European Commission Approves ADCETRIS® (brentuximab vedotin) with AVD, the First New Treatment in Decades for Adults with Previously Untreated CD30+ Stage IV Hodgkin Lymphoma

– ADCETRIS in Combination with AVD (Adriamycin, Vinblastine and
Dacarbazine) Demonstrated 29-Percent Reduction in the Risk of
Progression, Death or Need for Additional Anticancer Therapy for CD30+
Stage IV Patients –

– Milestone Marks Fifth Approved Indication for ADCETRIS in Europe,
Reinforcing Takeda’s Commitment to Developing Innovative Solutions for
People Living with CD30-Positive Malignancies –

CAMBRIDGE, Mass. and OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
today announced that the European Commission (EC) extended the current
marketing authorization of ADCETRIS (brentuximab vedotin) to include
treatment of adult patients with previously untreated CD30+ Stage IV
Hodgkin lymphoma in combination with AVD (Adriamycin, vinblastine and
dacarbazine). ADCETRIS is an antibody-drug conjugate (ADC) directed at
CD30, a defining marker of Hodgkin lymphoma. The decision follows a
positive opinion from the Committee for Medicinal Products for Human Use
(CHMP) on December 13, 2018.

“The decision by the European Commission is a welcomed advancement for
patients with previously untreated Stage IV Hodgkin lymphoma – a
population that has not been offered a new treatment option in decades,”
said Anna Sureda, M.D., Ph.D., Head of the Hematology Department and
Hematopoietic Stem Cell Transplant Programme, Institut Català
d’Oncologia – Hospital Duran i Reynals. “Patients with Stage IV disease
carry a higher risk of progression following their first therapy and
experience poorer outcomes as a result. The approval of this regimen may
help address this unmet need by providing European physicians and their
patients with a new option that showed significant benefit compared to
ABVD along with a safety profile consistent with when ADCETRIS is used
as a single agent.”

“We are pleased that the European Commission has approved ADCETRIS in
combination with AVD, which has the potential to represent an important
milestone for patients and serves as a testament to Takeda’s
longstanding commitment to the Hodgkin lymphoma community,” said Jesús
Gómez-Navarro, M.D., Vice President, Head of Oncology Clinical Research
and Development, Takeda. “The ECHELON-1 clinical trial demonstrated that
the addition of ADCETRIS and the removal of bleomycin from the standard
ABVD regimen yielded both efficacy and safety benefits in patients. We
look forward to making this therapy available for appropriate European
patients with Hodgkin lymphoma.”

The approval is based on the results of the randomized, open-label,
two-arm, multi-center Phase 3 ECHELON-1 study designed to compare
ADCETRIS plus AVD to ABVD (Adriamycin, bleomycin, vinblastine and
dacarbazine) as a therapy in adult patients with previously untreated
Hodgkin lymphoma. The trial achieved its primary endpoint resulting in a
statistically significant improvement in modified progression-free
survival (PFS) versus the control arm (Hazard ratio [HR] 0.77;
p-value=0.035), which corresponds to a 23 percent reduction in the risk
of progression, death or need for additional anticancer therapy. Key
subgroup analyses showed a larger effect in patients with Stage IV
Hodgkin lymphoma in the ADCETRIS plus AVD arm versus the control arm
(modified PFS; HR 0.71; p-value = 0.023).

The safety profile of ADCETRIS plus AVD in the ECHELON-1 trial was
generally consistent with that known for the single-agent components of
the regimen. The most common clinically relevant adverse events of any
grade that occurred in at least 15 percent of patients in the ADCETRIS
plus AVD and ABVD arms were: neutropenia, constipation, vomiting,
fatigue, peripheral sensory neuropathy, diarrhea, pyrexia, peripheral
neuropathy, abdominal pain and stomatitis. In both the ADCETRIS plus AVD
and ABVD arms, the most common Grade 3 or 4 events were neutropenia,
febrile neutropenia and neutrophil count decrease.

This decision by the European Commission means that ADCETRIS in
combination with AVD is now approved for marketing of this indication in
the 28 member states of the European Union and applicable in Norway,
Liechtenstein and Iceland. For further details about the European
Commission decision, please visit the European Medicines Agency website: www.ema.europe.eu/ema.

About 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. 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 Lymphoma Coalition, approximately 67,000 people
worldwide are diagnosed with Hodgkin lymphoma each year and more than
25,000 people die each year from this cancer.

Up to 30 percent of previously untreated Hodgkin lymphoma patients
progress following their first therapy depending on the stage of the
disease. Only 50 percent of patients with relapsed or refractory Hodgkin
lymphoma achieve long-term remission with high-dose chemotherapy and an
autologous stem cell transplant (ASCT), a historically used treatment
regimen, highlighting the need for successful treatments for previously
untreated patients.

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (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-positive 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 transplant (ASCT) consolidation
treatment of Hodgkin lymphoma patients at increased risk of relapse or
progression.

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.

ADCETRIS has received marketing authorization by regulatory authorities
in more than 70 countries for relapsed or refractory Hodgkin lymphoma
and sALCL. See important safety information below.

ADCETRIS is being evaluated broadly in more than 70 clinical trials,
including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and
another Phase 3 study in first-line CD30-positive peripheral T-cell
lymphomas (ECHELON-2), as well as trials in many additional types of
CD30-positive malignancies.

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.

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 HL,
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.

ADCETRIS (brentuximab vedotin) Important Safety Information (U.S.)

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.

Contacts

Japanese Media
Kazumi Kobayashi
[email protected]
+81
(0) 3-3278-2095

Media outside Japan
Amanda Loder
[email protected]
+1-212-259-0491

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