-Combination Data Show 85 Percent Objective
Response Rate and 63 Percent Complete Response Rate with an
Acceptable Safety Profile in these Pre-Transplant Relapsed or
Refractory Classical Hodgkin Lymphoma Patients-
-Data Support Recently Initiated Pivotal Phase
3 Clinical Trial Evaluating ADCETRIS and Opdivo Combination in
Relapsed Hodgkin Lymphoma-
Seattle Genetics, Inc. (Nasdaq: SGEN) and Bristol-Myers Squibb
Company (NYSE: BMY) today highlighted an updated interim analysis
from the ongoing phase 1/2 clinical trial evaluating ADCETRIS
(brentuximab vedotin) and Opdivo (nivolumab) in relapsed or
refractory (RR) classical Hodgkin lymphoma (HL) at the
International Conference on Malignant Lymphoma (ICML) in Lugano,
Switzerland. The data reported from 62 patients, including 59
evaluable for response, will be featured in an oral presentation on
June 15, 2017. ADCETRIS is an antibody-drug conjugate (ADC)
directed to CD30, a defining marker of classical HL. Opdivo is a
programmed death-1 (PD-1) immune checkpoint inhibitor that is
designed to help restore anti-tumor immune response. ADCETRIS and
Opdivo are not approved in combination for the treatment of RR
classical HL or for other indications.
“The phase 1/2 study combining the antibody-drug conjugate
brentuximab vedotin with the PD-1 immune checkpoint inhibitor
nivolumab 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 additive activity,” said Alex
Herrera, M.D., lead trial investigator and assistant professor at
the City of Hope, Duarte, California. “The interim results support
further exploration of this novel regimen, free of traditional
chemotherapy.”
“We are evaluating ADCETRIS in novel combinations in order to
identify potential treatment regimens for patients with
CD30-expressing lymphomas,” said Jonathan Drachman, M.D., Chief
Medical Officer and Executive Vice President, Research and
Development of Seattle Genetics. “We are pleased to share updated
interim results from this ongoing phase 1/2 clinical trial
evaluating ADCETRIS in combination with Opdivo in relapsed or
refractory HL patients. Since our first patient treated with the
combination regimen, the data continue to demonstrate encouraging
activity with an acceptable safety profile. These updated data
support findings first presented at ASH 2016. We have nearly
doubled the number of patients in our trial evaluating the
ADCETRIS/Opdivo combination strategy and recently announced a
collaboration with BMS to initiate a pivotal phase 3 clinical trial
in relapsed HL patients in mid-2017.”
“Bristol-Myers Squibb continues to strengthen our broad
Immuno-Oncology and hematology development programs for Opdivo,”
said Fouad Namouni, M.D., head of Oncology Development,
Bristol-Myers Squibb. “Our continued partnership with Seattle
Genetics, combines our deep I-O experience and shared commitment to
innovative combination treatment options that have the potential to
improve the lives of patients impacted by blood cancers. We look
forward to further evaluation of ADCETRIS in combination with
Opdivo for the treatment of relapsed Hodgkin lymphoma.”
Interim Results from a Phase 1/2 Study of Brentuximab Vedotin
in Combination with Nivolumab in Patients with Relapsed or
Refractory Hodgkin Lymphoma (Abstract #074, oral presentation at
6:05 p.m. CEST)
Data were reported from 62 patients with RR classical 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 36 years. Forty-five percent of patients had
primary refractory disease and 55 percent progressed after
responding to frontline therapy, among whom 90 percent received
standard of care frontline treatment ABVD (Adriamycin, bleomycin,
vinblastine and dacarbazine).
Key findings presented include:
- Of 59 response-evaluable patients, 50
patients (85 percent) had an objective response, including 37
patients (63 percent) with a complete response and 13 patients (22
percent) with a partial response. Five patients (eight percent) had
stable disease and four patients (seven percent) had progressive
disease.
- Of the 62 patients enrolled, 61
patients (98 percent) received one or more dose of the study
therapies. No patients remain on treatment, 58 patients (94
percent) have completed treatment and four patients (six percent)
discontinued prior to the end of treatment. At the time of data
analysis in the ongoing trial, 37 patients (60 percent) initiated
an ASCT and 12 patients (19 percent) received an alternative
salvage therapy subsequent to combination therapy. No unusual
post-ASCT adverse events were reported. Preliminary analysis shows
no impact of ADCETRIS and Opdivo combination on stem cell
mobilization or engraftment.
- Prior to ASCT, the most common
adverse events of any grade occurring in more than 25 percent of
patients were nausea (56 percent); fatigue (43 percent);
infusion-related reactions (IRRs, 36 percent); pruritus (31
percent); headache (28 percent); and diarrhea, rash and vomiting
(all at 26 percent). Treatment-related serious adverse events
occurred in five patients (eight percent), including pneumonitis
and pyrexia (two patients each) and colitis, malaise, nausea,
pneumonia, respiratory failure and sepsis (one patient each).
- Infusion related reactions (IRRs) were
observed in 41 percent of patients. All IRRs were Grade 3 or less,
with the rate of Grade 3 IRRs less than five percent.
ADCETRIS and Opdivo are being evaluated as combination therapy
in multiple ongoing clinical trials. In addition to the study
presented at ICML, a pivotal phase 3 clinical trial evaluating
ADCETRIS in combination with Opdivo compared to ADCETRIS alone in
relapsed/refractory HL patients is planned to begin enrollment in
mid-2017. In addition, 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. 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 percent 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, more than 8,000 cases
of HL will be diagnosed in the United States during 2017 and
approximately 1,000 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
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.
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. ADCETRIS
has received marketing authorization by regulatory authorities in
67 countries for relapsed or refractory HL and systemic anaplastic
large cell lymphoma (sALCL). In addition, 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 Biologics License Application is planned in mid- 2017.
See important safety information below.
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 and Yervoy combination regimen 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 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 and is commercially available globally
in 67 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 and in
collaboration with Astellas, enfortumab vedotin, an ADC in a
planned pivotal phase 2 trial for metastatic urothelial cancer.
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, Celldex, Genentech,
GlaxoSmithKline and Pfizer. More information can be found at
www.seattlegenetics.com
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’ individual 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 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 toxicityEvents 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 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.
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. 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, 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.
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 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; Checkmate 275
- urothelial carcinoma.
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 Co.,
Ltd. 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 future
potential therapeutic uses of ADCETRIS (including in combination
with Opdivo) and future clinical and regulatory progress. 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 risks related to adverse clinical
results associated with the use of ADCETRIS or Opdivo (or the
combination), the failure of the companies to continue their
collaboration or execute on the planned clinical trials or adverse
regulatory action. More information about the risks and
uncertainties faced by Seattle Genetics is contained in the
Company’s Quarterly Report on Form 10-Q for the quarter ended March
31, 2017 filed with the Securities and Exchange Commission. Seattle
Genetics disclaims any intention or obligation to update or revise
any forward-looking statements, whether as a result of new
information, future events or otherwise.
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 ADCETRIS in combination with Opdivo will be successfully
developed or approved 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20170615005339/en/
Bristol-Myers SquibbMedia:Audrey Abernathy,
609-419-5375audrey.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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