TOKYO and BOTHELL, Wash., Feb.
12, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE:
4503, President and CEO: Kenji
Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN)
today announced results from the second cohort (cohort 2) of
patients in the pivotal phase 2 single-arm EV-201 trial. In the
trial, 52 percent of patients who received PADCEV®
(enfortumab vedotin-ejfv) had an objective response (95 percent
Confidence Interval [CI]: 40.8, 62.4) and the median duration of
response was 10.9 months (95 percent CI: 5.8, NR). Twenty percent
of patients had a complete response, the absence of detectable
cancer, after PADCEV treatment, and 31 percent had a partial
response. Adverse events were consistent with those observed in
previous trial data, with the most common all-grade
treatment-related adverse events (AEs) being alopecia (51 percent),
peripheral sensory neuropathy (47 percent), and fatigue (34
percent).
Cohort 2 of the EV-201 trial evaluated PADCEV in patients with
locally advanced or metastatic urothelial cancer who had been
previously treated with a PD-1/L1 inhibitor, had not received a
platinum-containing chemotherapy in this setting, and were
ineligible for cisplatin. Urothelial cancer is the most common type
of bladder cancer and can also be found in the renal pelvis, ureter
and urethra.1
The findings were presented today in an oral presentation
as part of the virtual scientific program of the American Society
of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU)
(Abstract 394).
"Roughly half of all patients with locally advanced or
metastatic urothelial cancer have comorbidities that make them
ineligible for cisplatin-based chemotherapy and after progression
on first-line immunotherapy, there are few effective treatment
options," said Arjun Balar, M.D.,
Associate Professor of Medicine, Director Genitourinary Medical
Oncology Program, NYU Laura and Isaac Perlmutter Cancer Center, NYU
Langone Health and an investigator for the trial. "Results from
EV-201 cohort 2 indicate that enfortumab vedotin may be an
important therapeutic option for these patients."
"Fifty-two percent of patients in this study cohort responded to
PADCEV – including some patients who showed no detectable cancer
following treatment – an important result for people with this
difficult-to-treat form of urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice
President and Oncology Therapeutic Area Head, Astellas.
"We're pleased that PADCEV provided meaningful clinical benefit
to a group of patients who historically have very few options and
may choose not to pursue further treatment for the disease," said
Roger Dansey, M.D., Chief Medical
Officer, Seagen.
The results are expected to be submitted to the U.S. Food and
Drug Administration by the end of March as part of a supplemental
biologics licensing application. EV-201 results will also be
included in submissions to some global health authorities.
EV-201 Cohort 2 Trial Results
In cohort 2 of the
dual-cohort trial, 52 percent of patients who received PADCEV had
an objective response (46/89); (95 percent CI: 40.8, 62.4) per
blinded independent central review (the primary endpoint), with
20 percent of patients (18/89) experiencing a complete
response and 31 percent of patients experiencing a partial response
(28/89).
In the trial's secondary endpoints, duration of response lasted
a median of 10.9 months (95 percent CI: 5.8, NR). Patients
lived a median of 5.8 months without cancer progression
(progression-free survival) (95 percent CI: 5.0, 8.3), and had a
median overall survival of 14.7 months (95 percent CI:
10.5,18.2).
Grade 3 or greater treatment-related AEs of interest included
skin reactions (17 percent), peripheral neuropathy (8 percent) and
hyperglycemia (6 percent). Four deaths were reported as
treatment-related by investigators in patients age 75 years and
older with multiple comorbidities.
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.1 Globally, approximately 549,000 new cases of
bladder cancer and 200,000 deaths are reported
annually.2
About the EV-201 Trial
The EV-201 trial (NCT03219333)
is a single-arm, 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 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.3
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.3,4
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
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 submission of data from cohort 2 of
the EV-201 trial for presentation at an upcoming scientific
congress; intended regulatory actions, including plans to submit a
supplemental biologics licensing application to the FDA and to make
submissions to global health authorities; 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 possibilities
that we may experience delays in the submission of results to the
FDA; that the results from cohort 2 of the EV-201 trial may not be
support any approvals by regulatory authorities; that, even if
PADCEV receives an additional approval in the U.S. or an approval
in any global registrations, the product labeling may not be as
broad or desirable as anticipated; 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 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.
References
|
|
1
|
American Society of
Clinical Oncology. Bladder cancer: introduction (5-2019).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed January 27, 2021.
|
2
|
Cancer today: data
visualization tools for exploring the global cancer burden in
2020.
https://gco.iarc.fr/today/home. Accessed January 27,
2021.
|
3
|
PADCEV [package
insert] Northbrook, IL: Astellas Pharma Inc.
|
4
|
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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