Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology
company, today presented data from a phase 2 clinical trial
evaluating ADCETRIS (brentuximab vedotin) combination therapy in
frontline diffuse large B-cell lymphoma (DLBCL) at the 58th
American Society of Hematology (ASH) Annual Meeting and Exposition
taking place in San Diego, California, December 3-6, 2016. ADCETRIS
is an antibody-drug conjugate (ADC) directed to CD30, expressed on
several types of non-Hodgkin lymphoma. ADCETRIS is currently not
approved for the treatment of DLBCL.
Data from the phase 2 study in newly diagnosed intermediate-high
or high-risk DLBCL included the evaluation of ADCETRIS in
combination with either rituximab (Rituxan), cyclophosphamide,
doxorubicin, vincristine and prednisone (referred to as RCHOP) in
51 patients (Part 1); or RCHP (removing the vincristine) in 11
patients (Part 2). In Part 1, the objective response rate was 83
percent, including 69 percent complete remissions. In Part 2, the
objective response rate was 91 percent, including 82 percent
complete remissions. The most common adverse events in Part 1 and 2
were fatigue, peripheral sensory neuropathy, diarrhea, nausea,
alopecia and constipation.
“The data from this phase 2 trial demonstrate that ADCETRIS is
an active agent in the treatment of frontline DLBCL,” said Jonathan
Drachman, M.D., Chief Medical Officer and Executive Vice President,
Research and Development at Seattle Genetics. “However, based on
prioritization of our pipeline, we are discontinuing this trial and
have decided not to pursue a registrational pathway for ADCETRIS in
frontline DLBCL. We continue to evaluate ADCETRIS in the treatment
of relapsed or refractory DLBCL through an ongoing randomized phase
2 trial, as well as more broadly for other CD30-expressing
lymphomas, including the ECHELON-1 and ECHELON-2 phase 3 trials in
frontline classical Hodgkin lymphoma and frontline mature T-cell
lymphoma, respectively.”
Results of an Ongoing Phase 2 Study of Brentuximab Vedotin
with RCHP as Frontline Therapy in Patients with
High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (Abstract
#104, oral presentation at 9:45 a.m. PT)
Data were reported from Parts 1 and 2 of the phase 2 clinical
trial for intermediate-high or high-risk frontline DLBCL. In Part
1, 51 patients were treated once every three weeks with up to six
cycles of either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg
of ADCETRIS plus RCHOP. In Part 2, 11 patients were treated once
every three weeks with up to six cycles of 1.8 mg/kg of ADCETRIS
plus RCHP. The median age of patients in Part 1 was 67 years and in
Part 2 was 59 years. More than 90 percent of patients had stage III
or IV disease.
Key findings presented in an oral presentation include:
- For the 49 response-evaluable patients
in Part 1, 25 patients had CD30-expressing disease and 24 patients
had CD30-undetectable disease. Of the 25 with CD30-expressing
disease, 21 patients (84 percent) had an objective response, with
19 patients (76 percent) achieving a complete remission. Of the 24
patients who had CD30-undetectable disease, 20 patients (83
percent) had an objective response, with 15 patients (63 percent)
achieving a complete remission. Median progression-free survival
(PFS) and overall survival have not yet been reached. For
CD30-expressing patients, the estimated PFS rate at two years was
79 percent and the estimated two-year overall survival rate was 92
percent. For CD30-undetectable patients, the estimated two-year PFS
rate at was 52 percent and the estimated two-year overall survival
rate was 67 percent.
- For the 11 patients in Part 2, ten
patients (91 percent) had an objective response, with nine patients
(82 percent) achieving a complete remission. One patient (nine
percent) had a partial remission and one patient (nine percent) had
progressive disease. All responding patients had confirmed
CD30-expression by central review; the patient with progressive
disease was determined to be CD30-undetectable.
- The most common treatment-emergent
adverse events of any grade in Part 1 and 2 were fatigue (65 and 64
percent, respectively), peripheral sensory neuropathy (63 and 55
percent, respectively), diarrhea (57 and 27 percent, respectively),
nausea (56 and 73 percent, respectively), alopecia (27 and 73
percent, respectively) and constipation (33 and 55 percent,
respectively). The most common Grade 3 or 4 adverse events were
neutropenia, febrile neutropenia, dyspnea and anemia. When combined
with RCHP, 1.8 mg/kg of ADCETRIS appears more tolerable than in
combination with RCHOP, with no Grade 3 neuropathy, no motor
neuropathy and lower incidence of febrile neutropenia.
About ADCETRIS (Brentuximab Vedotin)
ADCETRIS is being evaluated broadly in more than 70 ongoing
clinical trials, including three phase 3 studies, the ongoing
ECHELON-1 trial in frontline classical Hodgkin lymphoma and the
ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, as
well as the completed ALCANZA trial in cutaneous T-cell lymphoma
for which a supplemental BLA is planned in the first half of
2017.
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 for intravenous injection has received approval from
the FDA for three indications: (1) regular approval for the
treatment of patients with classical Hodgkin lymphoma after failure
of autologous hematopoietic stem cell transplantation (auto-HSCT)
or after failure of at least two prior multi-agent chemotherapy
regimens in patients who are not auto-HSCT candidates, (2) regular
approval for the treatment of classical Hodgkin lymphoma patients
at high risk of relapse or progression as post-auto-HSCT
consolidation, and (3) accelerated approval for the treatment of
patients with systemic anaplastic large cell lymphoma (sALCL) after
failure of at least one prior multi-agent chemotherapy regimen. The
sALCL indication is approved under accelerated approval based on
overall response rate. Continued approval for the sALCL indication
may be contingent upon verification and description of clinical
benefit in confirmatory trials. Health Canada granted ADCETRIS
approval with conditions for relapsed or refractory Hodgkin
lymphoma and sALCL.
ADCETRIS was granted conditional marketing authorization by the
European Commission in October 2012 for two indications: (1) for
the treatment of adult patients with relapsed or refractory
CD30-positive Hodgkin lymphoma following autologous stem cell
transplant (ASCT), or following at least two prior therapies when
ASCT or multi-agent chemotherapy is not a treatment option, and (2)
the treatment of adult patients with relapsed or refractory sALCL.
The European Commission extended the current conditional approval
of ADCETRIS and approved ADCETRIS for the treatment of adult
patients with CD30-positive Hodgkin lymphoma at increased risk of
relapse or progression following ASCT.
ADCETRIS has received marketing authorization by regulatory
authorities in 65 countries. See important safety information
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 is an innovative biotechnology company that
develops and commercializes novel antibody-based therapies for the
treatment of cancer. The company’s industry-leading antibody-drug
conjugate (ADC) technology harnesses the targeting ability of
antibodies to deliver cell-killing agents directly to cancer cells.
ADCETRIS® (brentuximab vedotin), the company’s lead product, in
collaboration with Takeda Pharmaceutical Company Limited, is the
first in a new class of ADCs commercially available globally in 65
countries for relapsed classical Hodgkin lymphoma and relapsed
systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics
is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in
a phase 3 trial for acute myeloid leukemia. Headquartered in
Bothell, Washington, Seattle Genetics has a robust pipeline of
innovative therapies for blood-related cancers and solid tumors
designed to address significant unmet medical needs and improve
treatment outcomes for patients. The company has collaborations for
its proprietary ADC technology with a number of companies including
AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer.
More information can be found at www.seattlegenetics.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 patients
receiving ADCETRIS.
Contraindication
ADCETRIS is contraindicated with concomitant bleomycin due to
pulmonary toxicity (e.g., interstitial infiltration and/or
inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN): ADCETRIS
treatment causes a PN that is predominantly sensory. Cases of motor
PN have also been reported. ADCETRIS-induced PN is cumulative.
Monitor patients for symptoms of neuropathy, such as hypoesthesia,
hyperesthesia, paresthesia, discomfort, a burning sensation,
neuropathic pain or weakness and institute dose modifications
accordingly.
- Anaphylaxis and infusion reactions:
Infusion-related reactions, including anaphylaxis, have occurred
with ADCETRIS. Monitor patients during infusion. If an
infusion-related reaction occurs, interrupt the infusion and
institute appropriate medical management. If anaphylaxis occurs,
immediately and permanently discontinue the infusion and administer
appropriate medical therapy. Patients who experienced a prior
infusion-related reaction should be premedicated for subsequent
infusions. Premedication may include acetaminophen, an
antihistamine, and a corticosteroid.
- Hematologic toxicities: Prolonged (≥1
week) severe neutropenia and Grade 3 or 4 thrombocytopenia or
anemia can occur with ADCETRIS. Febrile neutropenia has been
reported with ADCETRIS. Monitor complete blood counts prior to each
dose of ADCETRIS and consider more frequent monitoring 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
patients treated with ADCETRIS. Closely monitor patients during
treatment for the emergence of possible 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
the use of ADCETRIS 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 the use of ADCETRIS in patients with
moderate or severe hepatic impairment.
- Hepatotoxicity: Serious cases of
hepatotoxicity, including fatal outcomes, have occurred with
ADCETRIS. Cases were consistent with hepatocellular injury,
including elevations of transaminases and/or bilirubin, and
occurred after the first dose of ADCETRIS or rechallenge.
Preexisting liver disease, elevated baseline liver enzymes, and
concomitant medications may also increase the risk. Monitor liver
enzymes and bilirubin. Patients experiencing new, worsening, or
recurrent hepatotoxicity may require a delay, change in dose, or
discontinuation of ADCETRIS.
- Progressive multifocal
leukoencephalopathy (PML): JC virus infection resulting in PML and
death has 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 the diagnosis of PML in
any patient presenting 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: Events of
noninfectious pulmonary toxicity including pneumonitis,
interstitial lung disease, and acute respiratory distress syndrome,
some with fatal outcomes, have been reported. Monitor patients for
signs and symptoms of pulmonary toxicity, 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:
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN), including fatal outcomes, have been reported with ADCETRIS.
If SJS or TEN occurs, discontinue ADCETRIS and administer
appropriate medical therapy.
- Gastrointestinal (GI) complications:
Fatal and serious GI complications, including perforation,
hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis,
neutropenic colitis, and ileus have been reported in
ADCETRIS-treated patients. 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 findings in animals, ADCETRIS can cause
fetal harm when administered to a pregnant woman. Females of
reproductive potential should avoid pregnancy during ADCETRIS
treatment and for at least 6 months after the final dose of
ADCETRIS.
Adverse Reactions
In two uncontrolled single-arm trials of ADCETRIS as monotherapy
in 160 patients with relapsed classical HL and sALCL, the most
common adverse reactions (≥20%), regardless of causality, were:
neutropenia, peripheral sensory neuropathy, fatigue, nausea,
anemia, upper respiratory tract infection, diarrhea, pyrexia, rash,
thrombocytopenia, cough and vomiting.
In a placebo-controlled trial of ADCETRIS in 329 patients with
classical HL at high risk of relapse or progression post-auto-HSCT,
the most common adverse reactions (≥20%) in the ADCETRIS-treatment
arm (167 patients), regardless of causality, were: neutropenia,
peripheral sensory neuropathy, thrombocytopenia, anemia, upper
respiratory tract infection, fatigue, peripheral motor neuropathy,
nausea, cough, and diarrhea.
Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp
inhibitors, has the potential to affect the exposure to monomethyl
auristatin E (MMAE).
Use in Specific Populations
MMAE exposure and adverse reactions are increased in patients
with moderate or severe hepatic impairment or severe renal
impairment. Avoid use.
Advise females of reproductive potential to avoid pregnancy
during ADCETRIS treatment and for at least 6 months after the final
dose of ADCETRIS.
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
www.ADCETRIS.com.
Forward-Looking Statement:
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
and commercial potential of ADCETRIS, including ADCETRIS’ potential
as a treatment for DLBCL and the anticipated benefits of Seattle
Genetics’ ADCETRIS clinical development program. 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 risks of adverse events associated with
ADCETRIS use, negative or unexpected results from the clinical
trials with ADCETRIS even after promising results in earlier
company- and investigator-sponsored trials, and adverse regulatory
actions affecting ADCETRIS, all of which could result in Seattle
Genetics being unable to expand ADCETRIS’ labeled indications of
use. Seattle Genetics may also experience delays in the conduct of
and obtaining data from ADCETRIS clinical trials, in each case for
a variety of reasons, including the inherent difficulty and
uncertainty of pharmaceutical product development. 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, 2016 filed with the Securities and Exchange
Commission. Seattle Genetics disclaims any intention or obligation
to update or revise any forward-looking statements, whether as a
result of new information, future events or otherwise.
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version on businesswire.com: http://www.businesswire.com/news/home/20161203005011/en/
Seattle Genetics, Inc.Investors:Peggy Pinkston,
425-527-4160ppinkston@seagen.comorMedia:Tricia Larson,
425-527-4180tlarson@seagen.com
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