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U.S. Food and Drug Administration Approves Opdivo® (nivolumab) as the First New Medication in Nearly 20 Years for Certain Patients with Previously Treated Small Cell Lung Cancer

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  • Opdivo is now the first Immuno-Oncology treatment approved for
    small cell lung cancer (SCLC) patients who received platinum-based
    chemotherapy and at least one other line of therapy
  • Approval based on overall response rate and duration of response
    from the SCLC cohort of the Phase 1/2 CheckMate -032 trial
    1

Bristol-Myers
Squibb Company
(NYSE:BMY) today announced that Opdivo (nivolumab)
received approval from the U.S. Food and Drug Administration (FDA) as
the first and only Immuno-Oncology treatment option for patients with
metastatic small cell lung cancer (SCLC) whose cancer has progressed
after platinum-based chemotherapy and at least one other line of therapy.1
Approval for this indication has been granted under accelerated approval
based on overall response rate (ORR) and duration of response (DOR).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials.1

"At Bristol-Myers Squibb, we recognize the critical need to provide
patients with cancer therapies that may offer more durable responses –
particularly for those living with hard-to-treat, aggressive diseases
like small cell lung cancer,"2 said Sabine Maier, M.D.,
development lead, thoracic cancers, Bristol-Myers Squibb. "This approval
builds on our heritage of bringing Immuno-Oncology therapies to patients
with other types of thoracic cancers. It also reinforces our commitment
to bringing transformative treatments to patients in urgent need of
effective new options."

Opdivo 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.1
Please see the Important Safety Information section below.

This approval for Opdivo in patients with SCLC whose cancer has
progressed after two or more prior lines of therapy was granted priority
review from the FDA.

The approval was based on data from the SCLC cohort of the ongoing Phase
1/2 CheckMate -032 study evaluating Opdivo in patients who
experienced disease progression after platinum-based chemotherapy.1
Of 109 patients receiving Opdivo after platinum-based
chemotherapy and at least one other prior line of therapy, 12%
(n=13/109; 95% CI: 6.5-19.5) responded to treatment based on assessment
by a Blinded Independent Central Review (BICR), regardless of PD-L1
expression.1,3 Twelve patients had a partial response (11%),
and one patient had a complete response (0.9%).1,3 Among
these responders, the median DOR was 17.9 months (95% CI: 7.9-42.1;
range: 3.0-42.1 months).3 Opdivo was discontinued in
10% of patients, and one dose was withheld in 25% of patients for an
adverse reaction.1 Serious adverse reactions occurred in 45%
of patients.1 The approved dosing for Opdivo in this
indication is 240 milligrams administered every 2 weeks by intravenous
infusion until disease progression or unacceptable toxicity.1

"While Immuno-Oncology innovations have dramatically changed how
oncologists approach certain cancers, we have had limited progress for
patients with small cell lung cancer," said Leora Horn, M.D., M.Sc.,
associate professor of medicine, Ingram associate professor of cancer
research, director of the thoracic oncology program and assistant vice
chairman for faculty development, Vanderbilt University Medical Center.
"Today's approval of nivolumab is particularly exciting considering it
is the first checkpoint inhibitor approved for these specific patients,
and now we can finally treat this devastating disease from a different
angle."1

Small cell lung cancer is one of two main types of lung cancer and
accounts for about 10% to 15% of all lung cancers.4 Small
cell lung cancer is an aggressive disease, and symptoms often are not
detected until the cancer is at an advanced stage.2 In the
United States, about 27,000 cases of SCLC are expected to be diagnosed
in 2018.5 From the time of diagnosis, five-year survival
rates for extensive stage SCLC, or Stage IV, are about 2%.6

"Small cell lung cancer can be a very challenging disease, particularly
for those who have already been through multiple types of treatment, as
most patients relapse within a year of diagnosis,"7 said
Andrea Ferris, president and chairman of LUNGevity Foundation. "This
approval marks a major milestone for the patients touched by this
unrelenting disease and may motivate them to pursue further treatment
where there previously were no other approved options."

Approval Based on CheckMate -032 Trial

CheckMate -032 is a Phase 1/2 multicenter, multi-cohort, open-label and
ongoing trial, including 245 patients with SCLC who had experienced
disease progression after platinum-based chemotherapy treated with Opdivo
monotherapy.1,8 Efficacy was based on 109 patients who
had experienced disease progression after platinum-based chemotherapy
and at least one other prior line of therapy.1 These patients
received 3 mg/kg of Opdivo given by intravenous infusion over 60
minutes every 2 weeks and were included regardless of their PD-L1 status.1
Infusions were administered to patients until disease progression or
unacceptable toxicity. The trial excluded patients with autoimmune
disease, medical conditions requiring systemic immunosuppression,
symptomatic interstitial lung disease, or untreated brain metastasis.1
Patients with treated brain metastases were eligible if neurologically
stable.1

The first tumor assessments were conducted 6 weeks after the first dose
and continued every 6 weeks for the first 24 weeks and every 12 weeks
thereafter.1 The major efficacy outcome measures were
confirmed ORR, which was further characterized by DOR, as assessed by a
BICR.1 The median duration of therapy in patients treated
with Opdivo in the CheckMate -032 trial was 1 month (range: 0 to
44.2+ months).1 Seventeen percent of patients received Opdivo
for greater than 6 months, and 9% of patients received Opdivo for
greater than one year.1

Select Safety Profile for the CheckMate -032
Trial

The safety was evaluated in 245 patients with SCLC who experienced
disease progression after platinum-based chemotherapy.1 The
most frequent serious adverse reactions reported in at least 2% of
patients were pneumonia, dyspnea, pneumonitis, pleural effusion and
dehydration.1 The most common adverse reactions (reported in
at least 20% of patients) were fatigue (45%), decreased appetite (27%),
musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%),
constipation (20%) and cough (20%).1,9

INDICATIONS

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 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 recurrent or metastatic squamous cell carcinoma of the
head and neck (SCCHN) with disease progression on or after
platinum-based therapy.

IMPORTANT SAFETY INFORMATION

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.

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. In patients receiving OPDIVO
monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of
patients.

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.

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 monotherapy, adrenal
insufficiency occurred in 1% (20/1994) 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 monotherapy, diabetes occurred in 0.9%
(17/1994) of patients.

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.

Immune-Mediated Skin Adverse Reactions

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.

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.

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, 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.

Embryo-Fetal Toxicity

Based on its mechanism of action, OPDIVO 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-containing
regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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.

Serious Adverse Reactions

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
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 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.

Common Adverse Reactions

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 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 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.

Checkmate Trials and Patient Populations

Checkmate 032–previously treated small cell lung cancer; Checkmate
017–squamous non-small cell lung cancer (NSCLC); Checkmate
057–non-squamous NSCLC; Checkmate 141–squamous cell carcinoma of the
head and neck.

Please see U.S. Full Prescribing Information for OPDIVO.

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 medicines, including Immuno-Oncology (I-O)
therapeutic approaches, for hard-to-treat cancers that could potentially
improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumor
cell and immune system pathways, 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 the
I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation
therapies across multiple tumors and potentially deliver the next wave
of therapies with a sense of urgency. We also continue to pioneer
research that will help facilitate a deeper understanding of the role of
immune biomarkers and how a patient's tumor biology can be used as a
guide for treatment decisions throughout their journey.

We understand making the promise of transformational medicines like I-O
therapies 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: August 2018. Princeton, NJ: Bristol-Myers
Squibb Company.

2. National Cancer Institute. Small Cell Lung Cancer Treatment. Lung
Cancer. https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq.
Updated April 20, 2018. Accessed May 30, 2018.

3. Data on file. NIVO 403. Princeton, NJ: Bristol-Myers Squibb.

4. American Cancer Society. Key Statistics About Small Cell Lung Cancer. https://www.cancer.org/cancer/small-cell-lung-cancer/about/key-statistics.html.
Revised January 4, 2018. Accessed May 30, 2018.

5. Decision Resources Group Epidemiology Data. Burlington, MA: Decision
Resources Group.

6. American Cancer Society. Small Cell Lung Cancer Survival Rates, by
Stage. https://www.cancer.org/cancer/small-cell-lung-cancer/detection-diagnosis-staging/survival-rates.html.
Accessed May 30, 2018.

7. Pietanza C, Byers L, Minna J, et al. Small Cell Lung Cancer: Will
Recent Progress Lead to Improved Outcomes? Clin Cancer Res.
2015;21(10):2244-2255.

8. ClinicalTrials.gov. A Study of Nivolumab by Itself or Nivolumab
Combined With Ipilimumab in Patients With Advanced or Metastatic Solid
Tumors (CheckMate -032). https://clinicaltrials.gov/ct2/show/NCT01928394?term=NCT01928394&rank=1.
Published August 23, 2013. Updated December 7, 2017. Accessed August 1,
2018.

9. Data on file. NIVO 414. Princeton, NJ: Bristol-Myers Squibb.

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