First FDA-Approved Regimen in Frontline Stage III or IV Classical
Hodgkin Lymphoma in More Than 40 Years
FDA Approval Based on Clinical Trial Results from the Phase 3
ECHELON-1 Clinical Trial
Label Expansion Represents Fifth Indication for ADCETRIS in the U.S.;
ECHELON-1 Trial Also Converts Prior Accelerated Approval to Regular
Approval in Treatment of Relapsed Systemic Anaplastic Large Cell Lymphoma
BOTHELL, Wash.–(BUSINESS WIRE)–Seattle
Genetics, Inc. (Nasdaq: SGEN) announced today that the U.S. Food and
Drug Administration (FDA) has approved ADCETRIS (brentuximab vedotin) in
combination with chemotherapy in adult patients with previously
untreated Stage III or IV classical Hodgkin lymphoma. The approval is
based on the successful outcome of the phase 3 ECHELON-1 clinical trial
that compared ADCETRIS plus AVD (Adriamycin, vinblastine and
dacarbazine) to ABVD (Adriamycin, bleomycin, vinblastine and
dacarbazine). In addition, data from the ECHELON-1 trial converted the
U.S. accelerated approval of ADCETRIS for the treatment of adults with
systemic anaplastic large cell lymphoma (sALCL) after failure of at
least one multi-agent chemotherapy regimen to regular approval. In
October 2017, the FDA granted Breakthrough Therapy Designation (BTD) to
ADCETRIS in combination with chemotherapy for the frontline treatment of
patients with advanced classical Hodgkin lymphoma. The FDA also granted
Priority Review for the supplemental Biologics License Application
(BLA), and the Prescription Drug User Fee Act (PDUFA) target action date
was May 1, 2018.
“The standard of care for treating newly diagnosed advanced Hodgkin
lymphoma has not changed in more than four decades. For years, the
physician community has been conducting clinical trials to identify
improved regimens that are both less toxic and more effective to no
avail,” said Joseph M. Connors, M.D., FRCPC, Clinical Director, Center
for Lymphoid Cancer at BC Cancer in Vancouver, Canada. “The ECHELON-1
study results demonstrated superior efficacy of the ADCETRIS plus
chemotherapy regimen when compared to the standard of care while
removing bleomycin, an agent that can cause unpredictable and sometimes
fatal lung toxicity, completely from the regimen. This represents a
meaningful advance for this often younger patient population.”
This is the fifth FDA-approved indication for ADCETRIS, which also has
regular approval for adult patients with: (1) classical Hodgkin lymphoma
(cHL) at high risk of relapse or progression as post-autologous
hematopoietic stem cell transplantation (auto-HSCT) consolidation, (2)
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, (3) sALCL after failure of at least one prior multi-agent
chemotherapy regimen, and (4) primary cutaneous anaplastic large cell
lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have
received prior systemic therapy.
“Currently, up to 30 percent of newly diagnosed advanced-stage classical
Hodgkin lymphoma patients will experience disease progression after
treatment with the current standard of care, representing a significant
need for improved treatment options for these often younger patients,”
said Clay Siegall, Ph.D., President and Chief Executive Officer of
Seattle Genetics. “The ECHELON-1 trial was a bold, five-year effort to
redefine the frontline treatment of Stage III/IV classical Hodgkin
lymphoma and provide patients with a more effective treatment regimen.
In the ECHELON-1 study, ADCETRIS plus AVD was shown to have superior
efficacy to ABVD. With today’s FDA approval, the physician and patient
community have a new treatment option for previously untreated Stage III
or IV Hodgkin lymphoma patients. We want to thank all of the patients,
physicians and their staff who participated in the ECHELON-1 trial which
supported the FDA approval of this novel regimen.”
The FDA approval is based on positive results from a phase 3 trial
called ECHELON-1 that were presented at the 59th American
Society of Hematology (ASH) annual meeting in December 2017 with
simultaneous publication in the New England Journal of Medicine.
Results from the ECHELON-1 trial in 1,334 Stage III or IV classical
Hodgkin lymphoma patients included:
The trial achieved its primary endpoint with the combination of
ADCETRIS plus AVD resulting in a statistically significant improvement
in modified progression-free survival (PFS) versus the control arm of
ABVD as assessed by an Independent Review Facility (IRF) (HR 0.77; 95%
CI, 0.60-0.98; p-value=0.035). This corresponds to a 23 percent
reduction in the risk of progression, death or need for additional
anticancer therapy in patients not in complete response (CR) after
Overall survival (OS) was a key secondary endpoint and the rate of CR
per IRF assessment at the end of the randomized regimen was a
secondary endpoint. At the time of the modified PFS analysis, an
interim OS analysis trended in favor or the ADCETRIS plus AVD arm, but
did not demonstrate significant difference (HR 0.72; 95% CI,
0.44-1.17; p-value=0.19). The CR rate was 73 percent on the ADCETRIS
plus AVD arm and 70 percent on the ABVD arm.
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 adverse events of any grade that occurred in at least
10 percent of patients in the ADCETRIS plus AVD arm were: anemia,
neutropenia, peripheral sensory neuropathy, constipation, vomiting,
diarrhea, pyrexia, decreased weight, stomatitis, abdominal pain,
febrile neutropenia, bone pain, insomnia, decreased appetite, back
pain, rashes/eruptions/exanthemas, dyspnea, peripheral motor
neuropathy, and increased alanine aminotransferase. In both the
ADCETRIS plus AVD and ABVD arms, the most common Grade 3 or 4 events
were neutropenia, febrile neutropenia, and anemia.
Based on ECHELON-1 clinical trial results, prophylactic growth factors
(G-CSF) should be administered starting at cycle one for Stage III or
IV classical Hodgkin lymphoma patients receiving ADCETRIS plus AVD.
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 8,500 cases of
Hodgkin lymphoma will be diagnosed in the United States during 2018 and
more than 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.
ADCETRIS is being evaluated broadly in more than 70 clinical trials,
including two ongoing phase 3 studies: the ECHELON-2 trial in frontline
mature T-cell lymphomas and the CHECKMATE 812 trial of ADCETRIS in
combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin
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 regular
approval for five indications in adult patients with: (1) previously
untreated Stage III or IV classical Hodgkin lymphoma (cHL), in
combination with chemotherapy, (2) cHL at high risk of relapse or
progression as post-autologous hematopoietic stem cell transplantation
(auto-HSCT) consolidation, (3) 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, (4) sALCL after failure of at least one
prior multi-agent chemotherapy regimen, and (5) primary cutaneous
anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis
fungoides (MF) who have received prior systemic therapy.
Health Canada granted ADCETRIS approval with conditions for relapsed or
refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional
approval for post-autologous stem cell transplantation (ASCT)
consolidation treatment of Hodgkin lymphoma patients at increased risk
of relapse or progression.
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) 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, and (4) for the treatment of adult patients with CD30-positive
cutaneous T-cell lymphoma (CTCL) after at least one prior systemic
ADCETRIS has received marketing authorization by regulatory authorities
in 71 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 is an innovative biotechnology company dedicated to
improving the lives of people with cancer through targeted therapies.
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. Seattle Genetics commercializes ADCETRIS®
(brentuximab vedotin) for the treatment of several types of
CD30-expressing lymphomas. The company is also advancing a robust
pipeline of novel therapies for solid tumors and blood-related cancers
designed to address significant unmet medical needs and improve
treatment outcomes for patients. More information can be found at www.seattlegenetics.com
and follow @SeattleGenetics on Twitter.
ADCETRIS (brentuximab vedotin) U.S. Select Important Safety
BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death can occur in
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
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 starting
with Cycle 1 for previously untreated patients who receive ADCETRIS in
combination with chemotherapy for Stage III or IV HL. Monitor complete
blood counts prior to each ADCETRIS dose. 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
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
Tumor lysis syndrome: Closely monitor patients with rapidly
proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The
frequency of ≥Grade 3 adverse reactions and deaths was greater in
patients with severe renal impairment compared to patients with normal
renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic
impairment: The frequency of ≥Grade 3 adverse reactions and deaths
was greater in patients with moderate or severe hepatic impairment
compared to patients with normal hepatic function. Avoid use in
patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in
ADCETRIS-treated patients. Cases were consistent with hepatocellular
injury, including elevations of transaminases and/or bilirubin, and
occurred after the first ADCETRIS dose or rechallenge. Preexisting
liver disease, elevated baseline liver enzymes, and concomitant
medications may increase the risk. Monitor liver enzymes and
bilirubin. Patients with new, worsening, or recurrent hepatotoxicity
may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML and
death have been reported in ADCETRIS-treated patients. First onset of
symptoms occurred at various times from initiation of ADCETRIS
therapy, with some cases occurring within 3 months of initial
exposure. Other possible contributory factors other than ADCETRIS
include prior therapies and underlying disease that may cause
immunosuppression. Consider PML diagnosis in patients with new-onset
signs and symptoms of central nervous system abnormalities. Hold
ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is
Pulmonary toxicity: Fatal and serious events of noninfectious
pulmonary toxicity including pneumonitis, interstitial lung disease,
and acute respiratory distress syndrome have been reported. Monitor
patients for signs and symptoms, including cough and dyspnea. In the
event of new or worsening pulmonary symptoms, hold ADCETRIS dosing
during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Fatal and serious cases of
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
have been reported with ADCETRIS. If SJS or TEN occurs, discontinue
ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of
acute pancreatitis have been reported. Other fatal and serious GI
complications include perforation, hemorrhage, erosion, ulcer,
intestinal obstruction, enterocolitis, neutropenic colitis, and ileus.
Lymphoma with preexisting GI involvement may increase the risk of
perforation. In the event of new or worsening GI symptoms, perform a
prompt diagnostic evaluation and treat appropriately.
Embryo-fetal toxicity: Based on the mechanism of action and
animal studies, ADCETRIS can cause fetal harm. Advise females of
reproductive potential of the potential risk to the fetus, and to
avoid pregnancy during ADCETRIS treatment and for at least 6 months
after the final dose of ADCETRIS.
Most Common (≥20%) Adverse Reactions: neutropenia, anemia, peripheral
sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting,
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
Moderate or severe hepatic impairment or severe renal impairment: MMAE
exposure and adverse reactions are increased. Avoid use.
Advise males with female sexual partners of reproductive potential to
use effective contraception during ADCETRIS treatment and for at least 6
months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid breastfeeding
while receiving ADCETRIS.
For additional Important Safety Information, including BOXED WARNING,
please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to the potential
utilization of ADCETRIS (brentuximab vedotin) for patients with
previously untreated Stage III or IV classical Hodgkin lymphoma. 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 Annual Report on Form 10-K for the year ended
December 31, 2017 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.
Seattle Genetics, Inc.
Peggy Pinkston, 425-527-4160