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
BOTHELL, Wash.–(BUSINESS WIRE)–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.
-
PET2-negative result was 85.8 percent in the ADCETRIS plus AVD arm
-
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.
Contacts
Media:
Monique Greer
(425) 527-4641
mgreer@seagen.com
Investors:
Peggy Pinkston
(425) 527-4160
ppinkston@seagen.com