-MF and pcALCL Represent the Most Common
Subtypes of Cutaneous T-Cell Lymphoma (CTCL)-
-FDA Approval Based on Clinical Trial Results
from the Phase 3 ALCANZA and Phase 2 Investigator-Sponsored Studies
in CTCL-
-Label Expansion Represents Fourth Indication
for ADCETRIS in the U.S.-
Seattle Genetics, Inc. (Nasdaq: SGEN) announced today that the
U.S. Food and Drug Administration (FDA) has approved ADCETRIS
(brentuximab vedotin) for the treatment of adult patients with
primary cutaneous anaplastic large cell lymphoma (pcALCL) and
CD30-expressing mycosis fungoides (MF) who have received prior
systemic therapy. Primary cutaneous ALCL and MF are the most common
subtypes of cutaneous T-cell lymphoma (CTCL). The approval is based
on data from the phase 3 ALCANZA trial and two phase 2
investigator-sponsored trials. The phase 3 ALCANZA study was
designed to compare ADCETRIS monotherapy administered every three
weeks versus physician’s choice of representative standard of care
options, methotrexate or bexarotene. The trial met its primary
endpoint with the ADCETRIS treatment arm demonstrating a highly
statistically significant improvement in the rate of objective
response lasting at least four months (ORR4) versus the control arm
as assessed by an independent review facility. ORR4 was 56.3
percent (95% CI: 44.1, 68.4) in the ADCETRIS arm compared to 12.5
percent (95% CI: 4.4, 20.6) in the control arm (p-value <0.001).
The most common adverse reactions (≥ 20 percent) were: anemia,
peripheral sensory neuropathy, nausea, diarrhea, fatigue and
neutropenia.
This is the fourth FDA-approved indication for ADCETRIS, which
also has: (1) regular approval for treatment of classical Hodgkin
lymphoma (cHL) patients who fail autologous hematopoietic stem cell
transplantation (auto-HSCT) or who fail at least two prior
multi-agent chemotherapy regimens and are not auto-HSCT candidates,
(2) regular approval for the treatment of patients with cHL at high
risk of relapse or progression as post-auto-HSCT consolidation, and
(3) accelerated approval for treatment of systemic anaplastic large
cell lymphoma (sALCL) patients who fail at least one prior
multi-agent chemotherapy regimen. Accelerated approval in the sALCL
indication is based on overall response rate, and continued
approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.
In November 2016, the FDA granted ADCETRIS Breakthrough Therapy
Designation (BTD) for the treatment of patients with pcALCL and
CD30-expressing MF who require systemic therapy and have received
one prior systemic therapy. The FDA also granted Priority Review
for the supplemental Biologics License Application (BLA), and the
Prescription Drug User Fee Act (PDUFA) target action date was
December 16, 2017.
“Cutaneous T-cell lymphoma is a blood cancer of the skin with no
known cure and few new treatment options. It is a disfiguring
disease in dire need of more effective and durable treatment
options to help keep this debilitating and painful disease at bay,”
said Susan Thornton, cutaneous lymphoma patient and chief executive
officer of the Cutaneous Lymphoma Foundation (CLF). “As both a
patient and representative of the cutaneous lymphoma community, we
welcome the FDA approval of ADCETRIS as a new treatment option for
the most common subtypes of cutaneous T-cell lymphoma in patients
who require systemic therapy and we look forward to sharing this
important milestone with patients and physicians.”
“Our phase 3 ALCANZA clinical trial evaluating ADCETRIS in
patients with primary cutaneous anaplastic large cell lymphoma and
mycosis fungoides, which are the most common types of cutaneous
T-cell lymphoma, demonstrated superior efficacy with durable
responses for long-term disease management when compared to
standard of care treatment options methotrexate and bexarotene,”
said Clay Siegall, Ph.D., President and Chief Executive Officer of
Seattle Genetics. “These data, along with data from
investigator-sponsored clinical trials, led to the FDA approval of
ADCETRIS as a treatment for patients with pcALCL or CD30-expressing
MF, which represent the most common subtypes of CTCL. This FDA
approval, which was granted more than a month in advance of the
PDUFA date, represents a significant milestone for the lymphoma
community. Our goal is to establish ADCETRIS as the foundation of
care in CD30-expressing lymphomas and this approval represents our
fourth FDA-approved indication.”
The FDA approval is based primarily on positive results from a
phase 3 trial called ALCANZA that were presented at the 58th
American Society of Hematology (ASH) annual meeting in December
2016 and published online in the Lancet in June 2017. Results from
the ALCANZA trial in 128 pcALCL and CD30-expressing MF patients
requiring systemic therapy included:
- The trial achieved its primary endpoint
with the ADCETRIS treatment arm demonstrating a highly
statistically significant improvement in the rate of ORR4 versus
the control arm as assessed by an independent review facility.
ORR4, as assessed by Global Response Score, was 56.3 percent in the
ADCETRIS arm compared to 12.5 percent in the control arm (p-value
<0.001).
- Key secondary endpoints specified in
the protocol, including objective response rate, complete response
rate and progression-free survival, were all highly statistically
significant in favor of the ADCETRIS arm.
- The objective response rate in the
ADCETRIS arm was 67.2 percent (95% CI: 55.7, 78.7) compared to 20.3
percent (95% CI: 10.5, 30.2) in the control arm.
- The CR rate in the ADCETRIS arm was
15.6 percent (95% CI: 7.8, 26.9) compared to 1.6 percent (95% CI:
0, 8.4) in the control arm (p-value = 0.0066).
- The median PFS in the ADCETRIS arm was
16.7 months (95% CI: 14.9, 22.8) compared to 3.5 months (95% CI:
2.4, 4.6) in the control arm (HR 0.270; 95% CI, 0.169, 0.430;
p-value <0.001).
- The safety profile associated with
ADCETRIS from the ALCANZA trial was generally consistent with the
existing prescribing information. The most common adverse events
occurring in 20 percent or more of patients of any grade include:
anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue
and neutropenia.
Additional data from two investigator-sponsored phase 2 trials
evaluating ADCETRIS in 73 MF patients were also incorporated into
the supplemental BLA representing a broader spectrum of
CD30-expression levels than that of the ALCANZA trial.
About CTCL
Lymphoma is a general term for a group of cancers that originate
in the lymphatic system. There are two major categories of
lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous
lymphomas are a category of non-Hodgkin lymphoma that primarily
involve the skin. According to the Cutaneous Lymphoma Foundation,
CTCL is the most common type of cutaneous lymphoma and typically
presents with red, scaly patches or thickened plaques of skin that
often mimic eczema or chronic dermatitis. The most common subtypes
of CTCL include mycosis fungoides and primary cutaneous anaplastic
large cell lymphoma. Progression from limited skin involvement may
be accompanied by skin tumor formation, ulceration and exfoliation,
complicated by itching and infections. Advanced stages are defined
by involvement of lymph nodes, peripheral blood and internal
organs.
According to the American Cancer Society and the Leukemia and
Lymphoma Society, CTCL represents approximately four percent of
non-Hodgkin lymphoma, which is about 2,800 patients. Not all newly
diagnosed patients require systemic therapy. The standard
treatment for systemically pretreated CTCL includes skin-directed
therapies, radiation and systemic therapies. The systemic therapies
currently approved for treatment have demonstrated 30 to 45 percent
objective response rates, with low complete response rates.
About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30
and is being evaluated broadly in more than 70 clinical trials,
including three phase 3 studies: the ECHELON-1 trial in frontline
classical Hodgkin lymphoma from which positive top-line results
were recently reported, the ongoing ECHELON-2 trial in frontline
mature T-cell lymphomas, and the recently initiated CHECKMATE 812
trial of ADCETRIS in combination with Opdivo (nivolumab) for
relapsed/refractory Hodgkin lymphoma.
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody
attached by a protease-cleavable linker to a microtubule disrupting
agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’
proprietary technology. The ADC employs a linker system that is
designed to be stable in the bloodstream but to release MMAE upon
internalization into CD30-expressing tumor cells.
ADCETRIS injection for intravenous infusion has received FDA
approval for four indications: (1) regular approval for patients
with pcALCL and CD30-expressing MF and who have received prior
systemic therapy, (2) regular approval for the treatment of
patients with classical Hodgkin lymphoma after failure of
autologous hematopoietic stem cell transplantation (auto-HSCT) or
after failure of at least two prior multi-agent chemotherapy
regimens in patients who are not auto-HSCT candidates, (3) regular
approval for the treatment of classical Hodgkin lymphoma patients
at high risk of relapse or progression as post-auto-HSCT
consolidation, and (4) accelerated approval for the treatment of
patients with systemic anaplastic large cell lymphoma (sALCL) after
failure of at least one prior multi-agent chemotherapy regimen. The
sALCL indication is approved under accelerated approval based on
overall response rate. Continued approval for the sALCL indication
may be contingent upon verification and description of clinical
benefit in confirmatory trials.
Health Canada granted ADCETRIS approval with conditions for
relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and
non-conditional approval for post-ASCT consolidation treatment of
Hodgkin lymphoma patients at increased risk of relapse or
progression.
ADCETRIS was granted conditional marketing authorization by the
European Commission in October 2012 for two indications: (1) for
the treatment of adult patients with relapsed or refractory
CD30-positive Hodgkin lymphoma following autologous stem cell
transplant (ASCT), or following at least two prior therapies when
ASCT or multi-agent chemotherapy is not a treatment option, and (2)
the treatment of adult patients with relapsed or refractory sALCL.
The European Commission extended the current conditional marketing
authorization of ADCETRIS and approved ADCETRIS for the treatment
of adult patients with CD30-positive Hodgkin lymphoma at increased
risk of relapse or progression following ASCT.
ADCETRIS has received marketing authorization by regulatory
authorities in 68 countries for relapsed or refractory Hodgkin
lymphoma and sALCL. See important safety information below.
Seattle Genetics and Takeda are jointly developing ADCETRIS.
Under the terms of the collaboration agreement, Seattle Genetics
has U.S. and Canadian commercialization rights and Takeda has
rights to commercialize ADCETRIS in the rest of the world. Seattle
Genetics and Takeda are funding joint development costs for
ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely
responsible for development costs.
About Seattle Genetics
Seattle Genetics is an innovative biotechnology company
dedicated to improving the lives of people with cancer through
novel antibody-based therapies. The company’s industry-leading
antibody-drug conjugate (ADC) technology harnesses the targeting
ability of antibodies to deliver cell-killing agents directly to
cancer cells. Seattle Genetics commercializes ADCETRIS®
(brentuximab vedotin) for the treatment of several types of
CD30-expressing lymphomas. The company is also advancing a robust
pipeline of novel therapies for solid tumors and blood-related
cancers designed to address significant unmet medical needs and
improve treatment outcomes for patients. More information can be
found at www.seattlegenetics.com and follow @SeattleGenetics on
Twitter.
ADCETRIS (brentuximab vedotin) U.S. Important Safety
Information
BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
(PML)
JC virus infection resulting in PML and death can occur in
ADCETRIS-treated patients.
Contraindication
ADCETRIS concomitant with bleomycin due to pulmonary toxicity
(e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN):
ADCETRIS causes PN that is predominantly sensory. Cases of motor PN
have also been reported. ADCETRIS-induced PN is cumulative. Monitor
for symptoms such as hypoesthesia, hyperesthesia, paresthesia,
discomfort, a burning sensation, neuropathic pain, or weakness.
Institute dose modifications accordingly.
- Anaphylaxis and infusion
reactions: Infusion-related reactions (IRR), including
anaphylaxis have occurred with ADCETRIS. Monitor patients during
infusion. If an IRR occurs, interrupt the infusion and institute
appropriate medical management. If anaphylaxis occurs, immediately
and permanently discontinue the infusion and administer appropriate
medical therapy. Premedicate patients with a prior IRR before
subsequent infusions. Premedication may include acetaminophen, an
antihistamine, and a corticosteroid.
- Hematologic toxicities:
Prolonged (≥1 week) severe neutropenia and Grade 3 or 4
thrombocytopenia or anemia can occur with ADCETRIS. Febrile
neutropenia has been reported with ADCETRIS. Monitor complete blood
counts prior to each ADCETRIS dose. Consider more frequent
monitoring for patients with Grade 3 or 4 neutropenia. Monitor
patients for fever. If Grade 3 or 4 neutropenia develops, consider
dose delays, reductions, discontinuation, or G-CSF prophylaxis with
subsequent doses.
- Serious infections and opportunistic
infections: Infections such as pneumonia, bacteremia, and
sepsis or septic shock (including fatal outcomes) have been
reported in ADCETRIS-treated patients. Closely monitor patients
during treatment for bacterial, fungal, or viral infections.
- Tumor lysis syndrome: Closely
monitor patients with rapidly proliferating tumor and high tumor
burden.
- Increased toxicity in the presence
of severe renal impairment: The frequency of ≥Grade 3 adverse
reactions and deaths was greater in patients with severe renal
impairment compared to patients with normal renal function. Avoid
use in patients with severe renal impairment.
- Increased toxicity in the presence
of moderate or severe hepatic impairment: The frequency of
≥Grade 3 adverse reactions and deaths was greater in patients with
moderate or severe hepatic impairment compared to patients with
normal hepatic function. Avoid use in patients with moderate or
severe hepatic impairment.
- Hepatotoxicity: Serious cases,
including fatal outcomes, have occurred in ADCETRIS-treated
patients. Cases were consistent with hepatocellular injury,
including elevations of transaminases and/or bilirubin, and
occurred after the first ADCETRIS dose or rechallenge. Preexisting
liver disease, elevated baseline liver enzymes, and concomitant
medications may increase the risk. Monitor liver enzymes and
bilirubin. Patients with new, worsening, or recurrent
hepatotoxicity may require a delay, change in dose, or
discontinuation of ADCETRIS.
- PML: JC virus infection
resulting in PML and death has been reported in ADCETRIS-treated
patients. First onset of symptoms occurred at various times from
initiation of ADCETRIS therapy, with some cases occurring within 3
months of initial exposure. Other possible contributory factors
other than ADCETRIS include prior therapies and underlying disease
that may cause immunosuppression. Consider PML diagnosis in
patients with new-onset signs and symptoms of central nervous
system abnormalities. Hold ADCETRIS if PML is suspected and
discontinue ADCETRIS if PML is confirmed.
- Pulmonary toxicity:
Noninfectious pulmonary toxicity events including pneumonitis,
interstitial lung disease, and acute respiratory distress syndrome,
some with fatal outcomes, have been reported. Monitor patients for
signs and symptoms, including cough and dyspnea. In the event of
new or worsening pulmonary symptoms, hold ADCETRIS dosing during
evaluation and until symptomatic improvement.
- Serious dermatologic reactions:
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN), including fatal outcomes, have been reported with ADCETRIS.
If SJS or TEN occurs, discontinue ADCETRIS and administer
appropriate medical therapy.
- Gastrointestinal (GI)
complications: Acute pancreatitis, including fatal outcomes,
has been reported in ADCETRIS-treated patients. Other fatal and
serious GI complications, including perforation, hemorrhage,
erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic
colitis, and ileus have been reported in ADCETRIS-treated patients.
Lymphoma with preexisting GI involvement may increase the risk of
perforation. In the event of new or worsening GI symptoms, perform
a prompt diagnostic evaluation and treat appropriately.
- Embryo-fetal toxicity: Based on
the mechanism of action and animal studies, ADCETRIS can cause
fetal harm. Advise females of reproductive potential of the
potential risk to the fetus, and to avoid pregnancy during ADCETRIS
treatment and for at least 6 months after the final dose of
ADCETRIS.
Most Common (≥20%) Adverse Reactions: peripheral sensory
neuropathy, fatigue, nausea, diarrhea, neutropenia, upper
respiratory tract infection, and pyrexia.
Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp
inhibitors, has the potential to affect the exposure to monomethyl
auristatin E (MMAE).
Use in Specific Populations
Moderate or severe hepatic impairment or severe renal
impairment: MMAE exposure and adverse reactions are increased.
Avoid use.
Advise males with female sexual partners of reproductive
potential to use effective contraception during, and for at least 6
months after the final dose of ADCETRIS treatment.
Advise patients to report pregnancy immediately and avoid
breastfeeding while receiving ADCETRIS.
For additional Important Safety Information, including BOXED
WARNING, please see the full Prescribing Information for ADCETRIS
at www.seattlegenetics.com or
www.ADCETRIS.com.
Forward-Looking Statements
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential of ADCETRIS (brentuximab vedotin) for uses for which
ADCETRIS has not received regulatory approval and our goal is to
establish ADCETRIS as the foundation of care in CD30-expressing
lymphomas. 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
inability to show sufficient activity for uses that have not
received regulatory approval, the risk of adverse events, and
adverse regulatory action. More information about the risks and
uncertainties faced by Seattle Genetics is contained under the
caption “Risk Factors” included in the company’s Quarterly Report
on Form 10-Q for the quarter ended September 30, 2017 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20171109006193/en/
Seattle Genetics, Inc.Investors:Peggy Pinkston,
425-527-4160ppinkston@seagen.comorMedia:Tricia Larson,
425-527-4180tlarson@seagen.com
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