 of 12
healthy subjects receiving a single dose of LORBRENA with multiple
daily doses of rifampin, a strong CYP3A inducer. Grade 4 ALT or AST
elevations occurred in 50% of subjects, Grade 3 in 33% of subjects,
and Grade 2 in 8% of subjects. ALT or AST elevations occurred
within 3 days and returned to within normal limits after a median
of 15 days (7 to 34 days); median time to recovery in subjects with
Grade 3 or 4 or Grade 2 ALT or AST elevations was 18 days and 7
days, respectively. LORBRENA is contraindicated in patients taking
strong CYP3A inducers. Discontinue strong CYP3A inducers for 3
plasma half-lives of the strong CYP3A inducer prior to initiating
LORBRENA.
Central Nervous System (CNS) Effects: A broad spectrum of
CNS effects can occur; overall, CNS effects occurred in 52% of the
476 patients receiving LORBRENA. These included seizures (1.9%,
sometimes in conjunction with other neurologic findings), psychotic
effects (7%; 0.6% severe [Grade 3 or 4]), and changes in cognitive
function (28%; 2.9% severe), mood (including suicidal ideation)
(21%; 1.7% severe), speech (11%; 0.6% severe), mental status (1.3%;
1.1% severe), and sleep (12%). Median time to first onset of any
CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% and
10% of patients required permanent or temporary discontinuation of
LORBRENA, respectively, for a CNS effect; 8% required dose
reduction. Withhold and resume at same or reduced dose or
permanently discontinue based on severity.
Hyperlipidemia: Increases in serum cholesterol and
triglycerides can occur. Grade 3 or 4 elevations in total
cholesterol occurred in 18% and Grade 3 or 4 elevations in
triglycerides occurred in 19% of the 476 patients who received
LORBRENA. Median time to onset was 15 days for both
hypercholesterolemia and hypertriglyceridemia. Approximately 4% and
7% of patients required temporary discontinuation and 1% and 3% of
patients required dose reduction of LORBRENA for elevations in
cholesterol and in triglycerides in Study B7461001 and Study
B7461006, respectively. Eighty-three percent of patients required
initiation of lipid-lowering medications, with a median time to
onset of start of such medications of 17 days. Initiate or increase
the dose of lipid lowering agents in patients with hyperlipidemia.
Monitor serum cholesterol and triglycerides before initiating
LORBRENA, 1 and 2 months after initiating LORBRENA, and
periodically thereafter. Withhold and resume at same dose for the
first occurrence; resume at same or reduced dose of LORBRENA for
recurrence based on severity.
Atrioventricular (AV) Block: PR interval prolongation and
AV block can occur. In 476 patients who received LORBRENA at a dose
of 100 mg orally once daily and who had a baseline
electrocardiography (ECG), 1.9% experienced AV block and 0.2%
experienced Grade 3 AV block and underwent pacemaker placement.
Monitor ECG prior to initiating LORBRENA and periodically
thereafter. Withhold and resume at reduced or same dose in patients
who undergo pacemaker placement. Permanently discontinue for
recurrence in patients without a pacemaker.
Interstitial Lung Disease (ILD)/Pneumonitis: Severe or
life-threatening pulmonary adverse reactions consistent with
ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.9% of
patients, including Grade 3 or 4 ILD/pneumonitis in 0.6% of
patients. Four patients (0.8%) discontinued LORBRENA for
ILD/pneumonitis. Promptly investigate for ILD/pneumonitis in any
patient who presents with worsening of respiratory symptoms
indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever).
Immediately withhold LORBRENA in patients with suspected
ILD/pneumonitis. Permanently discontinue LORBRENA for
treatment-related ILD/pneumonitis of any severity.
Hypertension: Hypertension can occur in patients
receiving LORBRENA. Hypertension occurred in 13% of patients,
including Grade 3 or 4 in 6% of patients. Median time to onset of
hypertension was 6.4 months (1 day to 2.8 years). 2.3% of patients
temporarily discontinued LORBRENA for hypertension. Control blood
pressure prior to initiating LORBRENA. Monitor blood pressure after
2 weeks and at least monthly thereafter. Withhold and resume at
reduced dose or permanently discontinue based on severity.
Hyperglycemia: Hyperglycemia can occur in patients
receiving LORBRENA. Hyperglycemia occurred in 9% of patients,
including Grade 3 or 4 in 3.2% of patients. Median time to onset of
hyperglycemia was 4.8 months (1 day to 2.9 years). 0.8% of patients
temporarily discontinued LORBRENA for hyperglycemia. Assess fasting
serum glucose prior to initiating LORBRENA and monitor periodically
thereafter. Withhold and resume at reduced dose or permanently
discontinue based on severity.
Embryo-fetal Toxicity: LORBRENA can cause fetal harm.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use an effective non-hormonal
method of contraception, since LORBRENA can render hormonal
contraceptives ineffective, during treatment with LORBRENA and for
at least 6 months after the final dose. Advise males with female
partners of reproductive potential to use effective contraception
during treatment with LORBRENA and for 3 months after the final
dose.
Adverse Reactions: In the pooled safety population of 476
patients who received 100 mg LORBRENA once daily, the most frequent
(≥ 20%) adverse reactions were edema (56%), peripheral neuropathy
(44%), weight gain (31%), cognitive effects (28%), fatigue (27%),
dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects
(21%), and cough (21%). The most frequent (≥ 20%) laboratory
abnormalities in patients receiving LORBRENA were
hypercholesterolemia (21%) and hypertriglyceridemia (21%).
In previously untreated patients, serious adverse reactions
occurred in 34% of the 149 patients treated with LORBRENA; the most
frequently reported serious adverse reactions were pneumonia
(4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive
effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions
occurred in 3.4% of patients and included pneumonia (0.7%),
respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary
embolism (0.7%), and sudden death (0.7%). In previously treated
patients, serious adverse reactions occurred in 32% of the 295
patients; the most frequently reported serious adverse reactions
were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status
changes (1.4%), and respiratory failure (1.4%). Fatal adverse
reactions occurred in 2.7% of patients and included pneumonia
(0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%),
embolism (0.3%), peripheral artery occlusion (0.3%), and
respiratory distress (0.3%).
Drug Interactions: LORBRENA is contraindicated in
patients taking strong CYP3A inducers. Avoid concomitant use with
moderate CYP3A inducers, strong CYP3A inhibitors, and fluconazole.
If concomitant use of moderate CYP3A inducers cannot be avoided,
increase the LORBRENA dose as recommended. If concomitant use with
a strong CYP3A inhibitor or fluconazole cannot be avoided, reduce
the LORBRENA dose as recommended. Avoid concomitant use of LORBRENA
with CYP3A substrates and P-gp substrates, which may reduce the
efficacy of these substrates.
Lactation: Because of the potential for serious adverse
reactions in breastfed infants, instruct women not to breastfeed
during treatment with LORBRENA and for 7 days after the final
dose.
Hepatic Impairment: No dose adjustment is recommended for
patients with mild hepatic impairment. The recommended dose of
LORBRENA has not been established for patients with moderate or
severe hepatic impairment.
Renal Impairment: Reduce the dose of LORBRENA for
patients with severe renal impairment. No dose adjustment is
recommended for patients with mild or moderate renal
impairment.
The full prescribing information for LORBRENA can be found
here.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines
wherever we believe we can make a meaningful difference in the
lives of people living with cancer. Today, we have an
industry-leading portfolio of 24 approved innovative cancer
medicines and biosimilars across more than 30 indications,
including breast, genitourinary, colorectal, blood and lung
cancers, as well as melanoma.
About Pfizer: Breakthroughs That Change Patients’
Lives
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, including innovative medicines and vaccines. 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 170 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 follow us on
Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us
on Facebook at Facebook.com/Pfizer.
DISCLOSURE NOTICE: The information contained in this
release is as of March 3, 2021. 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
LORBRENA® (lorlatinib) and an expanded indication in the U.S. to
include first-line treatment of people with anaplastic lymphoma
kinase (ALK)-positive non-small cell lung cancer, 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, uncertainties regarding
the commercial success of LORBRENA; the uncertainties inherent in
research and development, including the ability to meet anticipated
clinical endpoints, commencement and/or completion dates for our
clinical trials, regulatory submission dates, regulatory approval
dates and/or launch dates, as well as the possibility of
unfavorable new clinical data and further analyses of existing
clinical data; the risk that clinical trial data are subject to
differing interpretations and assessments by regulatory
authorities; whether regulatory authorities will be satisfied with
the design of and results from our clinical studies; whether and
when any drug applications may be filed in any additional
jurisdictions for LORBRENA for the expanded indication or in any
jurisdictions for any other potential indications for LORBRENA;
whether and when any such other applications may be approved by
regulatory authorities (including the Type II variation application
pending in the European Union), which will depend on a myriad
factors, including making a determination as to whether the
product's benefits outweigh its known risks and determination of
the product's efficacy and, if approved, whether such product
candidate will be commercially successful; decisions by regulatory
authorities impacting labeling, manufacturing processes, safety
and/or other matters that could affect the availability or
commercial potential of LORBRENA; uncertainties regarding the
impact of COVID-19 on Pfizer’s business, operations and financial
results; 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, 2020 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 Peters S. Alectinib versus crizotinib in untreated
ALK-positive non–small-cell lung cancer. N Engl J Med.
2017;377:829-38.
2 Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib
versus platinum-based chemotherapy in advanced ALKrearranged
non-small-cell lung cancer (ASCEND-4): a randomised, open-label,
phase 3 study. Lancet. 2017;389:917–929.
3 Gainor JF, Tseng D, Yoda S, et al. Patterns of metastatic
spread and mechanisms of resistance to crizotinib in ROS1-positive
non-small-cell lung cancer. JCO Precis Oncol. 2017;2017.
4 World Health Organization. International Agency for Research
on Cancer. GLOBOCAN 2018: Lung fact sheet.
http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed January 2021.
5 American Cancer Society. What is lung cancer?
https://www.cancer.org/cancer/lung-cancer/about/what-is.html.
Accessed February 2021.
6 Garber K. ALK, lung cancer, and personalized therapy: portent
of the future? J Natl Cancer Inst. 2010;102:672-675.
7 National Cancer Institute. Cancer Stat Facts: Lung and
bronchus cancer. https://seer.cancer.gov/statfacts/html/lungb.html.
Accessed February 2021.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20210303006042/en/
Media: Eamonn Nolan +1 (212) 733-4626 Eamonn.Nolan@pfizer.com
Investor: Bryan Dunn +1 (212) 733-8917 Bryan.Dunn@pfizer.com
Pfizer (NYSE:PFE)
Historical Stock Chart
From Aug 2024 to Sep 2024
Pfizer (NYSE:PFE)
Historical Stock Chart
From Sep 2023 to Sep 2024