TOKYO and BOTHELL, Wash., Feb.
19, 2020 /PRNewswire/ -- Astellas Pharma Inc. (TSE:
4503, President and CEO: Kenji
Yasukawa, Ph.D., "Astellas") and Seattle Genetics, Inc.
(Nasdaq:SGEN) today announced that the U.S. Food and Drug
Administration (FDA) has granted Breakthrough Therapy designation
for PADCEV™ (enfortumab vedotin-ejfv) in combination
with Merck's (known as MSD outside the
United States and Canada)
anti-PD-1 therapy KEYTRUDA® (pembrolizumab) for the
treatment of patients with unresectable locally advanced or
metastatic urothelial cancer who are unable to receive
cisplatin-based chemotherapy in the first-line setting.
The FDA's Breakthrough Therapy process is designed to expedite
the development and review of drugs that are intended to treat a
serious or life-threatening condition. Designation is based upon
preliminary clinical evidence indicating that the drug may
demonstrate substantial improvement over available therapies on one
or more clinically significant endpoints.
"The FDA's Breakthrough Therapy designation reflects the
encouraging preliminary evidence for the combination of PADCEV and
pembrolizumab in previously untreated advanced urothelial cancer to
benefit patients who are in need of effective treatment options,"
said Andrew Krivoshik, M.D., Ph.D.,
Senior Vice President and Oncology Therapeutic Area Head, Astellas.
"We look forward to continuing our work with the FDA as we progress
our clinical development program as quickly as possible."
"This is an important step in our investigation of PADCEV in
combination with pembrolizumab as a first-line therapy for patients
with advanced urothelial cancer who are unable to receive
cisplatin-based chemotherapy," said Roger
Dansey, M.D., Chief Medical Officer, Seattle Genetics.
"Based on encouraging early clinical activity, we recently
initiated a phase 3 trial of this platinum-free combination and
look forward to potentially addressing an unmet need for
patients."
The Breakthrough Therapy designation was granted based on
results from the dose-escalation cohort and expansion cohort A of
the phase 1b/2 trial, EV-103
(NCT03288545), evaluating patients with locally advanced or
metastatic urothelial cancer who are unable to receive
cisplatin-based chemotherapy treated in the first-line setting
with PADCEV in combination with pembrolizumab. Initial results from
the trial were presented at the European Society of Medical
Oncology (ESMO) 2019 Congress, and updated findings at the 2020
Genitourinary Cancers Symposium. EV-103 is an ongoing,
multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination,
evaluating safety, tolerability and efficacy in muscle invasive,
locally advanced and first- and second-line metastatic urothelial
cancer.
About Bladder and Urothelial Cancer
It is estimated that approximately 81,000 people in the U.S. 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, ureter and urethra.2
Globally, approximately 549,000 people were diagnosed with
bladder cancer in 2018, and there were approximately 200,000 deaths
worldwide.3
The recommended first-line treatment for patients
with advanced urothelial cancer is a cisplatin-based
chemotherapy. For patients who are unable to receive cisplatin,
such as people with kidney impairment, a carboplatin-based regimen
is recommended. However, fewer than half of patients respond to
carboplatin-based regimens and outcomes are typically poorer
compared to cisplatin-based regimens.4
About PADCEV
PADCEV (enfortumab vedotin-ejfv) 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 Seattle Genetics.
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, hemoglobin decreased, phosphate
decreased, lipase increased, sodium decreased, glucose increased,
urate increased, neutrophils decreased.
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., based in Tokyo,
Japan, is a company dedicated to improving the health of
people around the world through the provision of innovative and
reliable pharmaceutical products. 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 Bothell,
Washington, and has offices 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
Seattle Genetics and Astellas are co-developing PADCEV (enfortumab
vedotin-ejfv) under a collaboration that was entered into in 2007
and expanded in 2009. Under the collaboration, the companies are
sharing costs and profits on a 50:50 basis worldwide.
About the Astellas, Seattle Genetics and Merck
Collaboration
Seattle Genetics and Astellas entered a clinical collaboration
agreement with Merck to evaluate the combination of Seattle
Genetics' and Astellas' PADCEV™ (enfortumab vedotin-ejfv) and
Merck's KEYTRUDA® (pembrolizumab), in patients with
previously untreated metastatic urothelial cancer. KEYTRUDA is a
registered trademark of Merck Sharp & Dohme Corp., a subsidiary
of Merck & Co., Inc., Kenilworth,
NJ, USA.
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 development of PADCEV
in combination with pembrolizumab as a first-line therapy for
patients with advanced urothelial cancer who are unable to
receive cisplatin-based chemotherapy, 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 possibility 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 Seattle
Genetics is contained under the caption "Risk Factors" included in
the company's Annual Report on Form 10-K for the year ended
December 31, 2019 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 American Cancer Society. Cancer Facts &
Figures
2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed
01-23-2020.
2 American Society of Clinical Oncology. Bladder
cancer: introduction (10-2017).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed 05-09-2019.
3 International Agency for Research on Cancer.
Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow
4 National Comprehensive Cancer Network (NCCN).
NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer.
Version 4; July 10, 2019.
https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.
5 PADCEV [package insert]. Northbrook, IL: Astellas, 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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