- Submissions will be Reviewed Under
Real-Time Oncology Review Based on Clinical Trials EV-301 and
Cohort 2 of EV-201 -
Seagen Inc. (Nasdaq:SGEN) and Astellas Pharma Inc. (TSE: 4503,
President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) 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 Seagen and Astellas.
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 drugson 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 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 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 Seagen and Astellas Collaboration
Seagen and Astellas are co-developing enfortumab vedotin under a
collaboration that was entered into in 2007 and expanded in
2009.
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.
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.
References
_________________________________
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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version on businesswire.com: https://www.businesswire.com/news/home/20210218005258/en/
Seagen Contacts: For Media and 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 Astellas Pharma
Inc. Corporate Advocacy & Relations TEL: +81-3-3244-3201 FAX:
+81-3-5201-7473
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