- Validation is supported by data from Phase 3 innovaTV 301
trial
Genmab A/S (Nasdaq: GMAB) and Pfizer, Inc.
(NYSE PFE) today announced that the European Medicines
Agency (EMA) has validated for review the marketing authorization
application (MAA) of tisotumab vedotin, an antibody-drug conjugate
(ADC), developed for the treatment of adult patients with recurrent
or metastatic cervical cancer with disease progression on or after
systemic therapy. If approved, tisotumab vedotin would be the first
ADC granted European Union (EU) marketing authorization for people
living with cervical cancer.
The MAA is based on data from the global, randomized, Phase 3
innovaTV 301 trial (NCT04697628), in which tisotumab vedotin
demonstrated superior overall survival (OS), progression-free
survival (PFS) and a confirmed objective response rate (ORR) in
patients with previously treated recurrent or metastatic cervical
cancer compared to chemotherapy. Data from the innovaTV 204 pivotal
Phase 2 single-arm clinical trial evaluating TIVDAK as monotherapy
in patients with previously treated recurrent or metastatic
cervical cancer was also included in the MAA. The safety profile of
tisotumab vedotin in innovaTV 301 was consistent with its known
safety profile as presented in the U.S. prescribing
information.
“The validation of our application is an important milestone
supporting our commitment to bringing a new therapeutic option for
recurring or metastatic cervical cancer to more patients,” said Jan
van de Winkel, Ph.D., Chief Executive Officer, Genmab. “There
continues to be a need for therapeutic options for these patients,
and we’re dedicated to delivering potential improved outcomes to
women diagnosed with this devastating disease.”
“Today’s milestone signifies our progress in exploring the
availability of tisotumab vedotin for more patients with recurrent
or metastatic cervical cancer,” said Roger Dansey, M.D., Chief
Development Officer, Oncology, Pfizer. “We remain dedicated to
collaborating closely with regulatory authorities, while we
navigate the process to potentially deliver a new therapeutic
option to people facing this debilitating disease.”
About Cervical Cancer
Cervical cancer remains a disease with high unmet need despite
advances in effective vaccination and screening practices to
prevent and diagnose pre-/early-stage cancers for curative
treatment. It is the fourth leading cause of cancer death in women
worldwide,i,ii with approximately 570,000 new cases diagnosed and
311,000 new deaths of women annually.iii,iv Recurrent and/or
metastatic cervical cancer is a particularly devastating and mostly
incurable disease; when diagnosed in later stages, less than 5
percent of these patients survive five years.v In the European
Union specifically, cervical cancer ranks 11th among the most
frequently occurring cancers in women and 12th among the most
frequent causes of cancer death in them.vi
About the innovaTV 301 Trial
The innovaTV 301 trial (NCT04697628) is a global, randomized,
open-label Phase 3 trial evaluating tisotumab vedotin versus
investigator’s choice of chemotherapy alone (topotecan,
vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502
patients with recurrent or metastatic cervical cancer who received
no more than two prior systemic regimens in the recurrent or
metastatic setting.
Patients with recurrent or metastatic cervical cancer with
squamous cell, adenocarcinoma, or adenosquamous histology, and
disease progression during or after treatment with chemotherapy
doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are
included. The primary endpoint is overall survival. The main
secondary outcomes are progression-free survival, confirmed
objective response rate, time to response, and duration of
response, as assessed by the investigator, as well as safety and
quality of life outcomes.
The study was conducted by Seagen, recently acquired by Pfizer,
in collaboration with Genmab, European Network of Gynaecological
Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the
Gynecologic Oncology Group (GOG) Foundation (study number GOG
3057). For more information about the Phase 3 innovaTV 301 clinical
trial and other clinical trials with tisotumab vedotin, please
visit www.clinicaltrials.gov.
About Tisotumab Vedotin
Tisotumab vedotin is an antibody-drug conjugate (ADC) composed
of Genmab’s human monoclonal antibody directed to tissue factor
(TF) and Pfizer’s ADC technology that utilizes a protease-cleavable
linker that covalently attaches the microtubule-disrupting agent
monomethyl auristatin E (MMAE) to the antibody. Determination of TF
expression is not required. Nonclinical data suggest that the
anticancer activity of tisotumab vedotin is due to the binding of
the ADC to TF-expressing cancer cells, followed by internalization
of the ADC-TF complex, and release of MMAE via proteolytic
cleavage. MMAE disrupts the microtubule network of actively
dividing cells, leading to cell cycle arrest and apoptotic cell
death. In vitro, tisotumab vedotin also mediates antibody-dependent
cellular phagocytosis and antibody-dependent cellular
cytotoxicity.
Tisotumab vedotin-tftv (Tivdak®) is approved in the U.S. under
the accelerated approval program, and a supplemental Biologics
License Application (sBLA) seeking to convert its accelerated
approval to a full approval was granted Priority Review by the U.S.
Food and Drug Administration (FDA). Use of tisotumab vedotin in
recurrent or metastatic cervical cancer is not approved in the
EU.
The U.S. Prescribing Information for TIVDAK includes a BOXED
WARNING for Ocular Toxicity as well as the following
Warnings and Precautions: peripheral neuropathy, hemorrhage,
pneumonitis, severe cutaneous adverse reactions, and embryo-fetal
toxicity. Please see below for additional Important Safety
Information.
TIVDAK® (tisotumab vedotin tftv) U.S. USES AND IMPORTANT
SAFETY INFORMATION
Use
TIVDAK is indicated in the U.S. for the treatment of adult
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trials.
Important Safety Information
BOXED WARNING: OCULAR TOXICITY
TIVDAK caused changes in the corneal epithelium and
conjunctiva resulting in changes in vision, including severe vision
loss, and corneal ulceration. Conduct an ophthalmic exam at
baseline, prior to each dose, and as clinically indicated. Adhere
to premedication and required eye care before, during, and after
infusion. Withhold TIVDAK until improvement and resume, reduce the
dose, or permanently discontinue, based on severity.
WARNINGS AND PRECAUTIONS
Ocular adverse reactions occurred in 60% of patients with
cervical cancer treated with TIVDAK across clinical trials. The
most common were conjunctival adverse reactions (40%), dry eye
(29%), corneal adverse reactions (21%), and blepharitis (8%). Grade
3 ocular adverse reactions occurred in 3.8% of patients, including
severe ulcerative keratitis in 3.2% of patients. One patient
experienced ulcerative keratitis with perforation requiring corneal
transplantation. Cases of symblepharon were reported in patients
with other tumor types treated with TIVDAK at the recommended
dose.
In innovaTV 204, 4% of patients experienced visual acuity
changes to 20/50 or worse including 1% of patients who experienced
a visual acuity change to 20/200. Of the patients who experienced
decreased visual acuity to 20/50 or worse, 75% resolved, including
the patient who experienced decreased visual acuity to 20/200.
Refer patients to an eye care provider for an ophthalmic exam,
including visual acuity and slit lamp exam, at baseline, prior to
each dose, and as clinically indicated. Adhere to premedication and
required eye care to reduce the risk of ocular adverse reactions.
Promptly refer patients to an eye care provider for any new or
worsening ocular signs and symptoms. Withhold dose, reduce the
dose, or permanently discontinue TIVDAK based on the severity of
the adverse reaction.
Peripheral Neuropathy (PN) occurred in 42% of cervical
cancer patients treated with TIVDAK across clinical trials; 8% of
patients experienced Grade 3 PN. PN adverse reactions included
peripheral neuropathy (20%), peripheral sensory neuropathy (11%),
peripheral sensorimotor neuropathy (5%), motor neuropathy (3%),
muscular weakness (3%), and demyelinating peripheral polyneuropathy
(1%). One patient with another tumor type treated with TIVDAK at
the recommended dose developed Guillain-Barré syndrome.
Hemorrhage occurred in 62% of cervical cancer patients
treated with TIVDAK across clinical trials. The most common all
grade hemorrhage adverse reactions were epistaxis (44%), hematuria
(10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in
5% of patients.
Monitor patients for signs and symptoms of hemorrhage. For
patients experiencing pulmonary or central nervous system (CNS)
hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage
in any other location, withhold until bleeding has resolved, blood
hemoglobin is stable, there is no bleeding diathesis that could
increase the risk of continuing therapy, and there is no anatomical
or pathologic condition that can increase the risk of hemorrhage
recurrence. After resolution, either resume treatment or
permanently discontinue TIVDAK.
Pneumonitis that is severe, life-threatening, or fatal
can occur in patients treated with antibody-drug conjugates
containing vedotin, including TIVDAK. Among patients with cervical
cancer treated with TIVDAK across clinical trials, 2 patients
(1.3%) experienced pneumonitis, including 1 patient who had a fatal
outcome.
Monitor patients for pulmonary symptoms of pneumonitis. Symptoms
may include hypoxia, cough, dyspnea or interstitial infiltrates on
radiologic exams. Infectious, neoplastic, and other causes for
symptoms should be excluded through appropriate investigations.
Withhold TIVDAK for patients who develop persistent or recurrent
Grade 2 pneumonitis and consider dose reduction. Permanently
discontinue TIVDAK in all patients with Grade 3 or 4
pneumonitis.
Severe cutaneous adverse reactions, including events of
fatal or life-threatening Stevens-Johnson syndrome (SJS), can occur
in patients treated with TIVDAK.
Monitor patients for signs or symptoms of severe cutaneous
adverse reactions, which include target lesions, worsening skin
reactions, blistering or peeling of the skin, painful sores in
mouth, nose, throat, or genital area, fever or flu-like symptoms,
and swollen lymph nodes. If signs or symptoms of severe cutaneous
adverse reactions occur, withhold TIVDAK until the etiology of the
reaction has been determined. Early consultation with a specialist
is recommended to ensure greater diagnostic accuracy and
appropriate management. Permanently discontinue TIVDAK for
confirmed Grade 3 or 4 severe cutaneous adverse reactions,
including SJS.
Embryo-fetal toxicity: TIVDAK can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with TIVDAK and for 2
months after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with TIVDAK and for 4 months after the last
dose.
Adverse Reactions
Serious adverse reactions occurred in 43% of patients; the most
common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN,
sepsis, constipation, and pyrexia (each 3%). Fatal adverse
reactions occurred in 4% of patients who received TIVDAK, including
septic shock, pneumonitis, sudden death, and multisystem organ
failure (each 1%).
Adverse reactions leading to permanent discontinuation occurred
in 13% of patients receiving TIVDAK; the most common (≥3%) were PN
(5%) and corneal adverse reactions (4%). Adverse reactions leading
to dose interruption occurred in 47% of patients; the most common
(≥3%) were PN (8%), conjunctival adverse reactions (4%), and
hemorrhage (4%). Adverse reactions leading to dose reduction
occurred in 23% of patients; the most common (≥3%) were
conjunctival adverse reactions (9%) and corneal adverse reactions
(8%).
The most common (≥25%) adverse reactions, including laboratory
abnormalities, were hemoglobin decreased (52%), fatigue (50%),
lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia
(39%), epistaxis (39%), conjunctival adverse reactions (37%),
hemorrhage (32%), leukocytes decreased (30%), creatinine increased
(29%), dry eye (29%), prothrombin international normalized ratio
increased (26%), activated partial thromboplastin time prolonged
(26%), diarrhea (25%), and rash (25%).
Drug Interactions
Strong CYP3A4 inhibitors: Concomitant use with strong
CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E
(MMAE) exposure, which may increase the risk of TIVDAK adverse
reactions. Closely monitor patients for TIVDAK adverse
reactions.
Use in Specific Populations
Moderate or severe hepatic impairment: MMAE exposure and
adverse reactions are increased. Avoid use.
Lactation: Advise lactating women not to breastfeed
during TIVDAK treatment and for at least 3 weeks after the last
dose.
Please see full prescribing information, including BOXED
WARNING for TIVDAK here.
About Genmab
Genmab is an international biotechnology company with a core
purpose guiding its unstoppable team to strive towards improving
the lives of patients through innovative and differentiated
antibody therapeutics. For more than 20 years, its passionate,
innovative and collaborative team has invented next-generation
antibody technology platforms and leveraged translational research
and data sciences, which has resulted in a proprietary pipeline
including bispecific T-cell engagers, next-generation immune
checkpoint modulators, effector function enhanced antibodies and
antibody-drug conjugates. To help develop and deliver novel
antibody therapies to patients, Genmab has formed 20+ strategic
partnerships with biotechnology and pharmaceutical companies. By
2030, Genmab’s vision is to transform the lives of people with
cancer and other serious diseases with Knock-Your-Socks-Off (KYSO™)
antibody medicines.
Established in 1999, Genmab is headquartered in Copenhagen,
Denmark with locations in Utrecht, the Netherlands, Princeton, New
Jersey, U.S. and Tokyo, Japan. For more information, please visit
Genmab.com and follow us on Twitter.com/Genmab.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in
cancer care. Our industry-leading portfolio and extensive pipeline
includes game-changing mechanisms of action to attack cancer from
multiple angles, including antibody-drug conjugates (ADCs), small
molecules, bispecifics and other immunotherapies. We are focused on
delivering transformative therapies in some of the world’s most
common cancers, including breast cancer, genitourinary cancer and
hematologic malignancies, as well as melanoma, gastrointestinal,
gynecological and thoracic cancers, which includes lung cancer.
Driven by science, we are committed to accelerating breakthroughs
to extend and improve patients’ lives. 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 X (Twitter) at @Pfizer and @Pfizer
News, LinkedIn, YouTube and like us on Facebook at
Facebook.com/Pfizer.
About the Pfizer and Genmab Collaboration
Tisotumab vedotin is being co-developed by Genmab and Pfizer,
under an agreement in which the companies share costs and profits
for the product on a 50:50 basis.
Genmab Forward Looking Statements
This Company Announcement contains forward looking statements.
The words “believe”, “expect”, “anticipate”, “intend” and “plan”
and similar expressions identify forward looking statements. Actual
results or performance may differ materially from any future
results or performance expressed or implied by such statements. The
important factors that could cause our actual results or
performance to differ materially include, among others, risks
associated with pre-clinical and clinical development of products,
uncertainties related to the outcome and conduct of clinical trials
including unforeseen safety issues, uncertainties related to
product manufacturing, the lack of market acceptance of our
products, our inability to manage growth, the competitive
environment in relation to our business area and markets, our
inability to attract and retain suitably qualified personnel, the
unenforceability or lack of protection of our patents and
proprietary rights, our relationships with affiliated entities,
changes and developments in technology which may render our
products or technologies obsolete, and other factors. For a further
discussion of these risks, please refer to the risk management
sections in Genmab’s most recent financial reports, which are
available on www.genmab.com and the risk factors included in
Genmab’s most recent Annual Report on Form 20-F and other filings
with the U.S. Securities and Exchange Commission (SEC), which are
available at www.sec.gov. Genmab does not undertake any obligation
to update or revise forward looking statements in this Company
Announcement nor to confirm such statements to reflect subsequent
events or circumstances after the date made or in relation to
actual results, unless required by law.
Genmab A/S and/or its subsidiaries own the following trademarks:
Genmab®; the Y-shaped Genmab logo®; Genmab in combination with the
Y-shaped Genmab logo®; HuMax®; DuoBody®; HexaBody®; DuoHexaBody®
and HexElect®. Tivdak® is a trademark of Pfizer Inc.
Pfizer Disclosure Notice
The information contained in this release is as of February 2,
2024. 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 Pfizer
Oncology and TIVDAK® (tisotumab vedotin-tftv), including the MAA
pending with the EMA for TIVDAK for the treatment of adult patients
with recurrent or metastatic cervical cancer with disease
progression on or after first-line therapy, potential to convert
the accelerated approval of TIVDAK in the U.S. to full approval and
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 TIVDAK; 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 drug applications may be filed in particular jurisdictions for
TIVDAK; whether and when any applications that may be pending or
filed for TIVDAK may be approved by regulatory authorities
(including the sBLA seeking to convert the accelerated approval of
TIVDAK to full approval in the U.S. and the MAA pending with the
EMA, for the treatment of patients with recurrent or metastatic
cervical cancer with disease progression on or after first-line
therapy), 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 TIVDAK 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 TIVDAK; whether the
collaboration between Pfizer and Genmab will be successful;
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, 2022 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 US Securities and Exchange Commission and
available at www.sec.gov and www.pfizer.com.
______________________________
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Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:
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ii Torre LA, Islami F, Siegel RL, Ward EM,
Jemal A. Global Cancer in women: burden and trends. Cancer
Epidemiol Biomark Prev. 2017;26(4):444–57.
https://doi.org/10.1158/1055-9965.EPI-16-0858.
iii Arbyn M, Weiderpass E, Bruni L, de
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mortality of cervical cancer in 2018: a worldwide analysis. Lancet
Glob Health. 2020;8(2):e191–203.
https://doi.org/10.1016/S2214-109X(19)30482-6.
iv Arbyn M, Castellsagué X, de Sanjosé S,
Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical
cancer in 2008. Ann Oncol. 2011;22(12):2675–86.
https://doi.org/10.1093/annonc/mdr015.
v Waggoner SE. Cervical cancer. Lancet.
2003;361(9376):2217–2225
vi “Cervical Cancer Burden in EU-27 -
Europa.Eu.” Cancer Factsheets in EU-27 Countries, ECIS - European
Cancer Information System, 17 Nov. 2021,
ecis.jrc.ec.europa.eu/pdf/factsheets/cervical_cancer_en-Nov_2021.pdf.
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INVESTOR & MEDIA CONTACTS
Genmab A/S Contacts: For Media: David Freundel
Senior Director, Communications & Corporate Affairs (609)
613-0504 dafr@genmab.com
For Investor Relations: Andrew Carlsen Vice President, Head of
Investor Relations +45 3377-9558 acn@genmab.com
Pfizer Contacts: For Media:
PfizerMediaRelations@Pfizer.com +1 (212) 733-1226
For Investor Relations: IR@Pfizer.com +1 (212) 733-4848
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