- Five-Year Update of the ECHELON-1 Clinical
Trial Shows Treatment with ADCETRIS in Combination with AVD
Chemotherapy Results in Superior Long-Term Outcomes when Compared
to ABVD in Frontline Advanced Hodgkin Lymphoma -
- Five-Year Results of the ECHELON-2 Clinical
Trial Continue to Demonstrate Significant Durable Improvement in
Progression-Free Survival and Overall Survival of ADCETRIS Plus CHP
Chemotherapy when Compared to CHOP in Frontline Peripheral T-Cell
Lymphoma -
- Nineteen Presentations Across Seagen
Programs, Including First Results from Phase 2 Clinical Trial of
ADCETRIS plus Opdivo® (Nivolumab) in Mediastinal Gray Zone Lymphoma
-
Seagen Inc. (Nasdaq:SGEN) today announced multiple ADCETRIS®
(brentuximab vedotin) data presentations at the 62nd American
Society of Hematology (ASH) Annual Meeting and Exposition, taking
place virtually December 5-8, 2020. Data presentations include
five-year updates from the phase 3 ECHELON-1 and ECHELON-2 clinical
trials evaluating ADCETRIS plus a chemotherapy combination regimen
in frontline advanced stage classical Hodgkin lymphoma (HL) and
CD30-expressing frontline peripheral T-cell lymphoma (PTCL),
respectively. In addition, first results were presented from an
ongoing phase 2 clinical trial evaluating ADCETRIS in combination
with Opdivo® (nivolumab) in relapsed or refractory mediastinal gray
zone lymphoma (MGZL), a rare type of non-Hodgkin lymphoma that
express CD30 with no standard of care. 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 non-Hodgkin
lymphoma, including PTCL. ADCETRIS is being evaluated globally in
more than 70 corporate- and investigator-sponsored clinical trials
across multiple settings in lymphoma and other indications.
ADCETRIS and Opdivo are not approved alone or in combination for
the treatment of relapsed or refractory MGZL.
“After five years of follow-up, an important clinical milestone,
both the ECHELON-1 and ECHELON-2 clinical trials demonstrate that
ADCETRIS plus chemotherapy resulted in superior and durable
outcomes when compared with standard chemotherapy regimens,” said
Roger Dansey, M.D., Chief Medical Officer at Seagen. “As most
relapses in Hodgkin lymphoma occur within five years of frontline
treatment, the results of the ECHELON-1 study suggest that patients
treated with ADCETRIS plus chemotherapy are more likely to
experience long-term remissions compared to those treated with the
ABVD regimen.”
Brentuximab Vedotin with Chemotherapy for Patients with
Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma:
5-Year Update of the ECHELON-1 Study (Abstract #2973, poster
presentation on Monday, December 7, 2020)
The ECHELON-1 clinical trial is evaluating ADCETRIS in
combination with AVD (Adriamycin [doxorubicin], vinblastine,
dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin,
vinblastine, dacarbazine) in patients with Stage III or IV
frontline classical HL. 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 progression-free survival (PFS) compared to the control
arm of ABVD as assessed by independent review facility (IRF; hazard
ratio (HR), 0.77; p=0.035). A five-year exploratory analysis was
conducted to examine PFS outcomes per investigator assessment in
the intent-to-treat population of 1,334 patients. Results
include:
- Patients in the ADCETRIS plus AVD arm had a 32 percent
reduction in the risk of a progression event compared to patients
in the ABVD arm. The five-year PFS rate for patients in the
ADCETRIS plus AVD arm was 82.2 percent compared to 75.3 percentin
the ABVD arm, an absolute difference of 6.9 percent (HR, 0.681 [95%
CI: 0.534, 0.867]). Median follow-up time was 60.9 months.
- Consistent benefit in PFS was observed among patients treated
with ADCETRIS plus AVD compared with ABVD, independent of disease
stage, age and prognostic score.
- Consistent improvements compared to ABVD were observed in
patients with Stage III (HR, 0.593; [95% CI: 0.385, 0.915]) and
Stage IV (HR, 0.731; [95% CI: 0.545, 0.980]) disease.
- As previously reported for 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 five-year update shows that among patients with peripheral
neuropathy, 85 percent in the ADCETRIS plus AVD arm and 86 percent
in the ABVD arm reported complete resolution or improvement at last
follow-up.
- There were fewer secondary malignancies in the ADCETRIS plus
AVD arm. Among 48 patients with reported secondary malignancies, 19
[(nine hematological malignancies and 10 solid tumors)] were in the
ADCETRIS plus AVD arm and 29 [(15 hematological malignancies and 14
solid tumors)] were in the ABVD arm.
- There were a higher number of pregnancies in the ADCETRIS plus
AVD arm compared to the ABVD arm. A total of 150 pregnancies were
reported among study participants and their partners, including 89
on the ADCETRIS plus AVD arm and 61 on the ABVD arm.
The ECHELON-2 Trial: 5-Year Results of a Randomized,
Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP)
Versus CHOP in Frontline Treatment of Patients with CD30-Positive
Peripheral T-Cell Lymphoma (Abstract #1150, poster presentation on
Saturday, December 5, 2020)
The ECHELON-2 clinical trial is evaluating ADCETRIS in
combination with CHP (cyclophosphamide, Adriamycin [doxorubicin],
prednisone) compared to CHOP (cyclophosphamide, Adriamycin
[doxorubicin], vincristine, prednisone) in frontline
CD30-expressing PTCL. 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 per blinded independent central review (HR,
0.71; p=0.0110). A five-year post-hoc exploratory analysis was
conducted to examine PFS outcome and overall survival (OS) per
investigator assessment in the intent-to-treat population of 452
patients. Key findings include:
- Patients in the ADCETRIS plus CHP arm had a 30 percent
reduction in the risk of a progression event compared to patients
in the CHOP arm. The five-year PFS rate for patients in the
ADCETRIS plus CHP arm was 51.4 percent compared to 43 percent in
the CHOP arm, an absolute difference of 8.4 percent (HR, 0.70 [95%
CI: 0.53, 0.91]).
- OS in the ADCETRIS plus CHP arm was improved compared to CHOP
(HR=0.72 [95% CI: 0.53, 0.99]). This represents a 28 percent
reduction in the risk of death. Median follow-up time was 66.8
months.
- Among 316 systemic anaplastic large-cell lymphoma (sALCL)
patients on study, patients in the ADCETRIS plus CHP arm had a 45
percent reduction in the risk of a progression event compared to
patients in the CHOP arm (HR, 0.55 [95% CI: 0.39, 0.79]). There was
a 34 percent reduction in the risk of death. Median follow-up time
for PFS was 42.7 months.
- Consistent improvement in both PFS and OS was observed among
patients treated with ADCETRIS plus CHP arm compared to the CHOP
arm across the majority of pre-specified subgroups.
- The five-year update shows that among patients with peripheral
neuropathy, 72 percent in the ADCETRIS plus CHP arm and 78 percent
in the CHOP arm reported complete resolution or improvement at last
follow-up. For ongoing peripheral neuropathy events, 98 percent in
the ADCETRIS plus CHP arm and 98 percent in the CHOP arm were Grade
1 or 2.
Nivolumab Combined with Brentuximab Vedotin for
Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary
Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study
(Abstract #2045, poster presentation on Sunday, December 6,
2020)
Data from the ongoing CheckMate 436 phase 2 clinical trial of 10
patients with relapsed or refractory MGZL who received a
combination of ADCETRIS plus Opdivo treatment after autologous stem
cell transplant or two or more lines of multi-agent chemotherapy if
ineligible for transplant will be presented for the first time.
Patients were treated once every three weeks or until disease
progression or unacceptable toxicity. The median age of patients
was 35 years. Key findings include:
- Of 10 response-evaluable patients, seven patients (70 percent)
had an objective response, including five patients (50 percent)
with a complete response and two patients (20 percent) with a
partial response. Two patients (20 percent) had progressive disease
and in one patient (10 percent) death occurred prior to disease
assessment.
- Median follow-up time was 12.4 months. Time to complete
response was 1.2-4.8 months and the duration was 1.5+ to 3.2+
months before patients were assessed for subsequent therapy. All
patients who achieved a complete response underwent a hematopoietic
cell transplant and follow-up is ongoing.
- The most common adverse events of any grade in at least 20
percent of patients were neutropenia and paresthesia (30 percent
each); thrombocytopenia, anemia and peripheral sensory neuropathy
(20 percent each). The most common Grade 3 adverse events were
neutropenia and thrombocytopenia (10 percent each). Three patient
deaths occurred due to disease progression.
About ADCETRIS
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 Seagen’s
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 cells.
ADCETRIS for 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 in 2013
for patients with (1) HL after failure of autologous stem cell
transplant (ASCT) or after failure of at least two multi-agent
chemotherapy regimens in patients who are not ASCT candidates and
(2) sALCL after failure of at least one multi-agent chemotherapy
regimen. Non-conditional approval was granted for (3) post-ASCT
consolidation treatment of patients with HL at increased risk of
relapse or progression in 2017, (4) adult patients with pcALCL or
CD30-expressing MF who have received prior systemic therapy in
2018, (5) for previously untreated patients with Stage IV HL in
combination with doxorubicin, vinblastine, and dacarbazine in 2019,
and (6) for previously untreated adult patients with sALCL,
peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or
angioimmunoblastic T-cell lymphoma (AITL), whose tumors express
CD30, in combination with cyclophosphamide, doxorubicin, prednisone
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 previously
untreated CD30-positive Stage IV Hodgkin lymphoma in combination
with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the
treatment of adult patients with CD30-positive Hodgkin lymphoma at
increased risk of relapse or progression following ASCT, (3) 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, (4) for the treatment of adult patients
with previously untreated sALCL in combination with
cyclophosphamide, doxorubicin and prednisone (CHP), (5) for the
treatment of adult patients with relapsed or refractory sALCL, and
(6) for the treatment of adult patients with CD30-positive
cutaneous T-cell lymphoma (CTCL) after at least one prior systemic
therapy.
ADCETRIS has received marketing authorization by regulatory
authorities in more than 70 countries for relapsed or refractory
Hodgkin lymphoma and sALCL. See U.S. important safety information,
including Boxed Warning, below.
Seagen and Takeda are jointly developing ADCETRIS. Under the
terms of the collaboration agreement, Seagen has U.S. and Canadian
commercialization rights and Takeda has rights to commercialize
ADCETRIS in the rest of the world. Seagen 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.
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.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for
patients who receive ADCETRIS in combination with chemotherapy for
previously untreated Stage III/IV cHL 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 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
have been reported in ADCETRIS-treated patients. First onset of
symptoms occurred at various times from initiation of ADCETRIS,
with some cases occurring within 3 months of initial exposure. In
addition to ADCETRIS therapy, other possible contributory factors
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, including severe abdominal pain, perform a prompt
diagnostic evaluation and treat appropriately.
- Hyperglycemia: Serious cases, such as new-onset
hyperglycemia, exacerbation of pre-existing diabetes mellitus, and
ketoacidosis (including fatal outcomes) have been reported with
ADCETRIS. Hyperglycemia occurred more frequently in patients with
high body mass index or diabetes. Monitor serum glucose and if
hyperglycemia develops, administer anti-hyperglycemic medications
as clinically indicated.
- 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.
Please see the full Prescribing Information, including BOXED
WARNING, for ADCETRIS here.
About Seagen
Seagen is a global biotechnology company that discovers,
develops and commercializes transformative cancer medicines to make
a meaningful difference in people’s lives. Seagen is headquartered
in the Seattle, Washington area, and has locations in California,
Canada, Switzerland and the European Union. For more information on
the company’s marketed products and robust pipeline, visit
www.seagen.com and follow @SeagenGlobal on Twitter.
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 plus chemotherapy combination
regimens in frontline advanced stage Hodgkin lymphoma, and
frontline peripheral T-cell lymphoma, and in combination with
Opdivo® (nivolumab) in relapsed or refractory mediastinal gray zone
lymphoma (MGZL). Actual results or developments may differ
materially from those projected or implied in these forward-looking
statements due to factors such as unexpected adverse events,
adverse regulatory actions, the degree of utilization and adoption
of an approved treatment regimen by prescribing physicians, the
difficulty and uncertainty of pharmaceutical product development,
negative or disappointing clinical trial results and risks related
to the duration and severity of the COVID-19 pandemic. More
information about the risks and uncertainties faced by Seagen is
contained under the caption “Risk Factors” included in the
Company’s Quarterly Report on Form 10-Q for the quarter ended
September 30, 2020 filed with the Securities and Exchange
Commission. Seagen 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20201207005193/en/
Investors and Media: Peggy Pinkston (425) 527-4160
ppinkston@seagen.com
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