Opdivo demonstrated a 23% reduction in the
risk of death and 2.5-month improvement in median overall survival
compared to chemotherapy
Results from Phase 3 ATTRACTION-3 trial to
be featured in a Presidential Symposium during the European Society
for Medical Oncology 2019 Annual Congress
Bristol-Myers Squibb Company (NYSE: BMY) and Ono Pharmaceutical
Co., Ltd. today announced results from the Phase 3 ATTRACTION-3
trial evaluating Opdivo (nivolumab) versus chemotherapy (docetaxel
or paclitaxel) for the treatment of patients with unresectable
advanced or recurrent esophageal squamous cell carcinoma (ESCC)
refractory or intolerant to combination therapy with
fluoropyrimidine and platinum-based drugs. For the primary endpoint
of overall survival (OS), Opdivo demonstrated a statistically
significant improvement over chemotherapy, with a 23% reduction in
risk of death [Hazard Ratio (HR) 0.77; 95% Confidence Interval
(CI): 0.62 to 0.96; p=0.019] and a 2.5-month improvement in median
OS [10.9 months (95% CI: 9.2 to 13.3)] compared to patients treated
with chemotherapy [8.4 months (95% CI: 7.2 to 9.9)]. The safety
profile of Opdivo in this trial was consistent with previously
reported studies in ESCC and other solid tumors.
These data (Presentation #LBA11) will be featured in the
Presidential Symposium on Monday, September 30 from 4:30-6:15 PM
CEST at the European Society for Medical Oncology (ESMO) 2019
Annual Congress in Barcelona, Spain and simultaneously published in
The Lancet Oncology.
Patients treated in the Opdivo arm showed 12- and 18-month OS
rates of 47% (95% CI: 40 to 54) and 31% (95% CI: 24 to 37),
respectively, versus 34% (95% CI: 28 to 41) and 21% (95% CI: 15 to
27) among patients in the chemotherapy arm. Survival benefit with
Opdivo was observed regardless of tumor PD-L1 expression levels. An
exploratory analysis of patient-reported outcomes showed
significant overall improvement in quality of life with Opdivo
versus chemotherapy.
“The significant survival benefit coupled with the favorable
safety profile and patient-reported outcomes observed in this trial
suggest Opdivo has the potential to represent an important new
second-line treatment option for patients with advanced esophageal
squamous cell carcinoma, offering the possibility to extend their
survival and improve their quality of life during treatment,” said
Dr. Byoung Chul Cho, Professor, Yonsei Cancer Center, Yonsei
University College of Medicine.
The objective response rates (ORR) between the two arms were
comparable at 19% (95% CI: 14 to 26) among patients receiving
Opdivo versus 22% (95% CI: 15 to 29) among those receiving
chemotherapy. However, the study showed Opdivo substantially
increased the median duration of response (DoR) for patients [6.9
months (95% CI: 5.4 to 11.1) versus 3.9 months (95% CI: 2.8 to
4.2)]. Seven patients in the Opdivo arm had ongoing responses at
data cutoff compared to two patients in the chemotherapy arm. An
overall HR of 1.08 (95% CI: 0.87 to 1.34) suggested no meaningful
difference in progression-free survival (PFS) between the Opdivo
and chemotherapy arms.
“These are very promising results for patients with advanced
esophageal squamous cell carcinoma for whom prognosis is typically
poor and are particularly important given Opdivo improved survival
regardless of PD-L1 status,” said Ian M. Waxman, M.D., development
lead, Gastrointestinal Cancers, Bristol-Myers Squibb. “We are
encouraged to see important progress being made in this tumor type
and look forward to broadening our research in gastrointestinal
tumors.”
Fewer treatment-related adverse events (TRAEs) were reported
with Opdivo versus chemotherapy, with a rate of 66% of any grade
TRAEs for patients receiving Opdivo compared to 95% for patients
receiving chemotherapy. Patients in the Opdivo arm also experienced
a lower incidence of Grade 3 or 4 TRAEs compared to those in the
chemotherapy arm (18% versus 63%), and the percentage of patients
experiencing TRAEs leading to discontinuation was the same in both
arms (9%).
About ATTRACTION-3
ATTRACTION-3 (ONO-4538-24/CA209-473; NCT02569242) is a Phase 3,
multi-center, randomized, open-label global study, evaluating
Opdivo versus chemotherapy (docetaxel or paclitaxel) for patients
with esophageal cancer refractory or intolerant to first-line
combination therapy with fluoropyrimidine and platinum-based drugs.
Patient enrollment occurred predominantly in Asia with 96% of
patients in both treatment arms from Asia. Patients were treated
until disease progression or unacceptable toxicity. The primary
endpoint of the trial is OS. Secondary endpoints include
investigator-assessed ORR, PFS, disease control rate, DoR and
safety. This trial was sponsored by Ono Pharmaceutical Co. Ltd. of
Japan, Bristol-Myers Squibb’s development partner for Opdivo.
About Esophageal Cancer
Esophageal cancer is the seventh most common cancer and the
sixth most common cause of death from cancer worldwide. The
five-year relative survival rate is 8% or less for patients
diagnosed with metastatic disease. The two most common types of
esophageal cancer are squamous cell carcinoma and adenocarcinoma,
which account for approximately 90% and 10% of all esophageal
cancers, respectively. Each year, an estimated 572,000 new cases
are diagnosed and approximately half a million deaths are caused by
esophageal cancer. The majority of cases are diagnosed in the
advanced setting and impact a patient’s daily life, including their
ability to eat and drink. The prevalence of esophageal cancer is
highest in Asia, with over 444,000 cases diagnosed yearly,
accounting for about 80% of all esophageal cancer cases
worldwide.
Bristol-Myers Squibb: Advancing
Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. The focus of our research is to increase quality,
long-term survival for patients and make cure a possibility.
Through a unique multidisciplinary approach powered by
translational science, we harness our deep scientific experience in
oncology and Immuno-Oncology (I-O) research to identify novel
treatments tailored to individual patient needs. Our researchers
are developing a diverse, purposefully built pipeline designed to
target different immune system pathways and address the complex and
specific interactions between the tumor, its microenvironment and
the immune system. We source innovation internally, and in
collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of
transformational medicines, like I-O, a reality for patients.
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 treated more
than 35,000 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 65 countries, including
the United States, the European Union, Japan and China. 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.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
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 metastatic small cell lung cancer (SCLC) with progression
after platinum-based chemotherapy and at least one other line of
therapy. 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 advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with intermediate or
poor risk, previously untreated advanced renal cell carcinoma
(RCC).
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), as a single agent, 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), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adults and pediatric patients 12
years and older 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.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
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 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6%
(25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 1.7% (2/119) 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 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated colitis occurred in 26% (107/407) of patients
including three fatal cases. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10%
(52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7%
(8/119) of patients.
In a separate Phase 3 trial 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 trial (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Cytomegalovirus (CMV) infection/reactivation has been reported
in patients with corticosteroid-refractory immune-mediated colitis.
In cases of corticosteroid-refractory colitis, consider repeating
infectious workup to exclude alternative etiologies. Addition of an
alternative immunosuppressive agent to the corticosteroid therapy,
or replacement of the corticosteroid therapy, should be considered
in corticosteroid-refractory immune-mediated colitis if other
causes are excluded.
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 1 mg/kg with YERVOY 3
mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119)
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 trial 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 trial 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 1 mg/kg
with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of
patients. In patients receiving OPDIVO monotherapy, adrenal
insufficiency occurred in 1% (20/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In RCC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 5.9% (7/119) 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 1 mg/kg with
YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving this
dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 22% (119/547) of patients.
Hyperthyroidism occurred in 12% (66/547) of patients receiving this
dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis
resulting in hypothyroidism occurred in 15% (18/119) of patients.
Hyperthyroidism occurred in 12% (14/119) of patients. In patients
receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994)
of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes
occurred in 2.7% (15/547) of patients.
In a separate Phase 3 trial 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. Six 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated
nephritis and renal dysfunction occurred in 2.2% (9/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and
renal dysfunction occurred in 1.7% (2/119) 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 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 14% (17/119) of
patients.
In a separate Phase 3 trial 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 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of
exposure. Encephalitis occurred in one RCC patient receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of
exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient
(0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days
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, aplastic anemia,
pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
which has been observed in patients receiving OPDIVO and may
require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions, which have
been reported in <1.0% of patients in clinical trials.
Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related
reactions. Interrupt or slow the rate of infusion in patients with
Grade 1 or 2. In patients receiving OPDIVO monotherapy as a
60-minute infusion, infusion-related reactions occurred in 6.4%
(127/1994) of patients. In a separate trial in which patients
received OPDIVO monotherapy as a 60-minute infusion or a 30-minute
infusion, infusion-related reactions occurred in 2.2% (8/368) and
2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368)
and 1.4% (5/369) of patients, respectively, experienced adverse
reactions within 48 hours of infusion that led to dose delay,
permanent discontinuation or withholding of OPDIVO. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks,
infusion-related reactions occurred in 2.5% (10/407) of patients.
In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
infusion-related reactions occurred in 5.1% (28/547) of patients.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, infusion-related reactions occurred in 4.2% (5/119) of
patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1 receptor blocking
antibody. Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1 receptor blocking antibody prior to
or after an allogeneic HSCT.
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 OPDIVO or YERVOY and for at least 5 months after the
last dose.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In clinical trials in patients with multiple myeloma, the
addition of OPDIVO to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with
multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
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 OPDIVO or YERVOY, advise women
not to breastfeed during treatment and for at least 5 months after
the last 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 (74%
and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4
adverse reactions (72% and 51%) 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 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).
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 ≥2% of patients receiving OPDIVO were
pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion,
pneumonitis, and respiratory failure. In Checkmate 032, serious
adverse reactions occurred in 45% of patients receiving OPDIVO
(n=245). The most frequent serious adverse reactions reported in at
least 2% of patients receiving OPDIVO were pneumonia, dyspnea,
pneumonitis, pleural effusion, and dehydration. 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 214,
serious adverse reactions occurred in 59% of patients receiving
OPDIVO plus YERVOY. The most frequent serious adverse reactions
reported in ≥2% of patients were diarrhea, pyrexia, pneumonia,
pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal
insufficiency, and colitis. 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 (n=236). The most
frequent serious adverse reactions reported in ≥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
≥2% of patients receiving OPDIVO were urinary tract infection,
sepsis, diarrhea, small intestine obstruction, and general physical
health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO with YERVOY, serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and dehydration. In
Checkmate 040, serious adverse reactions occurred in 49% of
patients (n=154). The most frequent serious adverse reactions
reported in ≥2% of patients were pyrexia, ascites, back pain,
general physical health deterioration, abdominal pain, and
pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions
occurred in 25% of OPDIVO-treated patients (n=452). The most
frequent Grade 3 and 4 adverse reactions reported in ≥2% of
OPDIVO-treated patients were diarrhea and increased lipase and
amylase. Serious adverse reactions occurred in 18% of
OPDIVO-treated patients.
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 (62%), diarrhea (54%),
rash (53%), nausea (44%), pyrexia (40%), pruritus (39%),
musculoskeletal pain (32%), vomiting (31%), decreased appetite
(29%), cough (27%), headache (26%), dyspnea (24%), upper
respiratory tract infection (23%), arthralgia (21%), and increased
transaminases (25%). In Checkmate 067, the most common (≥20%)
adverse reactions in the OPDIVO arm (n=313) were fatigue (59%),
rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea
(30%), cough (28%), pruritus (27%), upper respiratory tract
infection (22%), decreased appetite (22%), headache (22%),
constipation (21%), arthralgia (21%), and vomiting (20%). 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 032, the
most common adverse reactions (≥20%) in patients receiving OPDIVO
(n=245) were fatigue (45%), decreased appetite (27%),
musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea
(21%), constipation (20%), and cough (20%). In Checkmate 025, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=406) vs everolimus (n=397) were fatigue (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 214, the most common adverse
reactions (≥20%) reported in patients treated with OPDIVO plus
YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%),
musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough
(28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%),
dyspnea (20%), and vomiting (20%). 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 (n=236) 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 142 in
MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the
most common adverse reactions (≥20%) were fatigue (54%), diarrhea
(43%), abdominal pain (34%), nausea (34%), vomiting (28%),
musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%),
constipation (20%), and upper respiratory tract infection (20%). In
Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with
YERVOY, the most common adverse reactions (≥20%) were fatigue
(49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%),
abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%),
decreased appetite (20%), and vomiting (20%). 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%). In Checkmate 238, the most
common adverse reactions (≥20%) reported in OPDIVO-treated patients
(n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs
55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal
pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%),
nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and
abdominal pain (21% vs 23%). The most common immune-mediated
adverse reactions were rash (16%), diarrhea/colitis (6%), and
hepatitis (3%).
In a separate Phase 3 trial 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 037–previously treated metastatic melanoma;
Checkmate 066–previously untreated metastatic melanoma; Checkmate
067–previously untreated metastatic melanoma, as a single agent or
in combination with YERVOY; Checkmate 017–second-line treatment of
metastatic squamous non-small cell lung cancer; Checkmate
057–second-line treatment of metastatic non-squamous non-small cell
lung cancer; Checkmate 032–small cell lung cancer; Checkmate
025–previously treated renal cell carcinoma; Checkmate
214–previously untreated renal cell carcinoma, in combination with
YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate
141–recurrent or metastatic squamous cell carcinoma of the head and
neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or
dMMR metastatic colorectal cancer, as a single agent or in
combination with YERVOY; Checkmate 040–hepatocellular carcinoma;
Checkmate 238–adjuvant treatment of melanoma
About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., 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, Ono and Bristol-Myers
Squibb 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, Facebook and
Instagram.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on historical performance and current expectations and
projections about our future financial results, goals, plans and
objectives and involve inherent risks, assumptions and
uncertainties, including internal or external factors that could
delay, divert or change any of them in the next several years, that
are difficult to predict, may be beyond our control and could cause
our future financial results, goals, plans and objectives to differ
materially from those expressed in, or implied by, the statements.
These risks, assumptions, uncertainties and other factors include,
among others, that future study results will be consistent with the
results to date, that Opdivo may not achieve its primary study
endpoints or receive regulatory approval for the additional
indication described in this release in the currently anticipated
timeline or at all and, if approved, whether such product candidate
for such additional indication described in this release will be
commercially successful. No forward-looking statement can be
guaranteed. Forward-looking statements in this press release should
be evaluated together with the many risks and uncertainties that
affect Bristol-Myers Squibb’s business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for
the year ended December 31, 2018, as updated by our subsequent
Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and
other filings with the Securities and Exchange Commission. The
forward-looking statements included in this document are made only
as of the date of this document and except as otherwise required by
applicable law, Bristol-Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
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Bristol-Myers Squibb Company Media Inquiries:
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Power 609-252-7509 timothy.power@bms.com
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