- TIVDAK sBLA accepted for priority review, FDA action date is
May 9, 2024
- Submission based on positive results from global phase 3
innovaTV 301 trial demonstrating overall survival benefit of
tisotumab vedotin-tftv over chemotherapy
Genmab A/S (Nasdaq: GMAB) and Pfizer, Inc. (NYSE: PFE) announced
today that the U.S. Food and Drug Administration (FDA) has accepted
the supplemental Biologics License Application (sBLA) seeking to
convert the accelerated approval of TIVDAK® (tisotumab
vedotin-tftv) to full approval, for the treatment of patients with
recurrent or metastatic cervical cancer with disease progression on
or after first-line therapy. The application has been granted
Priority Review with a Prescription Drug User Fee Act (PDUFA)
action date of May 9, 2024.
The sBLA is supported by efficacy and safety data from the
global, randomized Phase 3 innovaTV 301 trial (NCT04697628), in
which tisotumab vedotin-tftv demonstrated superior overall survival
(OS), progression-free survival (PFS) and confirmed objective
response rate (ORR), as assessed by the investigator, in patients
with recurrent or metastatic cervical cancer compared to
chemotherapy. The safety profile of tisotumab vedotin-tftv in
innovaTV 301 was consistent with its known safety profile as
presented in the U.S. prescribing information. In October 2023,
results from the innovaTV 301 study were presented during the
Presidential Symposium at the European Society of Medical Oncology
(ESMO) Congress.
“Therapeutic options for metastatic cervical cancer that not
only demonstrate a survival advantage but also include a novel
approach to treating this condition are needed,” said Jan van de
Winkel, Ph.D., Chief Executive Officer, Genmab. “This milestone
underscores our commitment to continuing to deliver TIVDAK as a
treatment option to women in the U.S. diagnosed with cervical
cancer whose disease has progressed after first-line
treatment.”
“The Phase 3 innovaTV 301 trial demonstrated a favorable
benefit/risk profile, including improvement in overall survival,
and adds to the overall data supporting TIVDAK as a treatment
option for people with recurrent and metastatic cervical cancer who
have limited treatment options,” said Roger Dansey, M.D., Chief
Development Officer, Oncology, Pfizer. “The FDA acceptance of our
sBLA for review is important progress toward continuing to offer an
option that can extend the lives of more adults with cervical
cancer.”
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. Recurrent and/or metastatic cervical cancer is a
particularly devastating and mostly incurable disease; up to 15
percent of adults with cervical cancer are diagnosed with
metastatic disease at diagnosis1,2 and, for adults diagnosed at
earlier stages who receive treatment, up to 31.5 percent will
experience disease recurrence.3 It was estimated that, in 2023,
more than 13,960 new cases of invasive cervical cancer were
diagnosed in the U.S. and 4,310 adults would die from the
disease.4
About the innovaTV 301 Trial
The innovaTV 301 trial (NCT04697628) is a global, randomized,
open-label Phase 3 trial evaluating tisotumab vedotin-tftv 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 TIVDAK (tisotumab vedotin-tftv)
TIVDAK (tisotumab vedotin-tftv) 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-tftv 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-tftv also mediates antibody-dependent cellular phagocytosis
and antibody-dependent cellular cytotoxicity.
TIVDAK was granted accelerated approval in the U.S. by the FDA
in September 2021. The accelerated approval is based on tumor
response and durability of response 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. The data from innovaTV 301 will support global
regulatory submissions.
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®,HexElect® and KYSO™. Tivdak® is a trademark of Pfizer
Inc.
Pfizer Disclosure Notice
The information contained in this release is as of January 9,
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 potential
to convert the accelerated approval of TIVDAK to full approval,
potential benefits and plans for data from innovaTV 301 to support
global regulatory submissions, 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, 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 U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
1 National Cancer Institute. SEER Cancer Stat Facts: Cervical
Cancer. 2023. https://seer.cancer.gov/statfacts/html/cervix.html 2
McLachlan J, Boussios S, Okines A, et al. The impact of systemic
therapy beyond first-line treatment for advanced cervical cancer.
Clin Oncol (R Coll Radiol). 2017;29(3):153-60. 3 de Foucher T,
Bendifallah S, Ouldamer L, et al. Patterns of recurrence and
prognosis in locally advanced FIGO stage IB2 to IIB cervical
cancer: retrospective multicentre study from the FRANCOGYN Group.
Eur J Surg Oncol. 2019;45:659–665. doi: 10.1016/j.ejso.2018.11.014.
4 Key Statistics for Cervical Cancer. American Cancer Society.
Atlanta, GA. 2023.
https://www.cancer.org/cancer/types/cervical-cancer/about/key-statistics.html
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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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