Opdivo plus low-dose Yervoy combination
demonstrated long-term survival for patients with advanced
non-small cell lung cancer across PD-L1 expression levels
Median duration of response for patients
treated with Opdivo plus low-dose Yervoy was nearly four times
longer than chemotherapy across PD-L1 expression levels
Non-small cell lung cancer is the third
tumor type in which Opdivo plus Yervoy has demonstrated overall
survival benefit in a Phase 3 trial
Bristol-Myers Squibb Company (NYSE: BMY) today announced results
from Part 1 of the Phase 3 CheckMate -227 trial evaluating Opdivo
(nivolumab) plus low-dose Yervoy (ipilimumab) as first-line
treatment for patients with advanced non-small cell lung cancer
(NSCLC). Opdivo plus low-dose Yervoy met the independent co-primary
endpoint of overall survival, demonstrating superior benefit
compared to chemotherapy in patients whose tumors expressed PD-L1
≥1% [Hazard Ratio (HR) 0.79; 97.72% Confidence Interval (CI): 0.65
to 0.96]. Additionally, in an exploratory analysis, results showed
improved overall survival for patients treated with the combination
of Opdivo plus low-dose Yervoy with PD-L1 <1% (HR 0.62; 95% CI:
0.48 to 0.78). The two-year survival rate for patients treated with
the combination regimen was 40% for both patients whose tumors
expressed PD-L1 ≥1% and patients whose tumors expressed PD-L1
<1%. In the chemotherapy control arm, two-year survival rates
were 33% and 23%, respectively.
These results represent the first and only time a dual
Immuno-Oncology (I-O) therapy has demonstrated superior overall
survival versus chemotherapy in the first-line NSCLC setting and
will be featured in a Presidential Symposium at the European
Society for Medical Oncology (ESMO) 2019 Congress in Barcelona,
Spain (Presentation #LBA4_PR, Saturday, September 28, 4:30-6:20 PM
CEST).
The safety profile of Opdivo plus low-dose Yervoy was consistent
with previously reported studies in NSCLC and no new safety signals
were observed.
With a minimum follow-up of 29.3 months, patients treated with
Opdivo plus low-dose Yervoy, regardless of PD-L1 expression level,
experienced a nearly four times longer duration of response
compared to patients treated with chemotherapy. In patients with
PD-L1 ≥1%, the objective response rate was 35.9% (95% CI, 31.1 to
40.8) with Opdivo plus low-dose Yervoy (5.8% complete responses)
versus 30.0% (95% CI, 25.5 to 34.7) with chemotherapy (1.8%
complete responses). The median duration of response (DoR) for the
combination therapy arm was 23.2 months versus 6.2 months in the
chemotherapy arm. In patients with PD-L1 <1%, the objective
response rate was 27.3% (95% CI, 30.7 to 45.4) with Opdivo plus
low-dose Yervoy (2.1% complete responses) versus 23.1% (95% CI,
17.3 to 29.8) with chemotherapy (1.1% complete responses), with a
median DoR of 18 months for the combination therapy arm versus 4.8
months in the chemotherapy arm.
“These positive results validate the immunologic rationale for
the dual inhibition of PD-1 and CTLA-4 in the treatment of lung
cancer,” said Martin Reck, M.D., Ph.D., CheckMate -227 study
investigator, Lung Clinic Grosshansdorf, German Center of Lung
Research. “These data show that dual Immuno-Oncology therapy has
the potential to deliver deep and durable responses, with a clear
survival benefit, in first-line non-small cell lung cancer, without
the need for chemotherapy.”
“The Part 1 data from CheckMate -227 make Opdivo and Yervoy the
first and only dual Immuno-Oncology therapy to demonstrate superior
overall survival over chemotherapy in first-line non-small cell
lung cancer,” said Fouad Namouni, M.D., head, Oncology Development,
Bristol-Myers Squibb. “These results build upon the long-term
clinical data in first-line melanoma and renal cell carcinoma
demonstrating the benefit of combining Yervoy and Opdivo compared
to standard of care. We look forward to sharing these data with
regulatory authorities and through continued research, expanding
our understanding of the value of this unique combination for
patients with cancer.”
About CheckMate -227
CheckMate -227 is a multi-part open-label Phase 3 trial
evaluating Opdivo-based regimens versus platinum-doublet
chemotherapy in patients with first-line advanced non-small cell
lung cancer across non-squamous and squamous tumor histologies:
- Part 1:
- Part 1a: Opdivo plus low-dose Yervoy or Opdivo monotherapy
versus chemotherapy in patients whose tumors express PD-L1
- Part 1b: Opdivo plus low-dose Yervoy or Opdivo plus
chemotherapy versus chemotherapy in patients whose tumors do not
express PD-L1
- Part 2: Opdivo plus chemotherapy versus chemotherapy,
regardless of PD-L1
There are two co-primary endpoints in Part 1 for Opdivo plus
Yervoy (versus chemotherapy): overall survival (OS) in patients
whose tumors express PD-L1 (assessed in patients enrolled in Part
1a) and progression-free survival (PFS) in patients with TMB ≥10
mut/Mb across the PD-L1 spectrum (assessed in patients enrolled
across Parts 1a and 1b). Part 1 met both its co-primary endpoints
of PFS with the Opdivo plus Yervoy combination versus chemotherapy
in patients whose tumors have high (≥10 mutations/megabase, mut/mb)
TMB, regardless of PD-L1 expression, and OS demonstrating a
superior benefit for Opdivo plus low-dose Yervoy or Opdivo versus
chemotherapy in first-line NSCLC patients whose tumors express
PD-L1 ≥1%. Part 2 did not meet its primary endpoint for OS for
Opdivo plus chemotherapy versus chemotherapy alone, in patients
with non-squamous NSCLC.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally. The
two main types of lung cancer are non-small cell and small cell.
Non-small cell lung cancer (NSCLC) is one of the most common types
of lung cancer and accounts for up to 85% of diagnoses. Survival
rates vary depending on the stage and type of the cancer when
diagnosed. For patients diagnosed with metastatic lung cancer, the
five-year survival rate is approximately 5%.
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 60 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 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 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 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 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 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. 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 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 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 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 as a 60-minute infusion,
infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a separate study 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 an OPDIVO- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
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 an OPDIVO-containing regimen,
advise women to discontinue breastfeeding during treatment. Advise
women to discontinue breastfeeding 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 (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 effusions, 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 and in 43% of patients receiving sunitinib. 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
patients treated with sunitinib, they were pneumonia, pleural
effusion, and dyspnea. 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) vs sunitinib (n=535) were fatigue (58% vs 69%), rash
(39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs
40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs
25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased
appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs
28%). 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 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 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 plus low-dose Yervoy may not achieve
their primary study endpoints or receive regulatory approval for
the additional indications described in this release in the
currently anticipated timeline or at all and, if approved, whether
such product candidate for such additional indications 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: Eric Van Zanten 610-529-6219
eric.vanzanten@bms.com
Investors: Tim Power 609-252-7509
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