- TIVDAK is the first antibody-drug conjugate (ADC) to have
positive overall survival data for patients with previously treated
recurrent or metastatic cervical cancer
- Conversion to full approval from accelerated approval is based
on positive results from global Phase 3 study demonstrating overall
survival benefit of TIVDAK compared to chemotherapy
Pfizer Inc. (NYSE: PFE) and Genmab A/S (Nasdaq: GMAB) today
announced the U.S. Food and Drug Administration (FDA) approves the
supplemental Biologics License Application (sBLA) granting full
approval for TIVDAK® (tisotumab vedotin-tftv) for the treatment of
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy.
"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 approval is based on results from the global, randomized,
Phase 3 innovaTV 301 clinical trial (NCT04697628), which met its
primary endpoint, demonstrating overall survival (OS) benefit in
adult patients with previously treated recurrent or metastatic
cervical cancer treated with TIVDAK compared to chemotherapy.
Secondary endpoints of progression-free survival (PFS) and
confirmed objective response rate (ORR) were also met. In October
2023, results from the innovaTV 301 study were presented during the
Presidential session at the European Society of Medical Oncology
(ESMO) Congress.
The innovaTV 301 study demonstrated a 30% reduction in the risk
of death compared to chemotherapy (hazard ratio [HR]: 0.70 [95% CI:
0.54-0.89], two-sided p=0.0038)i. 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.”
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%).
“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.ii 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 sBLA application received a Priority Review Designation,
which is granted by the FDA to medicines that may offer significant
advances in treatment or may provide a treatment where no adequate
therapy exists.iii TIVDAK was originally 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 in patients
with previously treated recurrent or metastatic cervical cancer.
The FDA’s approval of the sBLA converts the accelerated approval
for TIVDAK to full approval in the U.S.
“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 chemotherapy 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. TIVDAK
received accelerated approval from the U.S. FDA in September 2021
for adult patients with recurrent or metastatic cervical cancer
with disease progression on or after chemotherapy.
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 signs and symptoms of hemorrhage. For
patients experiencing pulmonary or central nervous system
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 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 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.
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 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 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 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.
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.
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.comand 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.
i The threshold for statistical significance is 0.0226
(two-sided). ii Cervical Cancer: Statistics. American Society of
Clinical Oncology (ASCO). September 2023.
https://www.cancer.net/cancer-types/cervical-cancer/statistics 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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