-Data Presented in Oral Session at the American Society of Hematology (ASH) Annual Meeting with Simultaneous Publication in Blood-
-Combination Data Showed 83 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 the Ongoing Pivotal Phase 3 CHECKMATE 812 Clinical Trial Evaluating Combination of ADCETRIS and Opdivo in Relapsed Hodgkin Lymphoma-
Seattle
Genetics, Inc. (NASDAQ:SGEN) and Bristol-Myers
Squibb Company (NYSE:BMY) today highlighted updated interim results
from an ongoing phase 1/2 clinical trial evaluating the combination of
ADCETRIS (brentuximab vedotin) and Opdivo (nivolumab) in relapsed
or refractory classical Hodgkin lymphoma (HL) at the 59th
American Society of Hematology (ASH) Annual Meeting and Exposition
taking place in Atlanta, Georgia, December 9-12, 2017. The data were
also simultaneously published online in the journal Blood. The
data reported from 62 patients, including 60 evaluable for response,
were featured in an oral presentation and selected to be included in the
2018 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.
“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 CD30-targeted therapy with a
therapy designed to activate the immune system. The antitumor activity
of the drugs may be enhanced when administered in combination,” said
Alex Herrera, M.D., lead trial investigator and assistant professor at
the City of Hope Medical Center, Duarte, California. “The interim
results evaluating the combination regimen in relapsed or refractory HL
patients continue to look compelling, demonstrating both promising
activity in addition to a manageable overall safety profile. These data
support further exploration of this novel, chemotherapy-free
investigational regimen in HL patients.”
“We are evaluating ADCETRIS broadly as the foundation of care for
CD30-expressing lymphomas, including combination strategies that have
the potential to improve efficacy. At this year’s ASH Annual Meeting, we
are presenting significant clinical updates that support this goal,
including results from the phase 3 ECHELON-1 clinical trial evaluating
ADCETRIS in combination with chemotherapy in frontline HL as well as
interim results from this phase 1/2 study evaluating ADCETRIS in
combination with Opdivo in relapsed HL,” said Jonathan Drachman,
M.D., Chief Medical Officer and Executive Vice President, Research and
Development at Seattle Genetics. “Interim results from the trial
evaluating ADCETRIS in combination with Opdivo as pre-transplant
salvage therapy for classical HL patients continue to look promising,
demonstrating an 83 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 the ongoing pivotal phase 3 CHECKMATE 812
study in patients with relapsed HL, in partnership with Bristol-Myers
Squibb.”
“Our ongoing collaboration to evaluate Opdivo in combination with
Seattle Genetics’ ADCETRIS reinforces Bristol-Myers Squibb’s commitment
to addressing cancer from all angles for patients with high unmet
needs,” said Fouad Namouni, M.D., head of Oncology Development,
Bristol-Myers Squibb. “We look forward to further evaluation of the
ADCETRIS and Opdivo combination in Hodgkin lymphoma and other
hematologic malignancies in several ongoing trials.”
Interim Results from a Phase 1/2 Study of Brentuximab Vedotin in
Combination with Nivolumab in Patients with Relapsed or Refractory
Hodgkin Lymphoma (Abstract #649, oral presentation at 10:30 a.m. ET)
Data were reported from 62 patients with relapsed or refractory HL who
received the combination regimen of ADCETRIS plus Opdivo after
failure of frontline therapy. Patients were treated once every three
weeks, with up to four cycles of combination therapy in the outpatient
setting. 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 36 years. The majority of patients (95
percent) were refractory or had relapsed after receiving the standard of
care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and
dacarbazine) or some variation of the standard of care (ABVE-PC, R-ABVD).
Key findings presented include:
-
Of 60 response-evaluable patients, 50 patients (83 percent) had an
objective response, including 37 patients (62 percent) with a complete
response and 13 patients (22 percent) with a partial response. Five
patients (eight percent) had stable disease and five patients (eight
percent) had progressive disease. Median follow-up time was eight
months and median duration of response was not yet reached. The
estimated six-month progression-free survival rate was 89 percent.
-
Of the 62 patients enrolled, 58 patients completed all four cycles of
study treatment and four patients discontinued prior to the end of
treatment. At the time of data analysis, 54 patients received an ASCT.
Preliminary analysis shows no impact of combination treatment with
ADCETRIS and Opdivo on stem cell mobilization or engraftment.
-
The most common adverse events (AEs) of any grade occurring prior to
ASCT or subsequent salvage therapy in at least 20 percent of patients
were nausea, fatigue, infusion-related reaction (IRR), pruritus,
diarrhea, headache, cough, vomiting, dyspnea, nasal congestion,
pyrexia and rash. Grade 3 or 4 adverse events occurred in 19 patients
(31 percent), with 17 patients (28 percent) having Grade 3 AEs
(fatigue, IRR, pruritus and diarrhea) and two patients (three percent)
having Grade 4 AEs (thrombocytopenia and increased lipase).
-
Infusion-related reactions (IRRs) were observed in 44 percent of
patients, of which the majority (41 percent) were Grade 1 or 2. No
patients discontinued treatment due to an IRR.
-
Potential immune-related adverse events, excluding IRRs, occurred in
50 patients (82 percent), and five patients required treatment with
systemic steroids, including patients with Grade 3 diarrhea and Grade
2 colitis, Grade 3 aspartate aminotransferase elevation, Grade 4
colitis and pneumonitis (after receiving additional salvage therapy),
Grade 2 pneumonitis, and Grade 4 pneumonitis (after BEAM, as part of
the conditioning regimen). No patients discontinued treatment due to
an immune-related adverse event.
ADCETRIS and Opdivo are being evaluated as combination therapy in
multiple ongoing 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 enrolling patients with relapsed or refractory disease,
including diffuse large B-cell lymphoma (DLBCL), and other rare subtypes
of B-cell lymphoma, including mediastinal B-cell lymphoma and
mediastinal gray zone lymphoma. The companies have also extended the
clinical evaluation of ADCETRIS and Opdivo into a clinical trial
evaluating the combination as frontline treatment for older HL patients.
Lastly, the companies initiated a pivotal phase 3 clinical trial called
CHECKMATE 812 trial evaluating ADCETRIS alone versus ADCETRIS in
combination with Opdivo in relapsed/refractory 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 8,260 cases of
Hodgkin lymphoma will be diagnosed in the United States during 2017 and
more than 1,000 will die from the disease. According to the Lymphoma
Coalition, over 62,000 people worldwide are diagnosed with Hodgkin
lymphoma each year and approximately 25,000 people die each year from
this cancer.
About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30 and is
being evaluated broadly in more than 70 clinical trials, including three
phase 3 studies: the completed ECHELON-1 trial in frontline classical
Hodgkin lymphoma that supported the recent FDA Breakthrough Therapy
Designation and submission of the supplemental Biologics License
Application (BLA) for use in this setting, the ongoing ECHELON-2 trial
in frontline mature T-cell lymphomas, and the ongoing CHECKMATE 812
trial of ADCETRIS in combination with Opdivo (nivolumab) for
relapsed/refractory Hodgkin lymphoma.
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached
by a protease-cleavable linker to a microtubule disrupting agent,
monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary
technology. The ADC employs a linker system that is designed to be
stable in the bloodstream but to release MMAE upon internalization into
CD30-expressing tumor cells.
ADCETRIS injection for intravenous infusion has received FDA approval
for four indications: (1) regular approval for adult patients with
primary cutaneous anaplastic large cell lymphoma (pcALCL) or
CD30-expressing mycosis fungoides (MF) who have received prior systemic
therapy, (2) 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, (3) regular approval for the treatment of
classical Hodgkin lymphoma patients at high risk of relapse or
progression as post-auto-HSCT consolidation, and (4) 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 in 2013, and non-conditional
approval for post-ASCT consolidation treatment of Hodgkin lymphoma
patients at increased risk of relapse or progression.
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 marketing authorization 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 69 countries for relapsed or refractory Hodgkin lymphoma and sALCL.
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 60 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 50 countries,
including the United States and the European Union.
About Seattle Genetics
Seattle Genetics is an innovative biotechnology company dedicated to
improving the lives of people with cancer through novel antibody-based
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.
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research
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 for
hard-to-treat cancers that could potentially improve outcomes for these
patients.
We are leading the scientific understanding of I-O through our extensive
portfolio of investigational compounds and approved agents. Our
differentiated clinical development program is studying broad patient
populations across more than 50 types of cancers with 14 clinical-stage
molecules designed to target different immune system pathways. Our deep
expertise and innovative clinical trial designs position us to advance
I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation
therapies across multiple tumors and potentially deliver the next wave
of therapies 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 how patients’ tumor biology can be used as a guide
for treatment decisions throughout their journey.
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 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: 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 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
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: Serious cases, including fatal outcomes, 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: 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. 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 confirmed.
-
Pulmonary toxicity: Noninfectious pulmonary toxicity events
including pneumonitis, interstitial lung disease, and acute
respiratory distress syndrome, some with fatal outcomes, 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: 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: Acute pancreatitis,
including fatal outcomes, has been reported in ADCETRIS-treated
patients. Other 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
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: peripheral sensory
neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory
tract infection, and pyrexia.
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
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, and for at least 6 months after the
final dose of ADCETRIS treatment.
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 adult patients
with classical Hodgkin lymphoma (cHL) that has relapsed or progressed
after autologous hematopoietic stem cell transplantation (HSCT) and
brentuximab vedotin or after 3 or more lines of systemic therapy that
includes autologous HSCT. 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.
OPDIVO® (nivolumab) is indicated for the treatment of patients with
locally advanced or metastatic urothelial carcinoma who have disease
progression during or following platinum-containing chemotherapy or have
disease progression within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy. This indication is
approved under accelerated approval based on tumor response rate and
duration of response. 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 adult and
pediatric (12 years and older) patients with microsatellite instability
high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal
cancer (CRC) that has progressed following treatment with a
fluoropyrimidine, oxaliplatin, and irinotecan. This indication is
approved under accelerated approval based on overall response rate and
duration of response. 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
hepatocellular carcinoma (HCC) who have been previously treated with
sorafenib. This indication is approved under accelerated approval based
on tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
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 6.0% (16/266) of patients receiving OPDIVO.
Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients
receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
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. For patients without HCC, withhold OPDIVO for Grade 2 and
permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC,
withhold OPDIVO and administer corticosteroids if AST/ALT is within
normal limits at baseline and increases to >3 and up to 5 times the
upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at
baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT
is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10
times the ULN. Permanently discontinue OPDIVO and administer
corticosteroids if AST or ALT increases to >10 times the ULN or total
bilirubin increases >3 times the ULN. 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 Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.
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 the adverse reaction, permanently discontinue
or withhold OPDIVO, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. Across clinical
trials of OPDIVO monotherapy or in combination with YERVOY, the
following clinically significant immune-mediated adverse reactions, some
with fatal outcome, occurred in <1.0% of patients receiving OPDIVO:
myocarditis, rhabdomyolysis, myositis, 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), 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, adverse reactions leading to discontinuation
occurred in 7% and dose delays due to adverse reactions occurred in 34%
of patients (n=266). Serious adverse reactions occurred in 26% of
patients. The most frequent serious adverse reactions reported in ≥1% of
patients were pneumonia, infusion-related reaction, pyrexia, colitis or
diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died
from causes other than disease progression: 3 from adverse reactions
within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months
after completing OPDIVO, and 6 from complications of allogeneic HSCT. 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 infection, and sepsis. In
Checkmate 275, serious adverse reactions occurred in 54% of patients
receiving OPDIVO (n=270). The most frequent serious adverse reactions
reported in at least 2% of patients receiving OPDIVO were urinary tract
infection, sepsis, diarrhea, small intestine obstruction, and general
physical health deterioration. In Checkmate 040, serious adverse
reactions occurred in 49% of patients (n=154). The most frequent serious
adverse reactions reported in at least 2% of patients were pyrexia,
ascites, back pain, general physical health deterioration, abdominal
pain, and pneumonia.
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, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue
(39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain
(26%), rash (24%), nausea (20%) and pruritus (20%). 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 Checkmate 275, the most common adverse reactions (≥ 20%) reported in
patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal
pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate
040, the most common adverse reactions (≥20%) in patients receiving
OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal
pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and
decreased appetite (22%). The most common adverse reactions (≥20%) in
patients who received OPDIVO as a single agent were fatigue, rash,
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough,
dyspnea, constipation, decreased appetite, back pain, arthralgia, upper
respiratory tract infection, and pyrexia.
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%).
Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY,
including Boxed WARNING regarding immune-mediated adverse reactions
for YERVOY.
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; Checkmate 275 –
urothelial carcinoma; Checkmate 040 – hepatocellular carcinoma.
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 in combination with Opdivo,
and as the foundation of care for CD30-expressing lymphomas, and its
safety and efficacy for these uses, as well as other statements that are
not historical facts. 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
difficulty and uncertainty of pharmaceutical product development,
unexpected efficacy or safety events or profiles associated with the use
of each or drug or in combination, or adverse regulatory action. More
information about the risks and uncertainties faced by Seattle Genetics
is contained under the caption “Risk Factors” included in the company’s
Quarterly Report on Form 10-Q for the quarter ended September 30, 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.
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.
Among other risks, there can be no guarantee that the Opdivo plus
ADCETRIS combination will receive regulatory approval for any of the
indications described in this release. 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, 2016
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.
Bristol-Myers Squibb Media: Audrey Abernathy, 609-419-5375 audrey.abernathy@bms.com or Investors: Tim Power, 609-252-7509 timothy.power@bms.com orBill Szablewski, 609-252-5894 william.szablewski@bms.com or Seattle Genetics Investors: Peggy Pinkston, 425-527-4160 ppinkston@seagen.com or Media: Tricia Larson, 425-527-4180 tlarson@seagen.com