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Bristol-Myers Squibb's Opdivo® (nivolumab) + Low-Dose Yervoy® (ipilimumab) is the First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a Fluoropyrimidine, Oxaliplatin and...

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Bristol-Myers Squibb's Opdivo®
(nivolumab) + Low-Dose Yervoy
®
(ipilimumab) is the First Immuno-Oncology Combination Approved for
MSI-H/dMMR mCRC Patients Who Progressed Following Treatment with a
Fluoropyrimidine, Oxaliplatin and Irinotecan

  • In the CheckMate -142 trial, Opdivo + Yervoy
    demonstrated an overall response rate of 46% (95% CI: 35-58; n = 38/82)
    1
  • Opdivo + Yervoy is now approved in three tumor types, dosing and
    administration varies by tumor
    1

Bristol-Myers
Squibb Company
(NYSE:BMY) today announced Opdivo (nivolumab)
3 mg/kg plus low-dose Yervoy (ipilimumab) 1 mg/kg (injections for
intravenous use) received approval from the U.S. Food and Drug
Administration (FDA) for the treatment of adult and pediatric patients
12 years and older with microsatellite instability high (MSI-H) or
mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC)
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin and irinotecan.1 Approval for this indication has
been granted under accelerated approval based on overall response rate
(ORR) and duration of response (DOR).1 Continued approval for
this indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.

"Bristol-Myers Squibb is pleased to bring forward Opdivo plus Yervoy
as the first I-O/I-O combination therapy to be approved in this type of
colorectal cancer," said Ian M. Waxman, M.D., development lead,
gastrointestinal cancers, Bristol-Myers Squibb. "Our commitment to
studying Opdivo plus Yervoy, which target distinct but
complementary immune pathways, results from our strong belief that
rational combinations in biomarker-selected populations may improve
clinical benefit for patients."

Opdivo + Yervoy is associated with the following Warnings
and Precautions: immune-mediated pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, skin adverse
reactions, encephalitis, other adverse reactions; infusion reactions;
and embryo-fetal toxicity. Please see the Important Safety Information
section below, including Boxed WARNING for Yervoy regarding
immune-mediated adverse reactions, as well as additional information on
CheckMate -142.1,2

Today's approved indication was based on data from the ongoing Phase 2
CheckMate -142 study evaluating the Opdivo + Yervoy
combination in patients with MSI-H or dMMR mCRC previously treated with
a fluoropyrimidine-, oxaliplatin- or irinotecan-based chemotherapy.1,3,4
The application was granted Priority Review and Breakthrough Therapy
Designation by the FDA.

The Opdivo + Yervoy cohort of the CheckMate -142 trial
enrolled MSI-H/dMMR mCRC patients who had received at least one prior
line of therapy for metastatic disease, and efficacy was analyzed for
both patients who had received prior treatment with a fluoropyrimidine,
oxaliplatin and irinotecan (82 of the total 119 patients) as well as for
all enrolled patients.1

  • Among the 82 patients who received prior treatment with a
    fluoropyrimidine, oxaliplatin and irinotecan, 46% (95% CI: 35-58; n =
    38/82) responded to treatment with Opdivo + Yervoy as
    assessed by Independent Radiographic Review Committee (IRRC).1
    • The percentage of these patients with a complete response was 3.7%
      (n = 3/82), and the percentage of patients with a partial response
      was 43% (n = 35/82).1 Among these 38 responders, the
      median DOR was not reached (range: 1.9-23.2+ months); 89% of those
      patients had responses of six months or longer, and 21% had
      responses of 12 months or longer.1,5,6 This trial is
      ongoing.3
  • Among all enrolled patients, 49% (95% CI: 39-58; n = 58/119) responded
    to treatment with Opdivo + Yervoy; 4.2% (n = 5/119)
    experienced a complete response, while 45% (n = 53/119) experienced a
    partial response.1 Among these 58 responders, the median
    DOR was not reached (range: 1.9-23.2+ months)5,6; 83% of
    those patients had responses of six months or longer, and 19% had
    responses of 12 months or longer.1 In the combination
    cohort, 51 of 58 responders were ongoing at the time of database lock;
    78% of these ongoing responders had not reached 12 months of follow-up
    from the date of onset of response.1

The recommended dosing schedule includes the Opdivo + low-dose Yervoy
combination (Opdivo 3 mg/kg, administered as an I.V. infusion
over 30 minutes, followed by Yervoy 1 mg/kg, administered as an
I.V. infusion over 30 minutes, on the same day, every three weeks for
four doses), followed by Opdivo maintenance therapy (240 mg,
administered as an I.V. infusion over 30 minutes, every two weeks) after
completion of four doses of the combination until disease progression or
unacceptable toxicity.1 Please review the U.S. Full
Prescribing Information for Yervoy prior to initiation.

In the Opdivo + Yervoy cohort of CheckMate -142, 86% of
patients received all four doses of Opdivo + Yervoy.7
Opdivo was discontinued in 13% of patients and delayed in 45% of
patients due to an adverse reaction.1 Serious adverse
reactions occurred in 47% of patients.1

"Metastatic colorectal cancers with dMMR or MSI-H biomarkers can be
difficult to treat and some patients may need additional options," said
Heinz-Josef Lenz, M.D., FACP, L. Terrence Lanni Chair in
Gastrointestinal Cancer Research, Keck School of Medicine of University
of Southern California and principal investigator of the study at USC
Norris Comprehensive Cancer Center. "The FDA's approval of an I-O/I-O
combination provides us with an encouraging approach to address this
challenging disease in patients who have progressed following treatment
with three standard chemotherapy options."

The Opdivo + Yervoy combination is also approved in two
other tumor types. The Opdivo (3 mg/kg) + low-dose Yervoy
(1 mg/kg) combination is approved for previously untreated patients with
intermediate- or poor-risk advanced renal cell carcinoma. Opdivo
(1 mg/kg) + Yervoy (3 mg/kg) is approved for patients with
unresectable or metastatic melanoma under accelerated approval based on
progression-free survival. Opdivo as a single agent is approved
for the treatment of adult and pediatric (12 years and older) patients
with MSI-H or dMMR metastatic colorectal cancer that has progressed
following treatment with a fluoropyrimidine, oxaliplatin and irinotecan
under accelerated approval based on ORR and DOR. Continued approval for
these accelerated approval indications may be contingent upon
verification and description of clinical benefit in the confirmatory
trials. The infusion time for each indication differs, please see U.S.
Full Prescribing Information for Opdivo and Yervoy for
details.1

Approval Based on CheckMate -142 Trial

CheckMate -142 included a multicenter, non-randomized, multiple-parallel
cohort, open-label study investigating Opdivo + Yervoy in
patients with locally determined dMMR or MSI-H mCRC whose disease had
progressed during or after prior treatment with a fluoropyrimidine-,
oxaliplatin- or irinotecan-based chemotherapy.1,8 In the
combination cohort, patients received Opdivo 3 mg/kg with Yervoy
1 mg/kg every three weeks for four doses, followed by Opdivo 3
mg/kg as a single agent every two weeks.1 Treatment continued
until unacceptable toxicity or radiographic progression.1
Tumor assessments were conducted every six weeks for the first 24 weeks
and every 12 weeks thereafter.1 Efficacy outcome measures
included ORR as assessed by IRRC using Response Evaluation Criteria in
Solid Tumors (RECIST v1.1) and DOR.1 Data from this study
were presented in January at the 2018 Gastrointestinal Cancers Symposium
and published simultaneously in the Journal of Clinical Oncology.

Select Safety Profile for the CheckMate -142
Trial

The most frequent serious adverse reactions reported in at least 2% of
patients were colitis/diarrhea, hepatic events, abdominal pain, acute
kidney injury, pyrexia, and dehydration.1 The most common
adverse reactions (reported in at least 20% of patients) 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%).1

About MSI-H or dMMR Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the
rectum, which are part of the body's digestive or gastrointestinal
system.10 In the United States, CRC is the third most common
cancer.10 In 2018, it is estimated that there will be
approximately 140,000 new cases of the disease and that it will be the
third leading cause of cancer-related deaths among men and women
combined.10

DNA mismatch repair deficiency (dMMR) occurs when the proteins that
repair mismatch errors in DNA replication are missing or non-functional,
leading to microsatellite instability-high (MSI-H) tumors.11,12
Approximately 5% of metastatic CRC patients have dMMR or MSI-H tumors.13
Patients with these biomarkers are less likely to benefit from
conventional chemotherapy and typically have a poor prognosis.11,13,14

INDICATIONS

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), 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), 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 approved 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 (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous
use.

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.

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. Withhold OPDIVO for Grade 2 and permanently discontinue
OPDIVO for Grade 3 or 4. 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 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.

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
breastfeeding during treatment with YERVOY and for 3 months following
the final dose.

Serious Adverse Reactions

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 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 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.

Common Adverse Reactions

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 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%), and decreased
appetite (21% vs 29%). 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 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.

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 advancing 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 24
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. Through our
leading translational capabilities, we are pioneering immune biology
research and identifying a number of potentially predictive biomarkers,
including PD-L1, TMB, MSI-H/dMMR and LAG-3, advancing the possibility of
precision medicine for more patients with cancer.

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.

About Bristol-Myers Squibb's Patient Access
Support

Bristol-Myers Squibb remains committed to providing assistance so that
cancer patients who need our medicines can access them and expedite time
to therapy.

BMS Access Support®, the Bristol-Myers Squibb patient access
and reimbursement program, is designed to help appropriate patients
initiate and maintain access to BMS medicines during their treatment
journey. BMS Access Support offers benefit investigation, prior
authorization assistance and co-pay assistance for eligible,
commercially insured patients. More information about our access and
reimbursement support can be obtained by calling BMS Access Support®
at 1-800-861-0048 or by visiting www.bmsaccesssupport.com.

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
and Facebook.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based on
current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be evaluated
together with the many uncertainties that affect Bristol-Myers Squibb's
business, particularly those identified in the cautionary factors
discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the
year ended December 31, 2017 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.

References

1. Opdivo Prescribing Information. Opdivo U.S. Product
Information. Last Updated: July 2018. Princeton, NJ: Bristol-Myers
Squibb Company.

2. Yervoy Prescribing Information. Yervoy U.S. Product
Information. Last Updated: July 2018. Princeton, NJ: Bristol-Myers
Squibb Company.

3. ClinicalTrials.gov. An investigational immune-therapy study of
nivolumab, and nivolumab in combination with other anti-cancer drugs, in
colon cancer that has come back or has spread (CheckMate142). https://clinicaltrials.gov/ct2/show/NCT02060188?term=NCT02060188&rank=11.
Published November 22, 2017. Updated January 23, 2018. Accessed April
23, 2018.

4. The ASCO Post. FDA accepts sBLA for nivolumab plus ipilimumab in
previously treated MSI-H or dMMR metastatic colorectal cancer. http://www.ascopost.com/News/58676.
Published March 30, 2018. Accessed April 23, 2018.

5. Overman M, Lonardi S, Yeung KYM, et al. Durable clinical benefit with
nivolumab plus ipilimumab in DNA mismatch
repair-deficient/microsatellite instability-high metastatic colorectal
cancer. J Clin Oncol. 2018;36(8):773-779.

6. Data on file. NIVO 319, Princeton, NJ: Bristol-Myers Squibb.

7. Data on file. NIVO 377, Princeton, NJ: Bristol-Myers Squibb.

8. Bever K, Le D. An expanding role for immunotherapy in colorectal
cancer. J Natl Compr Canc Netw. 2017;15(3):410-410.

9. McLean J, Rho YS, Kuruba G, et al. Clinical practice patterns in
chemotherapeutic treatment regimens for metastatic colorectal cancer. Clin
Colorectal Cancer
. 2016;15(2):135-140.

10. American Cancer Society. About Colorectal Cancer. https://www.cancer.org/content/dam/CRC/PDF/Public/8604.00.pdf.
Updated February 21, 2018. Accessed May 18, 2018.

11. Koopman M, Kortman G, Mekenkamp L, et al. Deficient mismatch repair
system in patients with sporadic advanced colorectal cancer. Brit J
Cancer
. 2009;100:266-273.

12. Yacoub G, Nagalla S, Aklilu M. Oncologic Management of Hereditary
Colorectal Cancer. Clin Colon Rectal Surg. 2012;25:118–122.

13. Venderbosch S, Nagteagaal ID, Maughan TS, et al. Mismatch repair
status and BRAF mutation status in metastatic colorectal cancer
patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS
studies. Clin Cancer Res. 2014;20:5322-5330.

14. Müller CI, Schulmann K, Reinacher-Schick A, et al. Predictive and
prognostic value of microsatellite instability in patients with advanced
colorectal cancer treated with a fluoropyrimidine and oxaliplatin
containing first-line chemotherapy. A report of the AIO Colorectal Study
Group. Int J Colorectal Dis. 2008;23:1033-1039.

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