Company Announcement
- Full approval based on global Phase 3 study demonstrating
overall survival benefit of TIVDAK compared to
chemotherapy
- TIVDAK is the first antibody-drug conjugate in this patient
population to have positive overall survival data
Genmab A/S (Nasdaq: GMAB) and Pfizer Inc. (NYSE: PFE)
announced today the U.S. Food and Drug Administration (FDA) has
approved the supplemental Biologics License Application (sBLA) for
TIVDAK® (tisotumab vedotin-tftv) for the treatment of
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy. This FDA action converts the
September 2021 accelerated approval of TIVDAK to a full approval.
TIVDAK is the first antibody-drug conjugate (ADC) with demonstrated
overall survival data to be granted full FDA approval in this
patient population.
The approval is based on results from the global, randomized,
Phase 3 innovaTV 301 clinical trial (NCT04697628), in which TIVDAK
met its primary endpoint of overall survival (OS) in patients with
previously treated recurrent or metastatic cervical cancer compared
to chemotherapy. Secondary endpoints of progression-free survival
(PFS) and a confirmed objective response rate (ORR) were also met.
In October 2023, results from the innovaTV 301 study were initially
disclosed during the Presidential Symposium at the European Society
of Medical Oncology (ESMO) Congress.
“As a treating physician, it is encouraging to see overall
survival data among these patients and a manageable safety profile
with tisotumab vedotin,” said Brian Slomovitz, M.D., Director of
Gynecologic Oncology and Co-Chair of the Cancer Research Committee
at Mount Sinai Medical Center, Miami Beach. “Treatment options for
patients with advanced or recurrent cervical cancer are limited.
The five-year survival rate for patients who have metastatic
disease at diagnosis is less than 20% in the U.S.i There
is a high unmet need for more treatment options that have
demonstrated survival benefit in the contemporary treatment
landscape. The approval of tisotumab vedotin brings us a step
closer to fulfilling that need.”
The innovaTV 301 study met its primary endpoint of OS,
demonstrating a 30% reduction in the risk of death compared with
chemotherapy (Hazard ratio [HR]: 0.70 [95% CI: 0.54, 0.89],
two-sided p=0.0038ii). Median OS for patients treated
with TIVDAK was 11.5 months [95% CI: 9.8-14.9] versus chemotherapy
9.5 months [95% CI: 7.9-10.7].
“The full FDA approval of TIVDAK represents a significant
achievement for women with recurrent and metastatic cervical
cancer, reinforcing TIVDAK as a treatment option that has proven to
extend survival in patients whose disease has advanced after
initial treatments,” said Jan van de Winkel, Ph.D., Chief Executive
Officer of Genmab. “This milestone underscores the importance of
our ongoing clinical development program to assess the full
potential of tisotumab vedotin as a treatment option in other
indications.”
"Recurrent or metastatic cervical cancer is a particularly
devastating and mostly incurable disease, and patients are in need
of survival-extending treatment options,” said Chris Boshoff, M.D.,
Ph.D., Chief Oncology Officer, Executive Vice President at Pfizer.
“Today’s full approval by the FDA reinforces the important role of
TIVDAK for these patients, as the first antibody-drug conjugate
with statistically significant prolonged overall survival
data.”
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.
The safety profile of TIVDAK in innovaTV 301 was consistent with
its known safety profile as presented in the U.S. prescribing
information. No new safety issues were identified. The most common
(≥25%) adverse reactions, including laboratory abnormalities, in
patients receiving TIVDAK were hemoglobin decreased (41%),
peripheral neuropathy (38%), conjunctival adverse reactions (37%),
aspartate aminotransferase increased (34%), nausea (33%), alanine
aminotransferase increased (30%), fatigue (28%), sodium decreased
(27%), epistaxis (26%), and constipation (25%).
The sBLA application received a Priority Review Designation,
which is granted by the U.S. FDA to medicines that may offer
significant advances in treatment or may provide a treatment where
no adequate therapy exists.iii TIVDAK was granted
accelerated approval in the U.S. by the FDA in September 2021,
based on tumor response and durability of response from the
innovaTV 204 pivotal Phase 2 single-arm clinical trial evaluating
TIVDAK as a monotherapy in patients with previously treated
recurrent or metastatic cervical cancer.
“Today marks a great day for patients, especially adults
battling advanced cervical cancer,” said Tamika Felder, cervical
cancer patient advocate and Founder and Chief Visionary Officer,
Cervivor, Inc. “This full approval opens up new treatment paths for
this patient community who have long faced limited options.”
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% of adults with cervical cancer
present with metastatic disease at diagnosisiv,v and,
for adults diagnosed at earlier stages who receive treatment, up to
61%vi will experience disease recurrence. 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.vii
About the innovaTV 301 Trial
The innovaTV
301 trial (NCT04697628) is a global, 1:1 randomized, open-label
Phase 3 trial evaluating TIVDAK® (tisotumab
vedotin-tftv) versus investigator’s choice of single agent
chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan or
pemetrexed) in 502 patients with recurrent or metastatic cervical
cancer who received one or 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 was overall survival. The main
secondary outcomes were progression-free survival and objective
response rate.
The study was conducted by Seagen, which was acquired by Pfizer
in December 2023, 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), as well as other global gynecological oncology
cooperative groups. 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. 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.
Indication
TIVDAK is indicated for the
treatment of adult patients with recurrent or metastatic cervical
cancer (r/mCC) with disease progression on or after
chemotherapy.
Important Safety Information
BOXED WARNING: OCULAR TOXICITY
TIVDAK can cause severe ocular toxicities resulting in
changes in vision, including severe vision loss, and corneal
ulceration. Conduct an ophthalmic exam, including an assessment of
ocular symptoms, visual acuity, and slit lamp exam of the anterior
segment of the eye prior to initiation of TIVDAK, prior to every
cycle for the first nine cycles, and as clinically indicated.
Adhere to the required premedication and 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: TIVDAK can cause
severe ocular adverse reactions, including conjunctivitis,
keratopathy (keratitis, punctate keratitis, and ulcerative
keratitis), and dry eye (increased lacrimation, eye pain, eye
discharge, pruritus, irritation, and foreign body sensation), that
may lead to changes in vision and/or corneal ulceration.
Ocular adverse reactions occurred in 55% of patients with
cervical cancer treated with TIVDAK across clinical trials. The
most common were conjunctivitis (32%), dry eye (24%), keratopathy
(17%), and blepharitis (5%). Grade 3 ocular adverse reactions
occurred in 3.3% of patients, including severe ulcerative keratitis
in 1.2% of patients. Nine patients (2.1%) experienced ulcerative
keratitis (including one with perforation requiring corneal
transplantation), six (1.4%) conjunctival ulcer, four (0.9%)
corneal erosion, two (0.5%) conjunctival erosion, and two (0.5%)
symblepharon.
In innovaTV 301, 8 patients (3.2%) experienced delayed ocular
adverse reactions occurring more than 30 days after discontinuation
of TIVDAK. These adverse reactions included 3 patients with
ulcerative keratitis, and one patient (each) with keratitis,
punctate keratitis and corneal erosion, blepharitis and
conjunctival hyperemia, conjunctival scar, and conjunctivitis and
xerophthalmia.
Refer patients to an eye care provider to conduct an ophthalmic
exam prior to initiation of TIVDAK, prior to every cycle for the
first nine cycles, and as clinically indicated. The exam should
include visual acuity, slit lamp exam of the anterior segment of
the eye, and an assessment of normal eye movement and ocular signs
or symptoms which include dry or irritated eyes, eye secretions, or
blurry vision.
Adhere to the required premedication and eye care before,
during, and after infusion to reduce the risk of ocular adverse
reactions. Monitor for ocular toxicity and promptly refer patients
to an eye care provider for any new or worsening ocular signs and
symptoms. Withhold, reduce, or permanently discontinue TIVDAK based
on the severity or persistence of the ocular adverse reaction.
Peripheral Neuropathy (PN) occurred in 39% of cervical
cancer patients treated with TIVDAK across clinical trials; 6% of
patients experienced Grade 3 PN. PN adverse reactions included
peripheral sensory neuropathy (23%), PN (5%), paresthesia (3.8%),
peripheral sensorimotor neuropathy (3.3%), muscular weakness
(2.8%), and peripheral motor neuropathy (2.4%). One patient with
another tumor type treated with TIVDAK at the recommended dose
developed Guillain- Barre syndrome.
Monitor patients for signs and symptoms of neuropathy such as
paresthesia, tingling or a burning sensation, neuropathic pain,
muscle weakness, or dysesthesia. For new or worsening PN, withhold,
then dose reduce, or permanently discontinue TIVDAK based on the
severity of PN.
Hemorrhage occurred in 51% of cervical cancer
patients treated with TIVDAK across clinical trials. The most
common all grade hemorrhage adverse reaction was epistaxis (33%).
Grade 3 hemorrhage occurred in 4% of patients.
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 such
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.
Pneumonitis that is severe, life-threatening,
or fatal can occur in patients treated with antibody-drug
conjugates containing vedotin, including TIVDAK. Among cervical
cancer patients treated with TIVDAK across clinical trials, 4
patients (0.9%) 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 (SCAR),
including events of fatal or life-threatening Stevens-Johnson
syndrome (SJS), can occur in patients treated with TIVDAK. SCAR
occurred in 1.6% of cervical cancer patients treated with TIVDAK
across clinical trials. Grade ≥3 SCAR occurred in 0.5% of patients,
including 1 patient who had a fatal outcome.
Monitor patients for signs or symptoms of SCAR, 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 SCAR 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 SCAR, 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
Across clinical trials of TIVDAK in 425 patients with r/mCC, the
most common (≥25%) adverse reactions, including laboratory
abnormalities, were hemoglobin decreased (45%), PN (39%),
conjunctival adverse reactions (38%), nausea (37%), fatigue (36%),
aspartate aminotransferase increased (33%), epistaxis (33%),
alopecia (31%), alanine aminotransferase increased (30%), and
hemorrhage (28%).
innovaTV 301 Study: 250 patients with r/mCC with disease
progression on or after systemic therapy
Serious adverse reactions occurred in 33% of patients
receiving TIVDAK; the most common (≥2%) were urinary tract
infection (4.8%), small intestinal obstruction (2.4%), sepsis,
abdominal pain, and hemorrhage (each 2%). Fatal adverse
reactions occurred in 1.6% of patients who received TIVDAK,
including acute kidney injury, pneumonia, sepsis, and SJS (each
0.4%).
Adverse reactions leading to permanent discontinuation
occurred in 15% of patients receiving TIVDAK; the most common (≥3%)
were PN and ocular adverse reactions (each 6%). Adverse
reactions leading to dose interruption occurred in 39% of
patients receiving TIVDAK; the most common (≥3%) were ocular
adverse reactions (16%) and PN (6%). Adverse reactions leading
to dose reduction occurred in 30% of patients receiving TIVDAK;
the most common (≥3%) were PN and ocular adverse reactions (each
10%). The ocular adverse reactions included conjunctival disorders
(4.8%), keratopathy (4%), and dry eye (0.8%).
innovaTV 204 Study: 101 patients with r/mCC with disease
progression on or after chemotherapy
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, and hemorrhage (each 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%).
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 25 years, its passionate,
innovative and collaborative team has invented next-generation
antibody technology platforms and leveraged translational,
quantitative, and data sciences, resulting 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 LinkedIn and X.
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,
bispecific antibodies and other immunotherapy biologics. We are
focused on delivering transformative therapies in some of the
world’s most common cancers, including breast cancer, genitourinary
cancer, hematology-oncology and thoracic cancers, which includes
lung cancer. Driven by science, we are committed to accelerating
breakthroughs to extend and improve patients’ lives.
About the Pfizer and Genmab Collaboration
Tisotumab vedotin is co-owned 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 April 29,
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 its potential
benefits and its ongoing clinical development program, 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, 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, 2023 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.
i Cervical Cancer: Statistics. American Society of
Clinical Oncology (ASCO). September 2023.
https://www.cancer.net/cancer-types/cervical-cancer/statistics
ii The threshold for statistical significance is 0.0226
(two-sided).
iii Priority Review. U.S. Food and Drug Administration.
January 4, 2018.
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review
iv National Cancer Institute. SEER Cancer Stat Facts:
Cervical Cancer. 2023.
https://seer.cancer.gov/statfacts/html/cervix.html
v 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.
vi Pfaendler KS, Tewari KS. Changing paradigms in the
systemic treatment of advanced cervical cancer. Am J Obstet
Gynecol. 2016 Jan;214(1):22-30. doi: 10.1016/j.ajog.2015.07.022.
Epub 2015 Jul 26. PMID: 26212178; PMCID: PMC5613936.
vii 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 and Media Contacts:
Genmab A/S Contacts:
For Media:
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Corporate Affairs
T: +1 (609) 524-0065; E: mmp@genmab.com
For Investor Relations:
Andrew Carlsen, Vice President, Head of Investor Relations
T: +45 3377-9558; E: acn@genmab.com
Pfizer Contacts:
For Media:
PfizerMediaRelations@Pfizer.com
+1 (212) 733-1226
For Investor Relations:
IR@Pfizer.com
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