- TIVDAK demonstrated statistically significant overall
survival, progression-free survival and objective response rate
compared to chemotherapy in late-breaking results presented at ESMO
2023 congress
- Results from innovaTV 301 intended to serve as pivotal
confirmatory trial for U.S. accelerated approval and to support
global regulatory applications
Genmab A/S (Nasdaq: GMAB) and Seagen Inc.
(Nasdaq: SGEN) announced additional results today from the
Phase 3 innovaTV 301 randomized global trial, which showed
treatment with TIVDAK demonstrated a statistically significant and
clinically meaningful 30 percent reduction in the risk of death in
recurrent or metastatic cervical cancer patients with disease
progression on or after front-line therapy, compared with
chemotherapy (HR: 0.70, 95 percent CI: 0.54-0.89, p=0.0038i).
Topline results from innovaTV 301 were disclosed earlier this year
following a pre-specified interim analysis conducted through an
independent data monitoring committee. The additional results were
presented during the Presidential Symposium at the European Society
of Medical Oncology (ESMO) Congress 2023.
“Patients with cervical cancer have few treatment options once
their cancer comes back or spreads after initial treatment,” said
Ignace B. Vergote, M.D., Ph.D., co-founder of European Network of
Gynaecological Oncological Trial groups (ENGOT), and lead
investigator on the innovaTV 301/ENGOT cx-12/GOG 3057 clinical
trial. “The positive data, seen in a representative patient
population of recurrent or metastatic cervical cancer, demonstrate
the potential for TIVDAK to reshape clinical practice and provide
hope for patients who need a new treatment option.”
TIVDAK demonstrated the following results compared with
chemotherapy across primary and key secondary efficacy
endpoints:
- Overall survival (OS) was statistically significantly prolonged
with TIVDAK, demonstrating a 30 percent reduction in the risk of
death compared with chemotherapy (Hazard ratio [HR]: 0.70 [95
percent CI: 0.54, 0.89], p=0.0038).
- Progression-free survival (PFS) results were statistically
significant with TIVDAK, demonstrating a 33 percent reduction in
the risk of disease worsening or death compared with chemotherapy
(HR: 0.67 [95 percent CI, 0.54-0.82], p<0.0001).
- The confirmed objective response rate (ORR) was also
statistically significantly improved with TIVDAK (17.8 percent)
compared with chemotherapy (5.2 percent); odds ratio: 4.0 [95
percent CI, 2.1-7.6], p<0.0001). All the complete responses were
seen in the TIVDAK arm (2.4 percent), defined as patients with no
detectable evidence of a tumor over a specified time period.
- The disease control rate (DCR), defined as the percentage of
patients who achieved complete response, partial response or stable
disease, was 75.9 percent in the TIVDAK arm compared with 58.2
percent in the chemotherapy arm.
The safety profile of TIVDAK in innovaTV 301 was consistent with
its known safety profile as presented in the U.S. prescribing
information, and no new safety signals were observed.
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.
In innovaTV 301, treatment-related adverse events (TRAEs)
occurring in patients with TIVDAK were generally low grade and
manageable with supportive care or dose modifications. The
proportion of patients who experienced TRAEs of Grade 3 or higher
with chemotherapy was 45.2 percent compared with TIVDAK (29.2
percent), and the most frequent adverse events of special interest
of Grade 3 and higher with TIVDAK include peripheral neuropathy
(5.2 percent), ocular events (3.2 percent), and bleeding events
(0.8 percent).
The results of innovaTV 301, a global, randomized, open-label
Phase 3 trial, add to the previous results of innovaTV 204, which
served as the basis for the accelerated approval of TIVDAK in the
U.S. Subject to discussions with regulatory authorities, the
results from innovaTV 301 are intended to serve as the pivotal
confirmatory trial for the U.S. accelerated approval and support
potential global regulatory applications.
“We are excited to share the additional results of the innovaTV
301 trial, which demonstrated benefit in prolonging survival in
patients with recurrent or metastatic cervical cancer compared with
chemotherapy,” said Jan van de Winkel, Ph.D., Chief Executive
Officer, Genmab. “Together with our partners at Seagen, we look
forward to discussing the results of this pivotal confirmatory
trial with regulatory authorities with a view to potentially
delivering TIVDAK to more patients in need of alternative treatment
options in the future.”
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 16
percent of adults with cervical cancer are diagnosed with
metastatic disease at diagnosisii,iii and, for adults diagnosed at
earlier stages who receive treatment, up to 61 percent will
experience disease recurrence and progress to metastatic cervical
cancer.iv It is estimated that in 2023, more than 13,960 new cases
of invasive cervical cancer will be diagnosed in the U.S. and 4,310
adults will die from the disease.v
About the innovaTV 301 Trial
The innovaTV 301 trial (NCT04697628) is a global, 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 (n=253 TIVDAK; n=249 chemotherapy) with
recurrent or metastatic cervical cancer who received no more than
two prior systemic regimens, with a median survival follow-up of
10.8 months (95 percent CI, 10.3-11.6). The treatment arms were
balanced for demographics and disease characteristics, and
reflective of the real-world patient population in advanced
cervical cancer.
Patients with recurrent or metastatic cervical cancer with
squamous cell, adenocarcinoma, or adenosquamous histology, and
disease progression during or after treatment with a standard of
care systemic chemotherapy doublet or platinum-based therapy (if
eligible) are included. The main efficacy outcome measure is
overall survival. The key secondary endpoints are progression-free
survival and objective response rate, as assessed by the
investigator, as well as safety and quality of life outcomes.
The study was conducted by Seagen 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 Seagen’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 TIVDAK 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, TIVDAK also mediates
antibody-dependent cellular phagocytosis and antibody-dependent
cellular cytotoxicity.
In September 2021, the U.S. Food and Drug Administration granted
accelerated approval for TIVDAK in adult patients with recurrent or
metastatic cervical cancer with disease progression on or after
chemotherapy. TIVDAK is the first and only approved ADC for the
treatment of these patients with recurrent or metastatic cervical
cancer with disease progression on or after chemotherapy.
Indication
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- Barre 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 Seagen
Founded 25 years ago, Seagen Inc. is a global biotechnology
company that discovers, develops, manufactures and commercializes
targeted cancer therapeutics, with antibody-drug conjugates (ADCs)
at our core. Our colleagues work together with urgency to improve
and extend the lives of people living with cancer. An ADC
technology trailblazer, approximately one-third of FDA-approved and
marketed ADCs use Seagen technology. Seagen is headquartered in
Bothell, Washington and has locations in California, Canada,
Switzerland and across Europe. For additional information, visit
www.seagen.com and follow us on Twitter and LinkedIn.
About the Seagen and Genmab Collaboration
Tisotumab vedotin is being co-developed by Genmab and Seagen,
under an agreement in which the companies share costs and profits
for the product on a 50:50 basis.
Genmab Forward Looking Statements
This Media Release 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 Media
Release 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 Seagen Inc.
Seagen Forward Looking Statements
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the potential for
results from the innovaTV 301 clinical trial to serve as the
confirmatory trial for the U.S. accelerated approval and support
global regulatory applications; plans to discuss results with
regulatory authorities; the conduct of the ongoing innovaTV 301
trial; and the therapeutic potential of TIVDAK, including its
efficacy, safety and therapeutic uses. Actual results or
developments may differ materially from those projected or implied
in these forward-looking statements. Factors that may cause such a
difference include the possibility that results from the innovaTV
301 trial may not be sufficient to support the conversion of the
U.S. accelerated approval of TIVDAK to full approval or any global
regulatory approvals; that adverse events or safety signals may
occur; that adverse regulatory actions may occur; the possibility
of delays, setbacks or failures in clinical development activities,
the submission of regulatory applications and the regulatory review
process for a variety of reasons, including the inherent difficulty
and uncertainty of pharmaceutical product development; the
inability to provide information and institute safety mitigation
measures as may be required by the FDA or other regulatory
authorities from time to time; and failure to properly conduct or
manage clinical trials. More information about the risks and
uncertainties faced by Seagen is contained under the caption “Risk
Factors” included in the Company’s Quarterly Report on Form 10-Q
for the quarter ended June 30, 2023 filed with the Securities and
Exchange Commission. Seagen disclaims any intention or obligation
to update or revise any forward-looking statements, whether as a
result of new information, future events or otherwise, except as
required by law.
________________________________ i The threshold for statistical
significance is 0.0226 (2-sided). ii National Cancer Institute.
SEER Cancer Stat Facts: Cervical Cancer. 2020.
https://seer.cancer.gov/statfacts/html/cervix.html iii 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. iv Pfaendler KS, Tewari KS.
Changing paradigms in the systemic treatment of advanced cervical
cancer. Am J Obstet Gynecol. 2016;214(1):22-30. v 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, Global Communications
& Corporate Affairs (609) 613-0504, E: dafr@genmab.com
For Investor Relations: Andrew Carlsen, Vice President, Head of
Investor Relations +45 3377 9558; E: acn@genmab.com
Seagen Contacts: For Media: David Caouette Vice
President, Corporate Communications (310) 430-3476
dcaouette@seagen.com
For Investor Relations: Douglas Maffei, Ph.D. Vice President,
Head of Investor Relations & ESG (425) 527-4160
dmaffei@seagen.com
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