– Combination Data Showed 90 Percent Objective
Response Rate and 62 Percent Complete Response Rate with an
Acceptable Safety Profile in Pre-Transplant Relapsed or Refractory
Classical Hodgkin Lymphoma Patients –
– Data Support Continued Clinical Investigation
of ADCETRIS and Opdivo Combination in Hodgkin Lymphoma –
Seattle Genetics, Inc. (NASDAQ:SGEN) and Bristol-Myers Squibb
Company (NYSE:BMY) today highlighted the first reported data from
an ongoing phase 1/2 clinical trial evaluating ADCETRIS
(brentuximab vedotin) in combination with Opdivo (nivolumab) in
relapsed or refractory classical Hodgkin lymphoma (HL) at the 58th
American Society of Hematology (ASH) Annual Meeting and Exposition
taking place in San Diego, California, December 3-6, 2016. The data
reported from 42 patients, including 29 evaluable for response,
were featured in an oral presentation and selected to be included
in the 2017 Highlights of ASH post-meeting program. ADCETRIS is an
antibody-drug conjugate (ADC) directed to CD30, a defining marker
of classical HL that plays a role in tumor growth and survival.
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor
that is designed to harness the body’s own immune system to help
restore anti-tumor immune response. ADCETRIS and Opdivo are not
approved in combination for the treatment of relapsed or refractory
HL or for other indications.
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“The phase 1/2 study combining the antibody-drug conjugate
ADCETRIS with the PD-1 immune checkpoint inhibitor Opdivo is a
promising investigational approach as it combines a targeted
therapy with a therapy designed to activate the immune system and
the combination may have synergistic activity,” said Alex Herrera,
M.D., lead trial investigator and assistant professor at the City
of Hope Medical Center, Duarte, California. “The preliminary
results are compelling and support further exploration of this
novel regimen, free of traditional chemotherapy.”
“We are evaluating ADCETRIS broadly as the foundation of care
for CD30-expressing lymphomas, including combination strategies
that have the potential to improve efficacy,” said Jonathan
Drachman, M.D., Chief Medical Officer and Executive Vice President,
Research and Development at Seattle Genetics. “Preliminary data
from the trial evaluating ADCETRIS in combination with Opdivo as
pre-transplant salvage therapy for classical HL patients
demonstrate a 90 percent objective response rate, with a 62 percent
complete response rate and an acceptable safety profile. We look
forward to further evaluation of this innovative combination
regimen in other disease settings, including frontline older HL
patients and CD30-expressing non-Hodgkin lymphoma, in partnership
with Bristol-Myers Squibb.”
Fouad Namouni, M.D., Head of Development, Oncology,
Bristol-Myers Squibb, commented, “With these new data presented at
ASH, Bristol-Myers Squibb continues its efforts to strengthen its
broad Immuno-Oncology and hematology development programs for
Opdivo. Through our continued partnership with Seattle Genetics, we
hope to build on the significant progress we’ve made with Opdivo as
monotherapy and deliver new combination treatment options with the
potential to improve the lives of patients impacted by blood
cancers with high unmet needs.”
Preliminary Results from a Phase 1/2 Study of Brentuximab
Vedotin in Combination with Nivolumab in Patients with Relapsed or
Refractory Hodgkin Lymphoma (Abstract #1105, oral presentation at
4:30 p.m. PT)
Data were reported from 42 patients with relapsed or refractory
HL after failure of frontline therapy who received the combination
regimen of ADCETRIS plus Opdivo. Patients were treated once every
three weeks with up to four cycles of combination therapy. After
completion of the fourth cycle of treatment, patients were eligible
to undergo an autologous stem cell transplant (ASCT). The median
age of patients was 37 years. The majority of patients (88 percent)
were refractory or had progressed after receiving the standard of
care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine
and dacarbazine).
Key findings presented include:
- Of 29 response-evaluable patients, 26
patients (90 percent) had an objective response, including 18
patients (62 percent) with a complete metabolic response and eight
patients (28 percent) with a partial metabolic response. One
patient (three percent) had stable disease and two patients (seven
percent) had progressive disease.
- Of the 42 patients enrolled, all
patients (100 percent) received one or more dose of the study
therapies, 12 patients (29 percent) remain on treatment, 28
patients (67 percent) have completed treatment and two patients
(five percent) discontinued prior to the end of treatment. At the
time of data analysis in the ongoing trial, nine patients (21
percent) initiated an ASCT and two patients (five percent) received
an alternative salvage therapy prior to ASCT. Preliminary analysis
shows no impact of ADCETRIS and Opdivo combination on stem cell
mobilization or engraftment.
- The median number of doses administered
for both ADCETRIS and Opdivo was four. Of the 42 patients, no
patients had a dose reduction during treatment due to an adverse
event for either therapy. Dose delays occurred for three patients
(seven percent) with ADCETRIS treatment and four patients (10
percent) with Opdivo treatment. Reasons for dose delays were
urticaria, thrombosis, elevated lipase, chills and hypoxia.
- The most common adverse events of any
grade occurring prior to ASCT in more than 20 percent of patients
were fatigue, nausea, infusion related reaction, pruritus and rash.
One patient had a treatment-related serious adverse event after
Cycle 1 of ADCETRIS, with Grade 3 dehydration, Grade 1 asthenia and
nausea, Grade 2 hypercalcemia and malaise.
- Infusion-related reactions (IRR) were
observed in 38 percent of patients and most symptoms included
flushing and nausea (14 percent each); chest discomfort, dyspnea,
urticaria (12 percent each); cough and pruritis (10 percent each).
A protocol amendment was made requiring premedication with low-dose
corticosteroids and antihistamine. No patients discontinued
treatment due to an IRR.
- Potential immune-related adverse events
included IRR (36 percent [one IRR not reported as associated with
infusion]; Grade 1 or 2), rash (29 percent; Grade 1 or 2), diarrhea
(26 percent; Grade 1 or 2), transaminase elevation (10 percent;
Grade 1 and 3/4) and hypothyroidism (five percent; Grade 2). There
were no occurrences of pneumonitis or colitis.
ADCETRIS and Opdivo are being evaluated as combination therapy
in multiple ongoing phase 1/2 clinical trials. In addition to the
study presented at ASH, a trial titled “A Safety and Effectiveness
Study of Nivolumab in Combination With Brentuximab Vedotin to Treat
Non-Hodgkin Lymphomas” is ongoing and focused on patients with
relapsed or refractory disease, including diffuse large B-cell
lymphoma (DLBCL), and other rare subtypes of B-cell, including
mediastinal B-cell lymphoma and mediastinal gray zone lymphoma. In
addition, the companies recently extended the clinical evaluation
of ADCETRIS and Opdivo into a clinical trial evaluating the
combination as frontline treatment for older HL patients.
About Classical Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate
in the lymphatic system and is the most common type of blood
cancer. There are two major categories of lymphoma: HL, also known
as Hodgkin disease, and non-Hodgkin lymphoma. HL is a cancer that
starts in white blood cells called lymphocytes, which are part of
the body’s immune system. The disease is most often diagnosed in
early adulthood (ages 20-40) and late adulthood (older than 55
years of age). Classical Hodgkin lymphoma is the most common type
of HL, accounting for 95% of cases. Classical HL is distinguished
from other lymphomas by the characteristic presence of
CD30-positive Reed-Sternberg cells.
According to the American Cancer Society, approximately 8,500
cases of HL will be diagnosed in the United States during 2016 and
more than 1,100 will die from the disease. According to the
Lymphoma Coalition, over 62,000 people worldwide are diagnosed with
HL each year and approximately 25,000 people die each year from
this cancer. In the European Union, about 12,200 new cases and
2,600 deaths occurred in 2012 as a result of HL.
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 Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight
cancer, Opdivo has become an important treatment option
across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has
enrolled more than 25,000 patients. The Opdivo trials
have contributed to gaining a deeper understanding of the potential
role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of
PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune
checkpoint inhibitor to receive regulatory approval anywhere in the
world. Opdivo is currently approved in more than 57
countries, including the United States, the European Union and
Japan. In October 2015, the
company’s Opdivo + Yervoy combination was the
first Immuno-Oncology combination to receive regulatory approval
for the treatment of metastatic melanoma and is currently approved
in more than 47 countries, including the United States and the
European Union.
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
Bristol-Myers Squibb: At the Forefront of Immuno-Oncology
Science & Innovation
At Bristol-Myers Squibb, patients are at the center of
everything we do. Our vision for the future of cancer care is
focused on researching and developing transformational
Immuno-Oncology (I-O) medicines that will raise survival
expectations in hard-to-treat cancers and will change the way
patients live with cancer.
We are leading the scientific understanding of I-O through our
extensive portfolio of investigational and approved agents,
including the first combination of two I-O agents in metastatic
melanoma, and our differentiated clinical development program,
which is studying broad patient populations across more than 20
types of cancers with 11 clinical-stage molecules designed to
target different immune system pathways. Our deep expertise and
innovative clinical trial designs uniquely position us to advance
the science of combinations across multiple tumors and potentially
deliver the next wave of I-O combination regimens with a sense of
urgency. We also continue to pioneer research that will help
facilitate a deeper understanding of the role of immune biomarkers
and inform which patients will benefit most from I-O therapies.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
ADCETRIS (brentuximab vedotin) U.S. Important Safety
Information
BOXED WARNINGProgressive 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.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) with progression
on or after platinum-based chemotherapy. Patients with EGFR or ALK
genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and post-transplantation brentuximab vedotin. This
indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
IMPORTANT SAFETY
INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ
system; however, the most common severe immune-mediated adverse
reactions are enterocolitis, hepatitis, dermatitis (including toxic
epidermal necrolysis), neuropathy, and endocrinopathy. The majority
of these immune-mediated reactions initially manifested during
treatment; however, a minority occurred weeks to months after
discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy and evaluate clinical
chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have
been reported. Monitor patients for signs with radiographic imaging
and for symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or more severe pneumonitis. Permanently discontinue for
Grade 3 or 4 and withhold until resolution for Grade 2. In patients
receiving OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of
patients.
In CheckMate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 4.9% (13/263) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for
signs and symptoms of colitis. Administer corticosteroids for Grade
2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO
monotherapy for Grade 2 or 3 and permanently discontinue for Grade
4 or recurrent colitis upon re-initiation of OPDIVO. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent colitis.
In patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated colitis occurred in 26%
(107/407) of patients including three fatal cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal (diarrhea of ≥7 stools above baseline,
fever, ileus, peritoneal signs; Grade 3-5) immune-mediated
enterocolitis occurred in 34 (7%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 immune-mediated hepatitis. In patients receiving
OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8%
(35/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated hepatitis occurred in 13% (51/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade
3-5) occurred in 8 (2%) patients, with fatal hepatic failure in
0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated
adrenal insufficiency, autoimmune thyroid disorders, and Type 1
diabetes mellitus. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency, thyroid
function prior to and periodically during treatment, and
hyperglycemia. Administer hormone replacement as clinically
indicated and corticosteroids for Grade 2 or greater hypophysitis.
Withhold for Grade 2 or 3 and permanently discontinue for Grade 4
hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal
insufficiency. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement
therapy for hypothyroidism. Initiate medical management for control
of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO with
YERVOY, hypophysitis occurred in 9% (36/407) of patients. In
patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994) of patients. In patients receiving OPDIVO
with YERVOY, adrenal insufficiency occurred in 5% (21/407) of
patients. In patients receiving OPDIVO monotherapy, hypothyroidism
or thyroiditis resulting in hypothyroidism occurred in 9%
(171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994)
of patients receiving OPDIVO monotherapy. In patients receiving
OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving
OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy,
diabetes occurred in 0.9% (17/1994) of patients. In patients
receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%)
patients. All 9 patients had hypopituitarism, and some had
additional concomitant endocrinopathies such as adrenal
insufficiency, hypogonadism, and hypothyroidism. 6 of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In patients
receiving OPDIVO monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated rash occurred in 22.6% (92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. Withhold OPDIVO in patients with new-onset moderate to
severe neurologic signs or symptoms and evaluate to rule out other
causes. If other etiologies are ruled out, administer
corticosteroids and permanently discontinue OPDIVO for
immune-mediated encephalitis. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently
discontinue or withhold treatment, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO the following clinically
significant immune-mediated adverse reactions occurred in <1.0%
of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial
and abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism,
systemic inflammatory response syndrome, gastritis, duodenitis,
sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor
dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. Discontinue
OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt
or slow the rate of infusion in patients with Grade 1 or 2. In
patients receiving OPDIVO monotherapy, infusion-related reactions
occurred in 6.4% (127/1994) of patients. In patients receiving
OPDIVO with YERVOY, infusion-related reactions occurred in 2.5%
(10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from CheckMate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause
fetal harm when administered to a pregnant woman. Advise pregnant
women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with an OPDIVO- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human
milk. Because many drugs, including antibodies, are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from an OPDIVO-containing regimen,
advise women to discontinue breastfeeding during treatment. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Serious Adverse Reactions
In CheckMate 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions
occurred in 42% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse drug reactions reported in 2% to <5% of
patients receiving OPDIVO were abdominal pain, hyponatremia,
increased aspartate aminotransferase, and increased lipase. In
CheckMate 066, serious adverse reactions occurred in 36% of
patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions
occurred in 41% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse reactions reported in ≥2% of patients
receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). In CheckMate 067, serious adverse reactions (73%
and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313).
The most frequent (≥10%) serious adverse reactions in the OPDIVO
plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea
(13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%).
In CheckMate 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia,
pleural effusion, pneumonitis, and respiratory failure. In
CheckMate 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO (n=406). The most frequent serious
adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.
In CheckMate 205 and 039, among all patients (safety population
[n=263]), adverse reactions leading to discontinuation (4.2%) or to
dosing delays (23%) occurred. The most frequent serious adverse
reactions reported in ≥1% of patients were infusion-related
reaction, pneumonia, pleural effusion, pyrexia, rash and
pneumonitis. Ten patients died from causes other than disease
progression, including 6 who died from complications of allogeneic
HSCT. Serious adverse reactions occurred in 21% of patients in the
safety population (n=263) and 27% of patients in the subset of
patients evaluated for efficacy (efficacy population [n=95]). In
CheckMate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infections, and sepsis.
Common Adverse Reactions
In CheckMate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In CheckMate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
CheckMate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%),
diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and
dyspnea (20%). The most common (≥20%) adverse reactions in the
OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%),
and nausea (28%). In CheckMate 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite. In
CheckMate 025, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=406) vs everolimus (n=397) were
asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28%
vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs
32%), constipation (23% vs 18%), decreased appetite (23% vs 30%),
back pain (21% vs 16%), and arthralgia (20% vs 14%). In CheckMate
205 and 039, among all patients (safety population [n=263]) and the
subset of patients in the efficacy population (n=95), respectively,
the most common adverse reactions (≥20%) were fatigue (32% and
43%), upper respiratory tract infection (28% and 48%), pyrexia (24%
and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the
subset of patients in the efficacy population (n=95), the most
common adverse reactions also included rash (31%), musculoskeletal
pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and
peripheral neuropathy (21%). In CheckMate 141, the most common
adverse reactions (≥10%) in patients receiving OPDIVO were cough
and dyspnea at a higher incidence than investigator’s choice.
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at
3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%),
rash (29%), and colitis (8%).
CheckMate Trials and Patient Populations
CheckMate 067 – advanced melanoma alone or in combination
with YERVOY; CheckMate 037 and 066 – advanced melanoma;
CheckMate 017 – squamous non-small cell lung cancer (NSCLC);
CheckMate 057 – non-squamous NSCLC; CheckMate 025 –
renal cell carcinoma; CheckMate 205/039 – classical Hodgkin
lymphoma; CheckMate 141 – squamous cell carcinoma of the
head and neck
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
About the Bristol-Myers Squibb and Ono Pharmaceutical
Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its
territorial rights to develop and commercialize Opdivo globally
except in Japan, South Korea and Taiwan, where Ono had retained all
rights to the compound at the time. On July 23, 2014, Bristol-Myers
Squibb and Ono further expanded the companies’ strategic
collaboration agreement to jointly develop and commercialize
multiple immunotherapies – as single agents and combination
regimens – for patients with cancer in Japan, South Korea and
Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
Seattle Genetics 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 combination treatment with Opdivo, the anticipated benefits of
Seattle Genetics’ ADCETRIS clinical development program, and the
potential submission of applications (e.g., a supplemental
Biologics License Application in the U.S.) seeking label expansion
for ADCETRIS. 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 ADCETRIS and Opdivo combination trials,
and adverse regulatory actions affecting ADCETRIS, all of which
could result in Seattle Genetics being unable to expand ADCETRIS’
labeled indications. Seattle Genetics may also experience delays in
the conduct of and obtaining data from the ADCETRIS and Opdivo
combination studies and its other 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.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains “forward-looking statements” as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb’s business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb’s Annual Report on Form 10-K for the year ended December 31,
2015 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, 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/20161205006385/en/
Bristol-Myers SquibbMedia:Audrey Abernathy,
919-605-4521audrey.abernathy@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.comorSeattle
GeneticsInvestors:Peggy Pinkston,
425-527-4160ppinkston@seagen.comorMedia:Tricia Larson,
425-527-4180tlarson@seagen.com
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