- Trial Stopped Early Due to Positive
Results at Planned Interim Analysis -
- Data Intended to Support Global
Registrations and Convert Accelerated to Regular Approval in U.S.
-
Seattle Genetics, Inc. (Nasdaq:SGEN) and Astellas Pharma Inc.
(TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”)
today announced that a phase 3 trial of PADCEV® (enfortumab
vedotin-ejfv) met its primary endpoint of overall survival compared
to chemotherapy. The results were reviewed by an independent Data
Monitoring Committee following a planned interim analysis. The
global EV-301 clinical trial compared PADCEV 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.
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In the trial, PADCEV significantly improved overall survival
(OS), with a 30 percent reduction in risk of death (Hazard Ratio
[HR]=0.70; [95% Confidence Interval (CI): 0.56, 0.89]; p=0.001).
PADCEV also significantly improved progression-free survival (PFS),
a secondary endpoint, with a 39 percent reduction in risk of
disease progression or death (HR=0.61 [95% CI: 0.50, 0.75];
p<0.00001).
For patients in the PADCEV arm of the trial, adverse events were
consistent with those listed in the U.S. Prescribing Information,
with rash, hyperglycemia, decreased neutrophil count, fatigue,
anemia and decreased appetite as the most frequent Grade 3 or
greater adverse event(s) occurring in more than 5 percent of
patients. Data from EV-301 will be submitted for presentation at an
upcoming scientific congress. Patients in the chemotherapy arm of
the trial will be offered the opportunity to receive PADCEV.
The results will be submitted to the U.S. Food and Drug
Administration (FDA) as the confirmatory trial following the drug’s
accelerated approval in 2019. EV-301 is also intended to support
global registrations.
“These survival results from the confirmatory trial for PADCEV
are welcome news for patients whose cancer has progressed after
platinum-based chemotherapy and immunotherapy,” said Roger Dansey,
M.D., Chief Medical Officer at Seattle Genetics. “We continue to
explore PADCEV’s activity across the spectrum of urothelial cancer
including its potential for use in earlier lines of therapy.”
“EV-301 is the first randomized trial to show overall survival
results compared to chemotherapy in patients with locally advanced
or metastatic urothelial cancer who previously have received
platinum-based treatment and a PD-1 or PD-L1 inhibitor, and we are
encouraged by the potential this may have in helping patients who
have otherwise limited alternatives,” said Andrew Krivoshik, M.D.,
Ph.D., Senior Vice President and Oncology Therapeutic Area Head,
Astellas. “We look forward to discussing these results with global
health authorities.”
Globally, approximately 580,000 people will be diagnosed with
bladder cancer in 2020.1 Urothelial cancer accounts for 90 percent
of all bladder cancers 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.2 Approximately 80
percent of people do not respond to PD-1 or PD-L1 inhibitors after
a platinum-containing therapy has failed as an initial treatment
for advanced disease.3
About the EV-301 Trial
The EV-301 trial (NCT03474107) is a global, multicenter,
open-label, randomized phase 3 trial designed to evaluate PADCEV
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 or PD-L1 inhibitor and platinum-based therapies. The primary
endpoint is overall survival of participants treated with PADCEV
compared to those treated with chemotherapy. Secondary endpoints
include progression-free survival, duration of response, and
overall response rate, as well as assessment of safety/tolerability
and quality-of-life parameters.
For more information about the EV-301 clinical trial, please
visit www.clinicaltrials.gov.
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.4
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.4,5 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 Seattle Genetics.
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 Seattle Genetics
Seattle Genetics, Inc. is a global biotechnology company that
discovers, develops and commercializes transformative medicines
targeting cancer to make a meaningful difference in people’s lives.
The company is headquartered in the Seattle, Washington area, with
locations in California, Switzerland and the European Union. For
more information on our robust pipeline, visit
www.seattlegenetics.com and follow @SeattleGenetics on Twitter.
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 the Seattle Genetics and Astellas Collaboration
Seattle Genetics and Astellas are co-developing PADCEV
(enfortumab vedotin-ejfv) under a 50:50 worldwide development and
commercialization collaboration that was entered into in 2007 and
expanded in 2009.
Seattle Genetics 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 discuss the results with global health
authorities and seek global registrations; conduct of a
comprehensive clinical development program for PADCEV, which
includes exploring PADCEV’s activity in other types of urothelial
cancer and its potential for use in earlier lines of therapy; the
therapeutic potential of PADCEV, including its efficacy, safety and
therapeutic uses, and anticipated development activities, including
ongoing and future clinical trials. 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 that the data from the EV-301 trial may not be
selected for presentation at scientific congresses; the possibility
of delays in the submission of results to the FDA; that the results
from the EV-301 trial may not be enough 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;
the possibility that ongoing and subsequent clinical trials may
fail to establish sufficient activity; the risk of adverse events
or safety signals; and the possibility that adverse regulatory
actions may occur. More information about the risks and
uncertainties faced by Seattle Genetics is contained under the
caption “Risk Factors” included in the company’s Quarterly Report
on Form 10-Q for the quarter ended June 30, 2020 filed with the
Securities and Exchange Commission. Seattle Genetics 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.
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.
1 International Agency for Research on Cancer. Cancer Tomorrow:
Bladder. http://gco.iarc.fr/tomorrow. Accessed 07-31-2020. 2
American Society of Clinical Oncology. Bladder cancer: introduction
(10-2017). 3 Shah, Manasee V., et al “Targeted Literature Review of
the Burden of Illness in UC” (PCN108), Nov 2018. 4 PADCEV [package
insert] Northbrook, IL: Astellas, Inc. 5 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 source
version on businesswire.com: https://www.businesswire.com/news/home/20200918005101/en/
Seattle Genetics Contacts: For Media Monique Greer Vice
President, Corporate Communications (425) 527-4641
mgreer@seagen.com
For Investors Peggy Pinkston Vice President, Investor Relations
(425) 527-4160 ppinkston@seagen.com
Astellas Contacts: For Media Chris Goldrick Associate
Director, Portfolio Communications (847) 224-3014
chris.goldrick@astellas.com
For Investors Shin Ohkubo Executive Director, Investor Relations
+81-3-3244-3202 shin.ohkubo@astellas.com
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