- Enfortumab vedotin to be reviewed under
accelerated assessment for the treatment of locally advanced or
metastatic urothelial cancer -
Astellas Pharma Inc. (TSE: 4503, President and
CEO: Kenji Yasukawa, Ph.D., “Astellas”) and Seagen Inc.
(Nasdaq:SGEN) today announced that a marketing authorization
application (MAA) for enfortumab vedotin was accepted by the
European Medicines Agency (EMA). The MAA requests review of
enfortumab vedotin for the treatment of adult patients with locally
advanced or metastatic urothelial cancer who have received a
programmed death receptor-1 (PD-1) or programmed death-ligand 1
(PD-L1) inhibitor and who have received a platinum-containing
chemotherapy in the neoadjuvant/adjuvant, locally advanced or
metastatic setting. If approved, enfortumab vedotin would be the
first antibody-drug conjugate (ADC) available in the European Union
for people living with urothelial cancer.
Enfortumab vedotin will be reviewed under accelerated
assessment, which means the EMA’s Committee for Medicinal Products
for Human Use (CHMP) can reduce the timeframe for evaluation.
The MAA is based on the global phase 3 EV-301 trial, which
evaluated enfortumab vedotin versus chemotherapy in adult patients
with locally advanced or metastatic urothelial cancer who were
previously treated with platinum-based chemotherapy and a PD-1/L1
inhibitor. Results from the trial, which had a primary endpoint of
overall survival for patients treated with PADCEV versus
chemotherapy, were published in the New England Journal of
Medicine.
“In the European Union, it is estimated that 118,000 people are
diagnosed with urothelial cancer each year, and 52,000 die as a
result of the disease,” said Andrew Krivoshik, M.D., Ph.D., Senior
Vice President and Oncology Therapeutic Area Head, Astellas.
“People with advanced urothelial cancer face an urgent need for new
treatment options, which is reflected in the CHMP’s decision to
grant accelerated assessment. We will continue to work with the
CHMP toward our goal of securing marketing authorization as soon as
possible.”
About Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90
percent of cases), and can also be found in the renal pelvis (where
urine collects inside the kidney), ureter (tube that connects the
kidneys to the bladder) and urethra.1 Globally, approximately
549,000 new cases of bladder cancer and 200,000 deaths are reported
annually.2 In Europe, it is estimated that 118,000 patients are
diagnosed with this form of cancer and 52,000 deaths are reported
annually.3
Locally advanced and metastatic urothelial cancer is an
aggressive disease that is associated with poor survival and high
healthcare costs.4 Five-year relative survival rates for metastatic
disease are estimated to be approximately 7 percent.5
About the EV-301 Trial
The EV-301 trial (NCT03474107) is a global, multicenter,
open-label, randomized phase 3 trial designed to evaluate
enfortumab vedotin versus physician's choice of chemotherapy
(docetaxel, paclitaxel or vinflunine) in approximately 600 patients
with locally advanced or metastatic urothelial cancer who were
previously treated with a PD-1/L1 inhibitor and platinum-based
therapies. The primary endpoint is overall survival and secondary
endpoints include progression-free survival, overall response rate,
duration of response and disease control rate, as well as
assessment of safety/tolerability and quality-of-life
parameters.6
About Enfortumab Vedotin
Enfortumab vedotin is an antibody-drug conjugate (ADC) that is
directed against Nectin-4, a protein located on the surface of
cells and highly expressed in bladder cancer.7,8 Nonclinical data
suggest the anticancer activity of enfortumab vedotin is due to its
binding to Nectin-4 expressing cells followed by the
internalization and release of the anti-tumor agent monomethyl
auristatin E (MMAE) into the cell, which result in the cell not
reproducing (cell cycle arrest) and in programmed cell death
(apoptosis).8
PADCEV (enfortumab vedotin-ejfv) U.S. Important Safety
Information
Warnings and Precautions
Skin reactions: Severe cutaneous adverse reactions,
including fatal cases of Stevens-Johnson syndrome (SJS) or toxic
epidermal necrolysis (TEN), occurred in patients treated with
PADCEV. SJS and TEN occurred predominantly during the first cycle
of treatment but may occur later.
Skin reactions occurred in 54% of the 310 patients treated with
PADCEV in clinical trials. Twenty-six percent (26%) of patients had
maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions
occurred in 10% of patients and included symmetrical drug-related
intertriginous and flexural exanthema (SDRIFE), dermatitis bullous,
dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In
one clinical trial, the median time to onset of severe skin
reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who
experienced rash, 65% had complete resolution and 22% had partial
improvement.
Monitor patients closely throughout treatment for skin
reactions. Consider topical corticosteroids and antihistamines as
clinically indicated. Withhold PADCEV and consider referral for
specialized care for severe (Grade 3) skin reactions, suspected
SJS, or TEN. Permanently discontinue PADCEV in patients with
confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin
reactions.
Hyperglycemia occurred in patients treated with PADCEV,
including death and diabetic ketoacidosis, in those with and
without pre-existing diabetes mellitus. The incidence of Grade 3-4
hyperglycemia increased consistently in patients with higher body
mass index and in patients with higher baseline A1C. In one
clinical trial, 8% of patients developed Grade 3-4 hyperglycemia.
Patients with baseline hemoglobin A1C ≥8% were excluded. Closely
monitor blood glucose levels in patients with, or at risk for,
diabetes mellitus or hyperglycemia. If blood glucose is elevated
(>250 mg/dL), withhold PADCEV.
Peripheral neuropathy (PN), predominantly sensory,
occurred in 49% of the 310 patients treated with PADCEV in clinical
trials; 2% experienced Grade 3 reactions. In one clinical trial,
peripheral neuropathy occurred in patients treated with PADCEV with
or without preexisting peripheral neuropathy. The median time to
onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy
led to treatment discontinuation in 6% of patients. At the time of
their last evaluation, 19% had complete resolution, and 26% had
partial improvement. Monitor patients for symptoms of new or
worsening peripheral neuropathy and consider dose interruption or
dose reduction of PADCEV when peripheral neuropathy occurs.
Permanently discontinue PADCEV in patients that develop Grade ≥3
peripheral neuropathy.
Ocular disorders occurred in 46% of the 310 patients
treated with PADCEV. The majority of these events involved the
cornea and included keratitis, blurred vision, limbal stem cell
deficiency and other events associated with dry eyes. Dry eye
symptoms occurred in 36% of patients, and blurred vision occurred
in 14% of patients, during treatment with PADCEV. The median time
to onset to symptomatic ocular disorder was 1.9 months (range: 0.3
to 6.2). Monitor patients for ocular disorders. Consider artificial
tears for prophylaxis of dry eyes and ophthalmologic evaluation if
ocular symptoms occur or do not resolve. Consider treatment with
ophthalmic topical steroids, if indicated after an ophthalmic exam.
Consider dose interruption or dose reduction of PADCEV for
symptomatic ocular disorders.
Infusion site extravasation: Skin and soft tissue
reactions secondary to extravasation have been observed after
administration of PADCEV. Of the 310 patients, 1.3% of patients
experienced skin and soft tissue reactions. Reactions may be
delayed. Erythema, swelling, increased temperature, and pain
worsened until 2-7 days after extravasation and resolved within 1-4
weeks of peak. One percent (1%) of patients developed extravasation
reactions with secondary cellulitis, bullae, or exfoliation. Ensure
adequate venous access prior to starting PADCEV and monitor for
possible extravasation during administration. If extravasation
occurs, stop the infusion and monitor for adverse reactions.
Embryo-fetal toxicity: PADCEV can cause fetal harm when
administered to a pregnant woman. Advise patients of the potential
risk to the fetus. Advise female patients of reproductive potential
to use effective contraception during PADCEV treatment and for 2
months after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with PADCEV and for 4 months after the last
dose.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients treated
with PADCEV. The most common serious adverse reactions (≥3%) were
urinary tract infection (6%), cellulitis (5%), febrile neutropenia
(4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea
(3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of
patients, including acute respiratory failure, aspiration
pneumonia, cardiac disorder, and sepsis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of
patients; the most common adverse reaction leading to
discontinuation was peripheral neuropathy (6%). Adverse reactions
leading to dose interruption occurred in 64% of patients; the most
common adverse reactions leading to dose interruption were
peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse
reactions leading to dose reduction occurred in 34% of patients;
the most common adverse reactions leading to dose reduction were
peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (≥20%) were fatigue (56%),
peripheral neuropathy (56%), decreased appetite (52%), rash (52%),
alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry
eye (40%), pruritus (26%) and dry skin (26%). The most common Grade
≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and
fatigue (6%).
Lab Abnormalities
In one clinical trial, Grade 3-4 laboratory abnormalities
reported in ≥5% were: lymphocytes decreased (10%), hemoglobin
decreased (10%), phosphate decreased (10%), lipase increased (9%),
sodium decreased (8%), glucose increased (8%), urate increased
(7%), neutrophils decreased (5%).
Drug Interactions
Effects of other drugs on PADCEV Concomitant use with a
strong CYP3A4 inhibitor may increase free MMAE exposure, which may
increase the incidence or severity of PADCEV toxicities. Closely
monitor patients for signs of toxicity when PADCEV is given
concomitantly with strong CYP3A4 inhibitors.
Specific Populations
Lactation Advise lactating women not to breastfeed during
treatment with PADCEV and for at least 3 weeks after the last
dose.
Hepatic impairment Avoid the use of PADCEV in patients
with moderate or severe hepatic impairment.
For more information, please see the full Prescribing
Information for PADCEV here.
About the Astellas and Seagen Collaboration
Astellas and Seagen Inc. are co-developing enfortumab vedotin
under a 50:50 worldwide development and commercialization
collaboration. In the United States, Astellas and Seagen co-promote
enfortumab vedotin under the brand name PADCEV® (enfortumab
vedotin-ejfv). In the Americas outside the US, Seagen holds
responsibility for commercialization activities and regulatory
filings. Outside of the Americas, Astellas holds responsibility for
commercialization activities and regulatory filings.
Astellas Cautionary Notes
In this press release, statements made with respect to current
plans, estimates, strategies and beliefs and other statements that
are not historical facts are forward-looking statements about the
future performance of Astellas. These statements are based on
management’s current assumptions and beliefs in light of the
information currently available to it and involve known and unknown
risks and uncertainties. A number of factors could cause actual
results to differ materially from those discussed in the
forward-looking statements. Such factors include, but are not
limited to: (i) changes in general economic conditions and in laws
and regulations, relating to pharmaceutical markets, (ii) currency
exchange rate fluctuations, (iii) delays in new product launches,
(iv) the inability of Astellas to market existing and new products
effectively, (v) the inability of Astellas to continue to
effectively research and develop products accepted by customers in
highly competitive markets, and (vi) infringements of Astellas’
intellectual property rights by third parties.
Information about pharmaceutical products (including products
currently in development), which is included in this press release
is not intended to constitute an advertisement or medical
advice.
Seagen Forward Looking Statements
Certain statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential of enfortumab vedotin, including its efficacy, safety and
therapeutic uses; and the potential to obtain regulatory approval
of enfortumab vedotin in the European Union. 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, without limitation, the possibility that
enfortumab vedotin may not ultimately be approved in the European
Union for the treatment of adult patients with locally advanced or
metastatic urothelial cancer who have received a programmed death
receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor
and who have received a platinum-containing chemotherapy in the
neoadjuvant/adjuvant, locally advanced or metastatic setting, in a
timely manner or at all; and that setbacks in the development and
commercialization of enfortumab vedotin could occur as a result of
the difficulty and uncertainty of pharmaceutical product
development, the risk of adverse events or safety signals, failure
to establish sufficient efficacy in clinical trials, adverse
regulatory actions or other factors. More information about the
risks and uncertainties faced by Seagen is contained under the
caption “Risk Factors” included in the company’s Annual Report on
Form 10-K for the year ended December 31, 2020 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.
References _______________________________
1 American Society of Clinical Oncology. Bladder cancer:
introduction. Published October 2017.
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed March 4, 2021. 2 Cancer today: data visualization tools
for exploring the global cancer burden in 2020.
https://gco.iarc.fr/today/home. Accessed March 4, 2021. 3 Wong MC,
Fung FD, Leung C, et al. Scientific Reports. 2018;8(1):1129. 4 Shah
MV, McGovern A, Hepp Z. Targeted Literature Review of the Burden of
Illness in UC (PCN108). Value Health. 2018;21(3):S32-S33. 5 von der
Maase H, Sengelov L, Roberts J, Ricci S, et al. Long term survival
results of a randomized trial comparing gemcitabine plus cisplatin,
with methotrexate, vinblastine, doxorubicin, plus cisplatin in
patients with bladder cancer. J Clin Oncol. 2005;23(21):4602 8. 6
Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in
Previously Treated Advanced Urothelial Carcinoma. N Engl J Med.
2021; 10.1056/NEJMoa2035807. 7 PADCEV [package insert]. Northbrook,
IL: Astellas Pharma Inc. 8 Challita-Eid P, Satpayev D, Yang P, et
al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4
Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer
Models. Cancer Res 2016;76(10):3003-13.
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Astellas Contacts: For Media Chris Goldrick Associate
Director, Portfolio Communications (847) 224-3014
chris.goldrick@astellas.com
For Investors Astellas Pharma Inc. Corporate Advocacy &
Relations TEL: +81-3-3244-3201 FAX: +81-3-5201-7473
Seagen Contact: For Media and Investors Peggy Pinkston
Senior Vice President, Investor Relations (425) 527-4160
ppinkston@seagen.com
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