- Four-Year Data Continue to Show Superior
Progression-Free Survival of ADCETRIS in Combination with AVD when
Compared to ABVD in Frontline Advanced Hodgkin Lymphoma with 31
Percent Reduction in the Risk of Progression or Death -
- Additional Analysis from ECHELON-2 Phase 3
Clinical Trial Evaluating ADCETRIS Plus CHP Chemotherapy Also
Featured at ASH Annual Meeting -
Seattle Genetics, Inc. (Nasdaq:SGEN) and Takeda Pharmaceutical
Company Limited (TSE:4502/NYSE:TAK) today announced additional
analyses of results from the ECHELON-1 and ECHELON-2 frontline
phase 3 trials of ADCETRIS® (brentuximab vedotin). These analyses
were presented at the 61st Annual Meeting of the American Society
of Hematology (ASH) taking place December 7-10, 2019 in Orlando,
Fla. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30,
a defining marker of classical Hodgkin lymphoma and expressed on
the surface of several types of peripheral T-cell lymphomas
(PTCL).
This press release features multimedia. View
the full release here:
https://www.businesswire.com/news/home/20191209005169/en/
The ECHELON-1 analysis highlighted a four-year update of the
phase 3 clinical trial in a poster presentation. ECHELON-1 is
evaluating ADCETRIS in combination with AVD (Adriamycin
[doxorubicin], vinblastine and dacarbazine) compared to ABVD
(Adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine)
in patients with Stage III or IV frontline classical Hodgkin
lymphoma.
The ECHELON-2 phase 3 clinical trial data were presented in an
oral session at ASH and focused on the outcomes of the subset of
patients who underwent consolidative stem cell transplant.
ECHELON-2 is evaluating ADCETRIS in combination with CHP
(cyclophosphamide, doxorubicin, prednisone) compared to CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone) in
frontline CD30-expressing PTCL.
“For decades, the standard of care for the treatment of
frontline Hodgkin lymphoma has been combination chemotherapy,
called ABVD. Unfortunately, approximately 30 percent of patients
with advanced stage Hodgkin lymphoma do not respond or relapse
following treatment with this therapy,” said Roger Dansey, M.D.,
Chief Medical Officer at Seattle Genetics. “The four-year update
from the ECHELON-1 trial continues to support the robust and
durable frontline treatment benefit of ADCETRIS plus AVD, including
in both Stage III and IV disease settings, compared to ABVD across
subgroups, regardless of PET2 status. These data reinforce ADCETRIS
plus AVD as a treatment option that should be offered to all newly
diagnosed advanced stage patients with Hodgkin lymphoma.”
“Updated data from the ECHELON-1 trial and further insights from
ECHELON-2 build upon our continued understanding of the potential
ADCETRIS offers patients with CD30-positive lymphomas,” said Phil
Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda.
“We’re especially encouraged by the promising four-year follow-up
ECHELON-1 results being presented at ASH, as approximately one in
three patients with advanced Hodgkin lymphoma do not achieve
long-term remission after standard frontline therapy.”
Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical
Hodgkin Lymphoma (cHL): 4-Year Update of the ECHELON-1 Study
(Abstract #4026, poster presentation on Monday, December 9,
2019)
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 four-year post-hoc exploratory analysis was conducted
to examine PFS outcomes per investigator assessment in the
intent-to-treat population of 1,334 patients, including results by
PET2 status, age, stage and prognostic risk scores. Results
include:
- The four-year PFS rate for patients in the ADCETRIS plus AVD
arm was 81.7 percent compared to 75.1 percent in the ABVD arm, a
difference of 6.6 percent (HR, 0.69 [95% CI: 0.542, 0.881]). This
represents a 31 percent reduction in the risk of progression or
death. Median follow-up time was 48.4 months.
- A PFS benefit at four-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 86.2 percent in the ADCETRIS plus AVD
arm compared to 81.0 percent in the ABVD arm (HR, 0.69), a
difference of 5.2 percent.
- PET2-positive result was 62.1 percent in the ADCETRIS plus AVD
arm compared to 47.7 percent in the ABVD arm (HR, 0.65), a
difference of 14.4 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.
- Notably, improvements compared to ABVD were observed in
patients with Stage III (HR, 0.595; [95% CI: 0.386, 0.917]) and
Stage IV (HR, 0.745; [95% CI: 0.555, 1.001]) 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 four-year update shows that among patients with peripheral
neuropathy, 83 percent in the ADCETRIS plus AVD arm and 84 percent
in the ABVD arm reported complete resolution or improvement at last
follow-up.
More than 45 countries and regions have approved ADCETRIS in
combination with AVD for the treatment of patients with previously
untreated Stage III or IV Hodgkin lymphoma. 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 Hodgkin lymphoma in March 2018, based on the
results of the ECHELON-1 phase 3 clinical trial in which the
primary endpoint was modified PFS. In February 2019, the European
Commission (EC) approved ADCETRIS for the treatment of adult
patients with previously untreated CD30+ Stage IV Hodgkin lymphoma
in combination with AVD.
An Exploratory Analysis of Brentuximab Vedotin plus CHP
(A+CHP) in the Frontline Treatment of Patients with CD30+
Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative
Stem Cell Transplant (Abstract #464, oral presentation on Sunday,
December 8, 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 per blinded independent central review (HR, 0.71;
p=0.0110). In addition, the overall survival benefit in the
ADCETRIS plus CHP arm was statistically significant compared to
CHOP (HR, 0.66; p=0.0244). A post-hoc exploratory analysis
evaluated the impact of consolidative stem cell transplant in the
ECHELON-2 study for the patients who achieved CR treated with
ADCETRIS plus CHP. In the ADCETRIS plus CHP arm, this included 38
patients in CR who received a stem cell transplant and 76 patients
in CR who did not. Key findings of this analysis include:
- The PFS estimate favored the use of stem cell transplant (HR,
0.38; [95% CI: 0.18, 0.82]). After a median follow-up time of 35.9
months, the three-year PFS rate for the 38 patients who received a
stem cell transplant was 76.1 percent. After a median follow-up
time of 41.6 months, the three-year PFS rate for the 76 patients
who did not receive a stem cell transplant was 53.3 percent.
- As previously reported, the safety profile of ADCETRIS plus CHP
in the ECHELON-2 trial was comparable to CHOP and consistent with
the established safety profile of ADCETRIS in combination with
chemotherapy.
About Classical Hodgkin Lymphoma
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. Classical
Hodgkin lymphoma is distinguished from other types of lymphoma by
the presence of one characteristic type of cell, known as the
Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.
According to the American Cancer Society, approximately 8,110
cases of Hodgkin lymphoma will be diagnosed in the United States
during 2019 and 1,000 will die from the disease. Approximately half
of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV
disease. According to the Lymphoma Coalition, over 62,000 people
worldwide are diagnosed with Hodgkin lymphoma each year and
approximately 25,000 people die each year from this cancer.
About T-Cell Lymphomas
There are more than 60 subtypes of non-Hodgkin lymphomas which
are broadly divided into two major groups: B-cell lymphomas, which
develop from abnormal B-lymphocytes, and T-cell lymphomas, which
develop from abnormal T-lymphocytes. There are many different forms
of T-cell lymphomas, some of which are extremely rare. T-cell
lymphomas can be aggressive (fast-growing) or indolent
(slow-growing). PTCL accounts for approximately 10 percent of
non-Hodgkin lymphoma cases in the U.S. and Europe and may be as
high as 24 percent in parts of Asia.
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.
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 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 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 73 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 a late-stage pipeline including enfortumab vedotin for
metastatic urothelial cancer, currently being reviewed for approval
by the FDA, and tisotumab vedotin in clinical trials for metastatic
cervical cancer, which utilize our proprietary ADC technology. In
addition, tucatinib, a small molecule tyrosine kinase inhibitor, is
in late-stage development for HER2-positive metastatic breast
cancer and in clinical development for metastatic colorectal
cancer. We are also 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.
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a
global, values-based, R&D-driven biopharmaceutical leader
headquartered in Japan, committed to bringing Better Health and a
Brighter Future to patients by translating science into
highly-innovative medicines. Takeda focuses its R&D efforts on
four therapeutic areas: Oncology, Rare Diseases, Neuroscience and
Gastroenterology (GI). We also make targeted R&D investments in
Plasma-Derived Therapies and Vaccines. We are focusing on
developing highly innovative medicines that contribute to making a
difference in people's lives by advancing the frontier of new
treatment options and leveraging our enhanced collaborative R&D
engine and capabilities to create a robust, modality-diverse
pipeline. Our employees are committed to improving quality of life
for patients and to working with our partners in health care in
approximately 80 countries.
For more information, visit https://www.takeda.com
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
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. 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 preexisting
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
antihyperglycemic 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.
ADCETRIS (brentuximab vedotin) Important Safety Information
(European Union)
Please refer to Summary of Product Characteristics (SmPC) before
prescribing.
CONTRAINDICATIONS
ADCETRIS is contraindicated for patients with hypersensitivity
to brentuximab vedotin and its excipients. In addition, combined
use of ADCETRIS with bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John
Cunningham virus (JCV) reactivation resulting in progressive
multifocal leukoencephalopathy (PML) and death can occur in
patients treated with ADCETRIS. PML has been reported in patients
who received ADCETRIS after receiving multiple prior chemotherapy
regimens. PML is a rare demyelinating disease of the central
nervous system that results from reactivation of latent JCV and is
often fatal.
Closely monitor patients for new or worsening neurological,
cognitive, or behavioral signs or symptoms, which may be suggestive
of PML. Suggested evaluation of PML includes neurology
consultation, gadolinium-enhanced magnetic resonance imaging of the
brain, and cerebrospinal fluid analysis for JCV DNA by polymerase
chain reaction or a brain biopsy with evidence of JCV. A negative
JCV PCR does not exclude PML. Additional follow up and evaluation
may be warranted if no alternative diagnosis can be established
Hold dosing for any suspected case of PML and permanently
discontinue ADCETRIS if a diagnosis of PML is confirmed.
Be alert to PML symptoms that the patient may not notice (e.g.,
cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in
patients treated with ADCETRIS. Fatal outcomes have been reported.
Closely monitor patients for new or worsening abdominal pain, which
may be suggestive of acute pancreatitis. Patient evaluation may
include physical examination, laboratory evaluation for serum
amylase and serum lipase, and abdominal imaging, such as ultrasound
and other appropriate diagnostic measures. Hold ADCETRIS for any
suspected case of acute pancreatitis. ADCETRIS should be
discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some
with fatal outcomes, including pneumonitis, interstitial lung
disease, and acute respiratory distress syndrome (ARDS), have been
reported in patients receiving ADCETRIS. Although a causal
association with ADCETRIS has not been established, the risk of
pulmonary toxicity cannot be ruled out. Promptly evaluate and treat
new or worsening pulmonary symptoms (e.g., cough, dyspnoea)
appropriately. Consider holding dosing during evaluation and until
symptomatic improvement.
Serious infections and opportunistic infections: Serious
infections such as pneumonia, staphylococcal bacteremia,
sepsis/septic shock (including fatal outcomes), and herpes zoster,
and opportunistic infections such as Pneumocystis jiroveci
pneumonia and oral candidiasis have been reported in patients
treated with ADCETRIS. Carefully monitor patients during treatment
for emergence of possible serious and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed
IRR, as well as anaphylaxis, have been reported with ADCETRIS.
Carefully monitor patients during and after an infusion. If
anaphylaxis occurs, immediately and permanently discontinue
administration of ADCETRIS and administer appropriate medical
therapy. If an IRR occurs, interrupt the infusion and institute
appropriate medical management. The infusion may be restarted at a
slower rate after symptom resolution. Patients who have experienced
a prior IRR should be premedicated for subsequent infusions. IRRs
are more frequent and more severe in patients with antibodies to
ADCETRIS.
Tumor lysis syndrome (TLS): TLS has been reported with
ADCETRIS. Patients with rapidly proliferating tumor and high tumor
burden are at risk of TLS. Monitor these patients closely and
manage according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause
PN, both sensory and motor. ADCETRIS-induced PN is typically an
effect of cumulative exposure to ADCETRIS and is reversible in most
cases. Monitor patients for symptoms of neuropathy, such as
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning
sensation, neuropathic pain, or weakness. Patients experiencing new
or worsening PN may require a delay and a dose reduction or
discontinuation of ADCETRIS.
Hematological toxicities: Grade 3 or Grade 4 anemia,
thrombocytopenia, and prolonged (equal to or greater than one week)
Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor
complete blood counts prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been
reported with ADCETRIS. Complete blood counts should be monitored
prior to administration of each dose of treatment. Closely monitor
patients for fever and manage according to best medical practice if
febrile neutropenia develops.
When ADCETRIS is administered in combination with AVD, primary
prophylaxis with G-CSF is recommended for all patients beginning
with the first dose.
Stevens-Johnson syndrome (SJS): SJS and toxic epidermal
necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes
have been reported. Discontinue treatment with ADCETRIS if SJS or
TEN occurs and administer appropriate medical therapy.
Gastrointestinal (GI) Complications: GI complications,
some with fatal outcomes, including intestinal obstruction, ileus,
enterocolitis, neutropenic colitis, erosion, ulcer, perforation and
haemorrhage, have been reported with ADCETRIS. Promptly evaluate
and treat patients if new or worsening GI symptoms occur.
Hepatotoxicity: Elevations in alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) have been reported with
ADCETRIS. Serious cases of hepatotoxicity, including fatal
outcomes, have also occurred. Pre-existing liver disease,
comorbidities, and concomitant medications may also increase the
risk. Test liver function prior to treatment initiation and
routinely monitor during treatment. Patients experiencing
hepatotoxicity may require a delay, dose modification, or
discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during
trials in patients with an elevated body mass index (BMI) with or
without a history of diabetes mellitus. Closely monitor serum
glucose for patients who experiences an event of hyperglycemia.
Administer anti-diabetic treatment as appropriate.
Renal and Hepatic Impairment: There is limited experience
in patients with renal and hepatic impairment. Available data
indicate that MMAE clearance might be affected by severe renal
impairment, hepatic impairment, and by low serum albumin
concentrations.
CD30+ CTCL: The size of the treatment effect in CD30 +
CTCL subtypes other than mycosis fungoides (MF) and primary
cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due
to lack of high level evidence. In two single arm phase II studies
of ADCETRIS, disease activity has been shown in the subtypes Sézary
syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL
histology. These data suggest that efficacy and safety can be
extrapolated to other CTCL CD30+ subtypes. Carefully consider the
benefit-risk per patient and use with caution in other CD30+ CTCL
patient types.
Sodium content in excipients: This medicinal product
contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO
recommended maximum daily intake of 2 g sodium for an adult.
INTERACTIONS
Patients who are receiving a strong CYP3A4 and P-gp inhibitor,
concomitantly with ADCETRIS may have an increased risk of
neutropenia. If neutropenia develops, refer to dosing
recommendations for neutropenia (see SmPC section 4.2).
Co-administration of ADCETRIS with a CYP3A4 inducer did not alter
the plasma exposure of ADCETRIS, but it appeared to reduce plasma
concentrations of MMAE metabolites that could be assayed. ADCETRIS
is not expected to alter the exposure to drugs that are metabolized
by CYP3A4 enzymes.
PREGNANCY: Advise women of childbearing potential to use
two methods of effective contraception during treatment with
ADCETRIS and until 6 months after treatment. There are no data from
the use of ADCETRIS in pregnant women, although studies in animals
have shown reproductive toxicity. Do not use ADCETRIS during
pregnancy unless the benefit to the mother outweighs the potential
risks to the fetus.
LACTATION (breast-feeding): There are no data as to
whether ADCETRIS or its metabolites are excreted in human milk,
therefore a risk to the newborn/infant cannot be excluded. With the
potential risk, a decision should be made whether to discontinue
breast-feeding or discontinue/abstain from therapy with
ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has
resulted in testicular toxicity, and may alter male fertility.
Advise men being treated with ADCETRIS not to father a child during
treatment and for up to 6 months following the last dose.
Effects on ability to drive and use machines: ADCETRIS may
have a moderate influence on the ability to drive and use
machines.
UNDESIRABLE EFFECTS
Monotherapy: The most frequent adverse reactions (≥10%)
were infections, peripheral sensory neuropathy, nausea, fatigue,
diarrhoea, pyrexia, upper respiratory tract infection, neutropenia,
rash, cough, vomiting, arthralgia, peripheral motor neuropathy,
infusion-related reactions, pruritus, constipation, dyspnoea,
weight decreased, myalgia and abdominal pain. Serious adverse drug
reactions occurred in 12% of patients. The frequency of unique
serious adverse drug reactions was ≤1%. Adverse events led to
treatment discontinuation in 24% of patients.
Combination Therapy: In the study of ADCETRIS as
combination therapy with AVD in 662 patients with previously
untreated advanced Hodgkin lymphoma, the most common adverse
reactions (≥ 10%) were: neutropenia, nausea, constipation,
vomiting, fatigue, peripheral sensory neuropathy, diarrhoea,
pyrexia, alopecia, peripheral motor neuropathy, decreased weight,
abdominal pain, anaemia, stomatitis, febrile neutropenia, bone
pain, insomnia, decreased appetite, cough, headache, arthralgia,
back pain, dyspnoea, myalgia, upper respiratory tract infection,
alanine aminotransferase increased. Serious adverse reactions
occurred in 36% of patients. Serious adverse reactions occurring in
≥ 3% of patients included febrile neutropenia (17%), pyrexia (6%),
and neutropenia (3%). Adverse events led to treatment
discontinuation in 13% of patients.
Seattle Genetics 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 for patients with previously untreated stage
III or IV classical Hodgkin lymphoma and patients with previously
untreated systemic anaplastic large cell lymphoma (sALCL) or other
CD30-expressing peripheral T-cell lymphomas (PTCL). Actual results
or developments may differ materially from those projected or
implied in these forward-looking statements due to factors such as
utilization and adoption of the approved treatment regimen by
prescribing physicians, competitive conditions including the
availability of alternative treatment regimens, the availability
and extent of reimbursement, 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, 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20191209005169/en/
Seattle Genetics: Media Monique Greer (425) 527-4641
mgreer@seagen.com
Investors Peggy Pinkston (425) 527-4160 ppinkston@seagen.com
Takeda: Japanese Media Kazumi Kobayashi
kazumi.kobayashi@takeda.com +81 (0) 3-3278-2095
Media outside Japan Sara Noonan sara.noonan@takeda.com
+1-617-551-3683
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