Seattle Genetics, Inc. (Nasdaq:SGEN) today provided an update on
the phase 1b/2 multicohort EV-103 trial (also known as KEYNOTE-869)
of PADCEVTM (enfortumab vedotin-ejfv) in combination with anti-PD-1
therapy 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. Based on recent discussions with the U.S. Food
and Drug Administration (FDA), data from the randomized cohort K,
along with other data from the EV-103 trial evaluating PADCEV
combined with pembrolizumab as first-line therapy for
cisplatin-ineligible patients, could potentially support
registration under accelerated approval regulations in the United
States. 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
“We are excited that EV-103 provides PADCEV with a potential
pathway for U.S. accelerated approval in first-line metastatic
urothelial cancer,” said Roger Dansey, M.D., Chief Medical Officer
at Seattle Genetics. “Our initial data on the combination of PADCEV
and pembrolizumab in previously untreated patients who could not
receive cisplatin are encouraging.”
EV-103 is a multi-cohort, open-label, multicenter phase 1b/2
trial of PADCEV alone or in combination, evaluating safety,
tolerability and efficacy in muscle invasive urothelial cancer, and
in locally advanced or metastatic urothelial cancer in first- or
second-line settings. Cohort K from EV-103 is intended to enroll
150 patients randomized 1:1 to PADCEV monotherapy or PADCEV in
combination with pembrolizumab in locally advanced or metastatic
urothelial cancer patients who are ineligible for cisplatin-based
chemotherapy. The primary outcome measure is objective response
rate (ORR) per blinded independent central review (BICR) using
RECIST 1.1 and duration of response (DoR).
In addition to EV-103, the recently initiated EV-302 phase 3
randomized clinical trial is intended to support global
registrations and potentially serve as a confirmatory trial if
accelerated approval is granted based on EV-103. The EV-302 trial
is evaluating the combination of PADCEV and pembrolizumab with or
without chemotherapy versus chemotherapy alone in patients with
previously untreated locally advanced or metastatic urothelial
cancer. Importantly, EV-302 includes metastatic urothelial cancer
patients that are either eligible or ineligible for cisplatin-based
chemotherapy. The trial is expected to enroll 1,095 patients and
has dual primary endpoints of progression-free survival and overall
survival. Both the EV-103 and EV-302 trials are being conducted in
collaboration with Astellas and Merck.
FDA recently granted Breakthrough Therapy designation for PADCEV
in combination with 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 based on initial results from the EV-103
trial.
PADCEV (enfortumab vedotin-ejfv) was approved by the 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.2
About Bladder and Urothelial Cancer
It is estimated that approximately 81,000 people in the U.S.
will be diagnosed with bladder cancer in 2020.3 Urothelial cancer
accounts for 90 percent of all bladder cancers and can also be
found in the renal pelvis, ureter and urethra.4 Globally,
approximately 549,000 people were diagnosed with bladder cancer in
2018, and there were approximately 200,000 deaths worldwide.5
About PADCEV
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.6,7 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).8 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. For information on our response to the COVID-19 pandemic,
please visit our website.
About the Astellas and Seattle Genetics Collaboration
Seattle Genetics and Astellas are co-developing PADCEV 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 Seattle Genetics, Astellas and Merck
Collaboration
Seattle Genetics and Astellas entered a clinical collaboration
agreement with Merck to evaluate the combination of Seattle
Genetics’ and Astellas’ PADCEV 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.
Seattle Genetics Forward-Looking Statements
Certain statements made in this press release are forward
looking, such as those, among others, relating to the potential of
data from the EV-103 clinical trial to support accelerated approval
in the U.S. of PADCEV in combination with 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
possibility of using data from the EV-302 clinical trial to obtain
global regulatory approval or confirm accelerated approval of
PADCEV in the referenced first line setting; clinical development
plans relating to PADCEV; the therapeutic potential of PADCEV; 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 PADCEV
may fail to produce data sufficient to support regulatory
approvals; the fact that FDA has not made a final determination
regarding whether the data from the EV-103 clinical trial will be
sufficient to support accelerated approval in the U.S.; the risk
that the COVID-19 pandemic could delay our ability to conduct the
EV-103 clinical trial and delay FDA’s regulatory timelines,
including with respect to any potential accelerated approval; the
fact that adverse events or safety signals may occur and that
adverse regulatory actions or other setbacks could occur as PADCEV
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.
1Challita-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. 2 PADCEV [package insert]. Northbrook, IL:
Astellas, Inc. 3 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 02-20-2020. 4 American Society of Clinical Oncology.
Bladder cancer: introduction (10-2017).
https://www.cancer.net/cancer-types/bladder-cancer/introduction.
Accessed 05-09-2019. 5 International Agency for Research on Cancer.
Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. 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. 7 PADCEV [package insert]. Northbrook, IL:
Astellas, Inc. 8 PADCEV [package insert]. Northbrook, IL: Astellas,
Inc.
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version on businesswire.com: https://www.businesswire.com/news/home/20200402005249/en/
For Media Monique Greer Vice President, Corporate Communications
(425) 527-4641 mgreer@seagen.com
For Investors Peggy Pinkston Vice President, Investor Relations
(425) 527-4160 ppinkston@seagen.com
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