TOKYO and BOTHELL, Wash.,
Feb. 18, 2021 /PRNewswire/
-- Astellas Pharma Inc. (TSE: 4503, President and CEO:
Kenji Yasukawa, Ph.D., "Astellas")
and Seagen Inc. (Nasdaq:SGEN) today announced completion of
submissions for two supplemental Biologics License Applications
(sBLAs) to the U.S. Food and Drug Administration (FDA) for
PADCEV® (enfortumab vedotin-ejfv). One submission, based
on the phase 3 EV-301 trial, seeks to convert PADCEV's accelerated
approval to regular approval. The second submission, based on the
pivotal trial EV-201's second cohort, requests an expansion of the
current label to include patients with locally advanced or
metastatic urothelial cancer who have been previously treated with
a PD-1/L1 inhibitor and are ineligible for cisplatin.
The FDA is reviewing both applications under the Real-Time
Oncology Review (RTOR) pilot program. The RTOR program aims to
explore a more efficient review process to ensure that safe and
effective treatments are available to patients as early as
possible.
"The FDA's review of our applications under Real-Time Oncology
Review supports our efforts to expand PADCEV's availability as a
treatment option for more patients as quickly as possible," said
Andrew Krivoshik, M.D., Ph.D.,
Senior Vice President and Oncology Therapeutic Area Head, Astellas.
"Locally advanced or metastatic urothelial cancer is an aggressive
disease with limited treatment options."
The sBLA for regular approval of PADCEV in the U.S. is supported
by data from the global EV-301 phase 3 confirmatory trial, which
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.
The trial's primary endpoint was overall survival of patients
treated with PADCEV vs. chemotherapy, and full results were
presented at the 2021 American Society of Clinical Oncology
Genitourinary Cancers Symposium (ASCO GU) and published in the
New England Journal of Medicine.[1]
The second submission, for a label expansion in the U.S., is
based on results from the second cohort of EV-201, a pivotal phase
2 clinical trial evaluating PADCEV in patients with locally
advanced or metastatic urothelial cancer who had received prior
immunotherapy treatment but were not eligible for cisplatin. The
trial's primary endpoint was objective response rate, and full
results were presented at ASCO GU.[2]
"Advanced bladder cancer patients urgently need more treatment
options," said Roger Dansey, M.D.,
Chief Medical Officer, Seagen. "Based on recently presented
clinical trial results, PADCEV could address a significant unmet
need for more patients with advanced urothelial cancer after
initial immunotherapy treatment."
In 2019 PADCEV received accelerated approval in the U.S. for the
treatment of adult patients with locally advanced or metastatic
urothelial cancer who have previously received a PD-1/L1 inhibitor
and a platinum-containing chemotherapy before (neoadjuvant) or
after (adjuvant) surgery in a locally advanced or metastatic
urothelial cancer setting. PADCEV is currently only approved for
use in the U.S.
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 the EV-201 Trial
The EV-201 trial (NCT03219333) is a single-arm, dual-cohort,
pivotal phase 2 clinical trial of enfortumab vedotin for patients
with locally advanced or metastatic urothelial cancer who have been
previously treated with a PD-1 or PD-L1 inhibitor, including those
who have also been treated with a platinum-containing chemotherapy
(cohort 1) and those who have not received a platinum-containing
chemotherapy in this setting and who are ineligible for cisplatin
(cohort 2). The trial enrolled 128 patients in cohort 1 and 91
patients in cohort 2 at multiple centers internationally. The
primary endpoint is confirmed objective response rate per blinded
independent central review. Secondary endpoints include assessments
of duration of response, disease control rate, progression-free
survival, overall survival, safety and tolerability.
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.[3] Globally, approximately 549,000 new cases of
bladder cancer and 200,000 deaths are reported
annually.[4]
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.[5]
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.5,[6]
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).5 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 potential conversion of PADCEV's
current accelerated approval in the U.S. to regular approval and
the potential expansion of the current PADCEV label to include
patients with locally advanced or metastatic urothelial cancer who
have been previously treated with a PD-1/L1 inhibitor and are
ineligible for cisplatin, 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, without limitation, the possibility that
the sBLA submissions based on the EV-301 and EV-201 second cohort
clinical trials may not be accepted for filing by, or ultimately
approved by, the FDA in a timely manner or at all; that the results
of the EV-301 clinical trial may not be sufficient to convert
PADCEV's accelerated approval in the U.S. to regular approval and
that the results of the second cohort of the EV-201 clinical trial
may not be sufficient to support the requested label expansion;
that, even if PADCEV receives regular approval and even if the
PADCEV label is expanded based on the results of the second cohort
of the EV-201 clinical trial, the product labeling may not be as
broad or desirable as requested or anticipated; and that setbacks
in the development and commercialization of PADCEV could occur as a
result of the difficulty and uncertainty of pharmaceutical product
development, the risk of adverse events or safety signals, the
failure of ongoing and subsequent clinical trials to establish
sufficient efficacy, or as a result of adverse regulatory actions.
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.
[1] Powles T, Rosenberg J, Sonpavde G, et al.
Primary Results of EV-301: A Phase 3 Trial of Enfortumab Vedotin vs
Chemotherapy in Patients With Previously Treated Locally Advanced
or Metastatic Urothelial Carcinoma. ASCO Meeting Library 2021.
https://meetinglibrary.asco.org/record/194738/abstract.
Accessed February 11, 2021.
[2] Balar AV, McGregor B, Rosenberg J, et al. EV-201
Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with
locally advanced or metastatic urothelial cancer who received prior
PD-1/PD-L1 inhibitors. ASCO Meeting Library 2021.
https://meetinglibrary.asco.org/record/194731/abstract. Accessed
February 11, 2021.
[3] American Society of Clinical Oncology. Bladder
cancer: introduction (5-2019).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed January 27, 2021.
[4] Cancer today: data visualization tools for
exploring the global cancer burden in 2020.
https://gco.iarc.fr/today/home. Accessed January 27, 2021.
[5] PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.
[6] 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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