TOKYO and BOTHELL, Wash., Feb.
12, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503,
President and CEO: Kenji Yasukawa,
Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced
primary results from the phase 3 EV-301 trial comparing
PADCEV® (enfortumab vedotin-ejfv) to 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. At the time of pre-specified interim
analysis, patients who received PADCEV in the trial lived a median
of 3.9 months longer than those who received chemotherapy. Median
overall survival was 12.9 vs. 9.0 months, respectively (HR=0.70 [95
percent Confidence Interval (CI): 0.56-0.89], p=0.001). For
patients in the PADCEV arm of the trial, maculopapular rash,
fatigue and decreased neutrophil count were the most frequent Grade
3 or greater treatment-related adverse events (TRAEs) occurring in
more than 5 percent of patients.
Urothelial cancer is the most common type of bladder cancer and
can also be found in the renal pelvis, ureter and
urethra.1
The findings were published in the New England Journal
of Medicine and presented during the virtual scientific program
of the 2021 American Society of Clinical Oncology Genitourinary
Cancers Symposium (ASCO GU) (Abstract 393).
"Improving survival is especially meaningful in patients who
have had their cancer progress following chemotherapy or other
treatment," said Daniel P. Petrylak,
M.D., Professor of Medicine and of Urology, Yale Cancer Center, and
corresponding author of the published study.
"Enfortumab vedotin is the first medicine to reduce the risk of
death compared to chemotherapy in patients with locally advanced or
metastatic urothelial cancer who have received a
platinum-containing chemotherapy and an immunotherapy," said
Professor Thomas Powles, M.D.,
Director, Barts Cancer Centre, Queen Mary University of
London, who presented results at
ASCO GU.
Patients who received PADCEV in the trial also showed
improvement in the following secondary endpoints:
- Median progression-free survival, which is the time without
progression of cancer, was 5.6 months for PADCEV vs. 3.7 months for
chemotherapy (HR=0.62 [95 percent CI: 0.51-0.75];
p<0.00001).
- Overall response rate, the percentage of patients with either
complete or partial response, was 40.6 percent vs. 17.9 percent of
patients in the chemotherapy arm (p<0.001).
- Disease control rate (DCR), which is the percentage of patients
who have achieved complete response, partial response or had stable
disease, was 71.9 percent for PADCEV and 53.4 percent for
chemotherapy (p<0.001).
Other safety findings included:
- Rates of serious TRAEs were comparable between treatment arms
(23 percent of patients receiving PADCEV vs. 23 percent receiving
chemotherapy).
- Grade 3 or greater TRAEs were experienced by approximately 50
percent of patients in both study arms. Grade 3 or greater TRAEs
occurring in more than 5 percent of patients receiving PADCEV were
maculopapular rash (occurring in 7 percent of patients receiving
PADCEV vs. 0 percent of patients receiving chemotherapy), fatigue
(6 percent vs. 4.5 percent) and decreased neutrophil count (6
percent vs. 13 percent).
"Patients who received PADCEV lived longer than those who
received chemotherapy – an important finding, especially in light
of the high unmet need faced by people with advanced urothelial
cancer," said Andrew Krivoshik,
M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area
Head, Astellas.
"Since its accelerated approval by the FDA in late 2019,
physicians have adopted PADCEV into their practice, and these
confirmatory results provide additional evidence of its benefit for
people living with advanced bladder cancer," said Roger Dansey, M.D., Chief Medical Officer,
Seagen.
Results of EV-301 are expected to be submitted to the U.S. Food
and Drug Administration by the end of March as the confirmatory
trial following the drug's accelerated approval in 2019. The
results of EV-301 will also be included in submissions to global
health authorities.
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
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.
About PADCEV® (enfortumab vedotin-ejfv)
PADCEV was approved by the U.S. Food and Drug Administration (FDA)
in December 2019 and is indicated for the treatment of adult
patients with locally advanced or metastatic urothelial cancer who
have previously received a programmed death receptor-1 (PD-1) or
programmed death-ligand 1 (PD-L1) inhibitor and a
platinum-containing chemotherapy before (neoadjuvant) or after
(adjuvant) surgery or in a locally advanced or metastatic setting.
PADCEV was approved under the FDA's Accelerated Approval Program
based on tumor response rate. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.3
PADCEV is a first-in-class antibody-drug conjugate (ADC) that is
directed against Nectin-4, a protein located on the surface of
cells and highly expressed in bladder cancer.3,4
Nonclinical data suggest the anticancer activity of PADCEV 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).4 PADCEV is co-developed by Astellas and
Seagen.
PADCEV Important Safety Information
Warnings and Precautions
- Hyperglycemia occurred in patients treated with PADCEV,
including death and diabetic ketoacidosis (DKA), 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.
- 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),
bullous dermatitis, exfoliative dermatitis, 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 for skin reactions.
Consider appropriate treatment, such as topical corticosteroids and
antihistamines for skin reactions, as clinically indicated. For
severe (Grade 3) skin reactions, withhold PADCEV until improvement
or resolution and administer appropriate medical treatment.
Permanently discontinue PADCEV in patients that develop Grade 4 or
recurrent Grade 3 skin reactions.
- 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 Astellas
Astellas Pharma Inc. is a
pharmaceutical company conducting business in more than 70
countries around the world. We are promoting the Focus Area
Approach that is designed to identify opportunities for the
continuous creation of new drugs to address diseases with high
unmet medical needs by focusing on Biology and Modality.
Furthermore, we are also looking beyond our foundational Rx focus
to create Rx+® healthcare solutions that combine our
expertise and knowledge with cutting-edge technology in different
fields of external partners. Through these efforts, Astellas stands
on the forefront of healthcare change to turn innovative science
into value for patients. For more information, please visit our
website at https://www.astellas.com/en.
About Seagen
Seagen Inc. is a global
biotechnology company that discovers, develops and commercializes
transformative cancer medicines to make a meaningful difference in
people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in
California, Canada, Switzerland and the European Union. For more
information on our marketed products and robust pipeline, visit
www.seagen.com and follow @SeagenGlobal on Twitter.
About the Astellas and Seagen Collaboration
Astellas
and Seagen are co-developing enfortumab vedotin under a
collaboration that was entered into in 2007 and expanded in
2009.
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 submission of data from the EV-301
trial for presentation at an upcoming scientific congress; intended
regulatory actions, including plans to submit the results of the
EV-301 trial to the FDA as the confirmatory trial following the
drug's accelerated approval in the U.S. and plans to seek global
registrations; and the therapeutic potential of PADCEV, 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 possibilities that we may experience delays
in the submission of results to the FDA; that the results from the
EV-301 trial may not be sufficient to convert PADCEV's accelerated
approval in the U.S. to regular approval or to support any other
global registrations; that, even if PADCEV receives regular
approval in the U.S. or any other global registrations, the product
labeling may not be as broad or desirable as anticipated; that
ongoing and subsequent clinical trials may fail to establish
sufficient efficacy; that adverse events or safety signals may
occur; and that adverse regulatory actions may occur. 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 (5-2019).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed January 27, 2021.
2 Cancer today: data visualization tools for
exploring the global cancer burden in 2020.
https://gco.iarc.fr/today/home. Accessed January 27, 2021.
3 PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.
4 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.
View original content to download
multimedia:http://www.prnewswire.com/news-releases/astellas-and-seagen-announce-phase-3-trial-results-demonstrating-survival-advantage-of-padcev-enfortumab-vedotin-ejfv-in-patients-with-previously-treated-advanced-urothelial-cancer-301227720.html
SOURCE Astellas Pharma Inc.