TOKYO and BOTHELL, Wash., Sept.
18, 2020 /PRNewswire/ -- Astellas Pharma
Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle
Genetics, Inc. (Nasdaq:SGEN) 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.
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.
"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."
"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."
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 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 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 the Astellas and Seattle Genetics
Collaboration
Astellas and Seattle Genetics 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.
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.
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.
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.
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