BOTHELL, Wash. and TOKYO, Feb. 10,
2020 /PRNewswire/ -- Seattle Genetics,
Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE: 4503,
President and CEO: Kenji Yasukawa,
Ph.D., "Astellas") today announced updated results from the phase
1b/2 clinical trial EV-103 in
previously untreated patients with locally advanced or metastatic
urothelial cancer who were ineligible for treatment with
cisplatin-based chemotherapy. Forty-five patients were treated with
the combination of PADCEV™ (enfortumab vedotin-ejfv) and
pembrolizumab and were evaluated for safety and efficacy. After a
median follow-up of 11.5 months, the study results continue to meet
outcome measures for safety and demonstrate encouraging clinical
activity for this platinum-free combination in a first-line
setting. Updated results will be presented during an oral session
on Friday, February 14 at the 2020
Genitourinary Cancers Symposium in San
Francisco (Abstract #441). Initial results from the study
were presented at the European Society of Medical Oncology Congress
in September 2019.
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.1,2
"Cisplatin-based chemotherapy is the standard treatment for
first-line advanced urothelial cancer; however, it isn't an option
for many patients," said Jonathan E.
Rosenberg, M.D., Medical Oncologist and Chief, Genitourinary
Medical Oncology Service at Memorial Sloan Kettering Cancer Center
in New York. "I'm encouraged by these interim results,
including a median progression-free survival of a year for patients
who received the platinum-free combination of PADCEV and
pembrolizumab in the first-line setting."
In the study, 58 percent (26/45) of patients had a
treatment-related adverse event greater than or equal to Grade 3:
increase in lipase (18 percent; 8/45), rash (13 percent; 6/45),
hyperglycemia (13 percent; 6/45) and peripheral neuropathy (4
percent; 2/45); these rates were similar to those observed with
PADCEV monotherapy.3 Eighteen percent (8/45) of
patients had treatment-related immune-mediated adverse events of
clinical interest greater than or equal to Grade 3 that required
the use of systemic steroids (arthralgia, dermatitis bullous,
pneumonitis, lipase increased, rash erythematous, rash
maculo-papular, tubulointerstitial nephritis, myasthenia gravis).
None of the adverse events of clinical interest were Grade 5
events. Six patients (13 percent) discontinued treatment due to
treatment-related adverse events, most commonly peripheral sensory
neuropathy. As previously reported, there was one death deemed to
be treatment-related by the investigator attributed to multiple
organ dysfunction syndrome.
The data demonstrated the combination of PADCEV plus
pembrolizumab shrank tumors in the majority of patients, resulting
in a confirmed objective response rate (ORR) of 73.3 percent
(33/45; 95% Confidence Interval (CI): 58.1, 85.4) after a median
follow-up of 11.5 months (range, 0.7 to 19.2). Responses
included 15.6 percent (7/45) of patients who had a complete
response (CR) and 57.8 percent (26/45) of patients who had a
partial response. Median duration of response has not yet been
reached (range 1.2 to 12.9+ months). Eighteen (55%) of 33 responses
were ongoing at the time of analysis, with 83.9% of responses
lasting at least 6 months and 53.7% of responses lasting at least
12 months (Kaplan-Meier estimate). The median progression-free
survival was 12.3 months (95% CI: 7.98, -) and the 12-month overall
survival (OS) rate was 81.6 percent (95% CI: 62 to 91.8 percent);
median OS has not been reached.
"These updated data are encouraging and provide support for the
recently initiated phase 3 trial EV-302 that includes an arm
evaluating PADCEV in this platinum-free combination in the
first-line setting," said Roger
Dansey, M.D., Chief Medical Officer at Seattle Genetics.
"These additional results support continued evaluation of PADCEV
in combination with other agents and at earlier stages of treatment
for patients with urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice
President and Oncology Therapeutic Area Head at Astellas.
About the EV-103 Trial
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.
The dose-escalation cohort and expansion cohort A include
locally advanced or metastatic urothelial cancer patients who are
ineligible for cisplatin-based chemotherapy. Patients were dosed in
a 21-day cycle, receiving an intravenous (IV) infusion of
enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At
the time of this initial analysis, 45 patients (5 from the
dose-escalation cohort and 40 from the dose-expansion cohort A)
with locally advanced and/or metastatic urothelial cancer had been
treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in
the first-line setting.
The primary outcome measure of the cohorts included in this
analysis is safety. Key secondary objectives related to efficacy
include objective response rate (ORR), disease control rate (DCR),
duration of response (DoR), progression free survival (PFS) and
overall survival (OS). DoR, PFS and OS are not yet mature.
Additional cohorts in the EV-103 study will evaluate enfortumab
vedotin:
- as monotherapy or in combination with pembrolizumab or a
platinum chemotherapy in a first-line setting for metastatic
disease;
- in combination with pembrolizumab and carboplatin or cisplatin
in first-line metastatic disease;
- as a monotherapy or in combination with pembrolizumab in muscle
invasive disease;
- with pembrolizumab in second-line metastatic disease; and
- with gemcitabine in first- or second-line metastatic
disease.4
More information about PADCEV clinical trials can be found at
clinicaltrials.gov.
About Bladder and Urothelial Cancer
It is estimated that approximately 81,000 people in the U.S. will
be diagnosed with bladder cancer in 2020.5 Urothelial
cancer accounts for 90 percent of all bladder cancers and can also
be found in the renal pelvis, ureter and urethra.6
Globally, approximately 549,000 people were diagnosed with bladder
cancer in 2018, and there were approximately 200,000 deaths
worldwide.7
The recommended first-line treatment for patients with advanced
urothelial cancer is a cisplatin-based chemotherapy. For patients
who are ineligible for 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.8
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 may be contingent
upon verification and description of clinical benefit in
confirmatory trials.9
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.2,9 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).9 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 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
https://www.seattlegenetics.com and follow @SeattleGenetics on
Twitter.
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 the Astellas and Seattle Genetics Collaboration
Seattle Genetics and Astellas are co-developing 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.
Seattle Genetics Forward-Looking Statements
Certain statements made in this press release are forward looking,
such as those, among others, relating to the EV-103 and EV-302
clinical trials; clinical development plans relating to enfortumab
vedotin; the therapeutic potential of enfortumab vedotin; and its
possible safety, efficacy, and therapeutic uses, including in the
first-line setting. 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 of
enfortumab vedotin may fail to establish sufficient efficacy; that
adverse events or safety signals may occur and that adverse
regulatory actions or other setbacks could occur as enfortumab
vedotin advances in clinical trials even after promising results in
earlier clinical trials. 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.
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.
1 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.
2 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.
3 Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal
Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum
and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J
Clin Oncol 2019;37(29):2592-600.
4 ClinicalTrials.gov. A Study of Enfortumab Vedotin
Alone or With Other Therapies for Treatment of Urothelial Cancer
(EV-103). https://clinicaltrials.gov/ct2/show/NCT03288545.
5 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.
6 National Cancer Institute. Surveillance,
Epidemiology, and End Results Program. Cancer stat facts: bladder
cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed
05-01-2019.
7 International Agency for Research on Cancer.
Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow.
8 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.
9 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.
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