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European Commission Approves LORVIQUA® (lorlatinib) for Certain Adult Patients with Previously-Treated ALK-Positive Advanced Non-Small Cell Lung Cancer

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE: PFE) today announced that the European Commission
(EC) granted conditional marketing authorization for LORVIQUA®
(lorlatinib, available in the U.S., Canada and Japan under the brand
name LORBRENA®), as a monotherapy for the treatment of adult
patients with anaplastic lymphoma kinase (ALK)-positive advanced
non-small cell lung cancer (NSCLC) whose disease has progressed after
alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI)
therapy, or crizotinib and at least one other ALK TKI. LORVIQUA is a
third-generation ALK TKI that was specifically developed to penetrate
the blood brain barrier, in the presence or absence of resistance
mutations.

“Pfizer has worked to pioneer biomarker-driven medicine for patients
with ALK-positive non-small cell lung cancer and we continue to advance
patient care with the approval of LORVIQUA,” said Andreas Penk, M.D.,
regional president, Oncology International Developed Markets at Pfizer.
“We are proud that LORVIQUA is our second lung cancer medication
approved in Europe within two months and our third biomarker-driven
medicine for lung cancer. We look forward to making LORVIQUA available
for European patients with ALK-positive non-small cell lung cancer who
have progressed on prior therapy with a second generation ALK medicine.”

The conditional marketing authorization was based on results from a
non-randomized, dose-ranging and activity-estimating, multi-cohort,
multi-center Phase 1/2 study, B7461001, evaluating LORVIQUA for the
treatment of patients with ALK-positive advanced NSCLC, who were
previously treated with one or more ALK TKIs. A total of 139 patients
with ALK-positive metastatic NSCLC after treatment with at least one
second-generation ALK TKI, such as alectinib, brigatinib or ceritinib,
were enrolled in the Phase 2 portion of the study. Among these patients,
the overall response rate (ORR) for those who have been treated with one
prior ALK TKI (N=28) was 42.9% (95% CI: 24.5, 62.8) and 39.6% (95% CI:
30.5, 49.4) for those with two or more prior ALK TKI treatments (N=111).
In the trial, 67% of patients had a history of brain metastases.

“Over the last decade, our understanding of ALK-positive non-small cell
lung cancer has advanced dramatically, leading to multiple medications
for patients. However, the common challenges associated with treating
the disease, including resistance and brain metastases have created an
urgent need for additional treatment options,” said Enriqueta Felip,
M.D., Ph.D., Vall d’Hebron University Hospital, Vall d’Hebron Institute
of Oncology in Spain. “The LORVIQUA approval marks an exciting time in
lung cancer innovation and I look forward to using this next-generation
ALK inhibitor to treat my patients.”

Among 295 ALK-positive or ROS1-positive metastatic NSCLC patients who
received LORVIQUA 100 mg once daily in study B7461001, the most common
(≥ 20%) adverse reactions were hypercholesterolemia (84.4%),
hypertriglyceridemia (67.1%), edema (54.6%), peripheral neuropathy
(47.8%), cognitive effects (28.8%), fatigue (28.1%), weight increased
(26.4%), arthralgia (24.7%), mood effects (22.7%) and diarrhea (22.7%).

Conditional approval is granted to a medicinal product that fulfils an
unmet medical need, where the benefit-risk balance is positive and the
benefit of the product’s immediate availability outweighs the risk of
less comprehensive data than normally required.1 Under the
provisions of the conditional approval, Pfizer will provide additional
data from the post-marketing studies, including the Phase 3 CROWN study
of LORVIQUA versus crizotinib in the first-line treatment of patients
with ALK-positive NSCLC, which is currently ongoing.

About LORVIQUA® (lorlatinib)

LORVIQUA is a TKI that has been shown to be highly active in preclinical
lung cancer models harboring chromosomal rearrangements of ALK. LORVIQUA
was specifically developed to inhibit tumor mutations that drive
resistance to other ALK inhibitors and to penetrate the blood brain
barrier. LORVIQUA is approved in the EU as monotherapy for the treatment
of adult patients with ALK-positive advanced NSCLC whose disease has
progressed after:

  • alectinib or ceritinib as the first ALK TKI therapy; or
  • crizotinib and at least one other ALK TKI.

LORVIQUA is also approved:

  • Under the brand name LORBRENA® in Japan for the treatment
    of ALK fusion gene-positive unresectable advanced and/or recurrent
    NSCLC with resistance or intolerance to ALK tyrosine kinase
    inhibitor(s).
  • Under the brand name LORBRENA® in Canada, where it is
    conditionally approved as monotherapy for the treatment of adult
    patients with ALK-positive metastatic NSCLC who have progressed on:
    crizotinib and at least one other ALK inhibitor, or patients who have
    progressed on ceritinib or alectinib.
  • Under the brand name LORBRENA® in the U.S. 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
    • alectinib as the first ALK inhibitor therapy for metastatic
      disease; or
    • ceritinib as the first ALK inhibitor therapy for metastatic
      disease.

The U.S. indication is approved under accelerated approval based on
tumor response rate and duration of response. Continued approval for
this indication may be contingent upon verification and description of
clinical benefit in a confirmatory trial.

LORBRENA® (lorlatinib) IMPORTANT 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. Discontinue strong CYP3A inducers for 3 plasma
half-lives of the strong CYP3A inducer prior to initiating LORBRENA.
Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If
concomitant use of moderate CYP3A inducers cannot be avoided, monitor
AST, ALT, and bilirubin 48 hours after initiating LORBRENA and at least
3 times during the first week after initiating LORBRENA. Depending upon
the relative importance of each drug, discontinue LORBRENA or the CYP3A
inducer for persistent Grade 2 or higher hepatotoxicity.

Central Nervous System (CNS) Effects: A broad spectrum of CNS
effects can occur. These include seizures, hallucinations, and changes
in cognitive function, mood (including suicidal ideation), speech,
mental status, and sleep. Withhold and resume at the 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 17%
and Grade 3 or 4 elevations in triglycerides occurred in 17% of the 332
patients who received LORBRENA. Eighty percent of patients required
initiation of lipid-lowering medications, with a median time to onset of
start of such medications of 21 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 295 patients who received LORBRENA at a dose of 100
mg orally once daily and who had a baseline electrocardiography (ECG),
1% experienced AV block and 0.3% 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 1.5% of patients,
including Grade 3 or 4 ILD/pneumonitis in 1.2% of patients. Promptly
investigate for ILD/pneumonitis in any patient who presents with
worsening of respiratory symptoms indicative of ILD/pneumonitis.
Immediately withhold LORBRENA in patients with suspected
ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related
ILD/pneumonitis of any 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: 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%). The
most common (≥20%) adverse reactions were edema, peripheral neuropathy,
cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood
effects, and diarrhea; the most common (≥20%) laboratory abnormalities
were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia,
increased AST, hypoalbuminemia, increased ALT, increased lipase, and
increased alkaline phosphatase.

Drug Interactions: LORBRENA is contraindicated in patients taking
strong CYP3A inducers. Avoid concomitant use with moderate CYP3A
inducers and strong CYP3A inhibitors. If concomitant use of moderate
CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as
recommended. If concomitant use with a strong CYP3A inhibitor cannot be
avoided, reduce the LORBRENA dose as recommended. Concomitant use of
LORBRENA decreases the concentration of CYP3A 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: No dose adjustment is recommended for patients
with mild or moderate renal impairment. The recommended dose of LORBRENA
has not been established for patients with severe renal impairment.

Please see full prescribing information for LORBRENA in the U.S. here.

About Non-Small Cell Lung Cancer

Lung cancer is the most common cancer worldwide, with more than two
million new cases diagnosed globally in 2018.2 About 85
percent of all lung cancers are identified as non-small cell, and
approximately 75 percent of these are metastatic, or advanced, at
diagnosis.3

ALK gene rearrangement is a genetic alteration that drives the
development of lung cancer in some patients.4,5 Epidemiology
studies suggest that approximately three to five percent of NSCLC tumors
are ALK-positive.6

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

At Pfizer Oncology, we are committed to advancing medicines wherever we
believe we can make a meaningful difference on the lives of patients.
Today, Pfizer Oncology has an industry-leading portfolio of 18 approved
innovative cancer medicines and biosimilars across more than 20
indications, including breast, prostate, kidney, lung and hematology.
Pfizer Oncology is striving to change the trajectory of 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
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 follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedIn,
YouTube,
and like us on Facebook at Facebook.com/Pfizer.

DISCLOSURE NOTICE:

The information contained in this release is as of May 7, 2019.
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 LORVIQUA
(lorlatinib), a kinase inhibitor, and an approval by the European
Commission, including the potential benefits, that involve 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 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 applications for LORVIQUA may be filed in
other jurisdictions; whether and when any such other applications for
LORVIQUA that may be pending or filed may be approved by regulatory
authorities, which will depend on 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 LORVIQUA 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 LORVIQUA; 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, 2018 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 European Medicines Agency. Conditional Marketing
Authorisation. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing-authorisation.
Accessed March 2019.

2 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 September 2018.

3 Reade CA, Ganti AK. EGFR targeted therapy in
non-small cell lung cancer: potential role of cetuximab. Biologics.
2009;3:215–224.

4 Chiarle R, Voena C, Ambrogio C, et al. The anaplastic
lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer.
2008;8(1):11-23.

5 Guérin A, Sasane M, Zhang J, et al. ALK rearrangement
testing and treatment patterns for patients with ALK-positive
non-small cell lung cancer. Cancer Epidemiol.
2015;39(3):307-12.

6 Garber K. ALK, lung cancer, and personalized therapy:
portent of the future? J Natl Cancer Inst. 2010;102:672-675.

Contacts

Pfizer Media:
Jessica Smith (U.S.)
(212) 733-6213
[email protected]

Lisa O’Neill (EU)
(44) 7929 339 560
Lisa.O’[email protected]

Pfizer Investor:
Ryan Crowe
(212) 733-8160
[email protected]

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