Three-Year Update of ECHELON-1 Trial Continues
to Demonstrate Superior Clinical Activity of ADCETRIS in
Combination with Chemotherapy when Compared to ABVD in Frontline
Hodgkin Lymphoma
Analyses Describe ADCETRIS Activity in T-Cell
and B-Cell Non-Hodgkin Lymphomas Across All Levels of CD30
Expression
Seattle Genetics, Inc. (Nasdaq:SGEN) today announced additional
analyses of results from ECHELON-1 and ECHELON-2, the frontline
phase 3 trials of ADCETRIS® (brentuximab vedotin), at the 2019
American Society of Clinical Oncology (ASCO) Annual Meeting taking
place May 31 to June 4, 2019 in Chicago. The ECHELON-1 analysis
highlights a three-year update of this phase 3 clinical trial
evaluating ADCETRIS in combination with AVD (Adriamycin,
vinblastine and dacarbazine) compared to ABVD (Adriamycin,
bleomycin, vinblastine and dacarbazine) in stage III or IV
frontline classical Hodgkin lymphoma (HL) patients, including
analyses by cycle 2 PET (PET2) status and in patients less than 60
years old. In addition, two poster presentations evaluate CD30
expression and response to ADCETRIS treatment in the ECHELON-2
phase 3 clinical trial in peripheral T-cell lymphomas (PTCL) and an
analysis of five additional trials in T-cell and B-cell non-Hodgkin
lymphomas (NHL). ADCETRIS is an antibody-drug conjugate (ADC)
directed to CD30, a defining marker of classical HL and expressed
on the surface of several types of PTCL.
“We continue to evaluate ADCETRIS as the foundation of care for
patients with CD30-expressing lymphomas,” said Roger Dansey, M.D.,
Chief Medical Officer at Seattle Genetics. “Importantly, the
ECHELON-1 three-year analysis presented at this meeting demonstrate
a robust and durable treatment benefit of ADCETRIS plus AVD versus
ABVD across most subgroups and regardless of PET status. In
addition, other ADCETRIS presentations at the ASCO Meeting include
new analyses evaluating response by CD30 expression across several
non-Hodgkin lymphoma studies.”
“Tumor expression of CD30 by IHC in B-cell and T-cell
non-Hodgkin lymphomas can be quite variable between different
patients with the same diagnosis and even between different
biopsies within the same patient,” said Steven Horwitz, M.D.,
Department of Medicine, Lymphoma Service, Memorial Sloan Kettering
Cancer Center, New York, and an ADCETRIS clinical trial
investigator. “In two poster presentations at this year’s ASCO
Annual Meeting, results of the analyses suggest that a lower limit
or threshold of CD30 expression required for efficacy has not been
identified and individual patients may experience clinical benefit
from brentuximab vedotin regardless of the level of CD30
expression.”
Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical
Hodgkin Lymphoma: 3-year Update of the ECHELON-1 Study (Abstract
#7532, poster presentation on Monday, June 3, 2019)
This poster presentation examines progression-free survival
(PFS) outcomes per investigator assessment in the intent-to-treat
population of 1,334 patients at three-years by PET status and in
patients less than 60 years old. As previously reported, the
ECHELON-1 trial achieved its primary endpoint with the combination
of ADCETRIS plus AVD resulting in a statistically significant
improvement in modified PFS versus the control arm of ABVD as
assessed by independent review facility (IRF; hazard ratio [HR]
0.77; p-value=0.035). Modified PFS was defined as time to
progression, death, or evidence of non-complete response after
completion of frontline therapy per IRF followed by subsequent
anticancer therapy. Key findings from these analyses include:
- The three-year PFS for all patients in
the ADCETRIS plus AVD arm was 83.1 percent compared to 76 percent
in the ABVD arm (HR 0.70), a difference of 7.1 percent.
- PFS benefit at three-years for ADCETRIS
plus AVD was observed for all patients independent of PET2 status,
including in patients who are less than 60 years old.
- PET2-negative result was 85.8 percent
in the ADCETRIS plus AVD arm compared to 79.5 percent in the ABVD
arm (HR 0.69), a difference of 6.3 percent.
- PET2-positive result was 67.7 percent
in the ADCETRIS plus AVD arm compared to 51.5 percent in the ABVD
arm (HR 0.59), a difference of 16.2 percent.
- Consistent improvement in PFS was
observed among patients treated with ADCETRIS plus AVD compared
with ABVD across the majority of pre-specified subgroups, including
disease stage, age and prognostic score.
- As previously reported at the primary
analysis, on the ADCETRIS plus AVD arm, peripheral neuropathy
events were observed in 67 percent of patients compared to 43
percent in the ABVD arm. The three-year analysis shows that among
patients with peripheral neuropathy, 78 percent of in the ADCETRIS
plus AVD arm and 83 percent in the ABVD arm reported complete
resolution or improvement at last follow-up.
Response to A+CHP by CD30 Expression in the ECHELON-2 Trial
(Abstract #7538, poster presentation on Monday, June 3,
2019)
As previously reported, the ECHELON-2 trial met its primary
endpoint with the combination of ADCETRIS plus CHP resulting in a
statistically significant improvement in PFS versus the control arm
of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
per Blinded Independent Central Review (HR=0.71; p-value=0.0110).
In addition, overall survival in the ADCETRIS plus CHP arm was
statistically significant compared to CHOP (HR=0.66;
p-value=0.0244). Complete remission (CR) rate (p-value=0.0066) and
objective response rate (ORR; p-value=0.0032) for the ADCETRIS plus
CHP arm were also significantly increased. CD30 expression is a
hallmark of systemic anaplastic large cell lymphoma (sALCL), but it
is variably expressed among non-sALCL PTCL subtypes. As a lack of
correlation between CD30 expression and response to ADCETRIS has
been previously reported, an analysis was conducted to examine
response to ADCETRIS plus CHP by CD30 expression in 57 patients
with angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not
otherwise specified (PTCL-NOS) in the ECHELON-2 study, the two
histologies with variable expression. Key findings of this
exploratory analysis include:
- Among AITL and PTCL-NOS patients, the
ORR in patients treated with ADCETRIS plus CHP was independent of
the level of CD30 expression. CRs and PRs were observed in patients
with all levels of CD30 expression, including those with the lowest
level of 10 percent.
- The duration of complete response was
not associated with CD30 expression level for patients with AITL or
PTCL-NOS.
Response to Brentuximab Vedotin by CD30 Expression: Results
from Five Trials in PTCL, CTCL, and B-cell Lymphomas (Abstract
#7543, poster presentation on Monday, June 3, 2019)
Exploratory analyses were conducted to examine the correlation
between pretreatment CD30 expression level and ORR for patients
with CD30 expression greater than or equal to 10 percent, less than
10 percent, or undetectable (0 percent) by immunohistochemistry
(IHC). This analysis examined CD30 expression levels of 275
patients across five clinical studies in relapsed or refractory
PTCL, cutaneous T-cell lymphoma (CTCL), and B-cell NHL. All
patients in this analysis were treated with ADCETRIS monotherapy.
The key findings include:
- Responses were observed with ADCETRIS
treatment in patients with all levels of CD30 expression, including
in patients with no detectable CD30 expression by IHC.
- Response to ADCETRIS was not associated
with CD30 expression level.
The U.S. Food and Drug Administration (FDA) approved ADCETRIS in
combination with AVD for the treatment of adult patients with
previously untreated stage III or IV classical HL in March 2018,
based on the results of the ECHELON-1 phase 3 clinical trial. The
FDA approved ADCETRIS in combination with CHP (cyclophosphamide,
doxorubicin, and prednisone) for the treatment of adult patients
with previously untreated sALCL or other CD30-expressing PTCL,
including AITL and PTCL-NOS based on the results of the ECHELON-2
phase 3 trial, in November 2018.
About ADCETRIS
ADCETRIS is being evaluated broadly in more than 70 clinical
trials in CD30-expressing lymphomas. These include three completed
phase 3 trials: ECHELON-2 trial in frontline peripheral T-cell
lymphomas, ECHELON-1 in previously untreated Hodgkin lymphoma, and
ALCANZA in cutaneous T-cell lymphoma. The CHECKMATE 812 trial of
ADCETRIS in combination with Opdivo (nivolumab) for
relapsed/refractory Hodgkin lymphoma is ongoing.
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 six indications in adult patients with: (1) previously
untreated systemic anaplastic large cell lymphoma (sALCL) or other
CD30-expressing peripheral T-cell lymphomas (PTCL), including
angioimmunoblastic T-cell lymphoma and PTCL not otherwise
specified, in combination with cyclophosphamide, doxorubicin, and
prednisone, (2) previously untreated Stage III or IV classical
Hodgkin lymphoma (cHL), in combination with doxorubicin,
vinblastine, and dacarbazine, (3) cHL at high risk of relapse or
progression as post-autologous hematopoietic stem cell
transplantation (auto-HSCT) consolidation, (4) cHL after failure of
auto-HSCT or failure of at least two prior multi-agent chemotherapy
regimens in patients who are not auto-HSCT candidates, (5) sALCL
after failure of at least one prior multi-agent chemotherapy
regimen, and (6) primary cutaneous anaplastic large cell lymphoma
(pcALCL) or CD30-expressing mycosis fungoides (MF) who have
received prior systemic therapy.
Health Canada granted ADCETRIS approval with conditions for
relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and
non-conditional approval for post-autologous stem cell
transplantation (ASCT) consolidation treatment of Hodgkin lymphoma
patients at increased risk of relapse or progression in 2017,
adults with pcALCL or CD30-expressing MF who have had prior
systemic therapy in 2018, and for previously untreated Stage IV
Hodgkin lymphoma in combination with doxorubicin, vinblastine, and
dacarbazine in 2019.
ADCETRIS received conditional marketing authorization from the
European Commission in October 2012. The approved indications in
Europe are: (1) for the treatment of adult patients with relapsed
or refractory CD30-positive Hodgkin lymphoma following ASCT, or
following at least two prior therapies when ASCT or multi-agent
chemotherapy is not a treatment option, (2) for the treatment of
adult patients with relapsed or refractory sALCL, (3) for the
treatment of adult patients with CD30-positive Hodgkin lymphoma at
increased risk of relapse or progression following ASCT, (4) for
the treatment of adult patients with CD30-positive cutaneous T-cell
lymphoma (CTCL) after at least one prior systemic therapy and (5)
for the treatment of adult patients with previously untreated
CD30-positive Stage IV Hodgkin lymphoma in combination with AVD
(Adriamycin®, vinblastine and dacarbazine).
ADCETRIS has received marketing authorization by regulatory
authorities in 72 countries for relapsed or refractory Hodgkin
lymphoma and sALCL. See select important safety information,
including Boxed Warning, 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, Inc. is an emerging multi-product, global
biotechnology company that develops and commercializes
transformative therapies targeting cancer to make a meaningful
difference in people’s lives. ADCETRIS® (brentuximab vedotin)
utilizes the company’s industry-leading antibody-drug conjugate
(ADC) technology and is currently approved for the treatment of
multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company
has established a pipeline of novel targeted therapies at various
stages of clinical testing, including three in ongoing pivotal
trials for solid tumors. Enfortumab vedotin for metastatic
urothelial cancer and tisotumab vedotin for metastatic cervical
cancer utilize our proprietary ADC technology. Tucatinib, a small
molecule tyrosine kinase inhibitor, is in a pivotal trial for
HER2-positive metastatic breast cancer. In addition, we are
leveraging our expertise in empowered antibodies to build a
portfolio of proprietary immuno-oncology agents in clinical trials
targeting hematologic malignancies and solid tumors. The company is
headquartered in Bothell, Washington, and has a European office in
Switzerland. For more information on our robust pipeline, visit
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: Fatal
and serious cases of febrile neutropenia have been reported with
ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4
thrombocytopenia or anemia can occur with ADCETRIS. Start primary
prophylaxis with G-CSF beginning with Cycle 1 for patients who
receive ADCETRIS in combination with chemotherapy for previously
untreated Stage III or IV classical HL or previously untreated
PTCL. Monitor complete blood counts prior to each ADCETRIS dose.
Monitor more frequently 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 ADCETRIS 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: Fatal and
serious cases 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: Fatal cases of JC virus
infection resulting in PML and death have 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: Fatal and
serious events of noninfectious pulmonary toxicity including
pneumonitis, interstitial lung disease, and acute respiratory
distress syndrome 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:
Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS
or TEN occurs, discontinue ADCETRIS and administer appropriate
medical therapy.
- Gastrointestinal (GI)
complications: Fatal and serious cases of acute pancreatitis
have been reported. Other fatal and serious GI complications
include perforation, hemorrhage, erosion, ulcer, intestinal
obstruction, enterocolitis, neutropenic colitis, and ileus.
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% in any study) Adverse Reactions:
Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia,
upper respiratory tract infection, pyrexia, constipation, vomiting,
alopecia, decreased weight, abdominal pain, anemia, stomatitis,
lymphopenia and mucositis
Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers 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 ADCETRIS treatment
and for at least 6 months after the final dose of ADCETRIS.
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
http://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 possible uses
and benefits of ADCETRIS as the foundation of care for
CD30-expressing lymphomas and in certain clinical settings. 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 potential lack of efficacy or
risk of adverse events associated with the use of ADCETRIS in
certain clinical settings. 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 March 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20190603005142/en/
Media:Monique Greer(425) 527-4641mgreer@seagen.com
Investors:Peggy Pinkston(425) 527-4160ppinkston@seagen.com
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