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U.S. Food and Drug Administration (FDA) Accepts Application for Opdivo Plus Low-Dose Yervoy for Treatment of First-Line Non-Small Cell Lung Cancer in Patients with Tumor Mutational Burden ≥10 mut/Mb

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First-ever application for an I-O/I-O combination in lung cancer
to be accepted

Submission based on positive results from Part 1 of the Phase 3
study CheckMate -227

Bristol-Myers
Squibb Company
(NYSE:BMY) announced today that the U.S. Food and
Drug Administration (FDA) has accepted its supplemental Biologics
License Application (sBLA) for Opdivo (nivolumab) plus low-dose Yervoy
(ipilimumab) for the treatment of first-line advanced non-small cell
lung cancer (NSCLC) in patients with tumor mutational burden (TMB) ≥10
mutations per megabase (mut/Mb). The target FDA action date is February
20, 2019.

Sabine Maier, M.D., development lead, thoracic cancers, Bristol-Myers
Squibb, commented, "Lung cancer is a complex disease, and we believe
multiple treatment approaches, including those that are
biomarker-driven, are needed to help individual patients. We look
forward to working with the FDA throughout the review process to bring
this important treatment option to patients."

The application was based on results from Part 1 of CheckMate -227, the
first and only global Phase 3 study to evaluate an I-O/I-O regimen
versus chemotherapy in a population of first-line NSCLC patients with
TMB ≥10 mut/Mb, across squamous and non-squamous tumor histologies and
the PD-L1 expression spectrum. These data were presented at the American
Association for Cancer Research Annual Meeting 2018 and published in The
New England Journal of Medicine
.

About CheckMate -227

CheckMate -227 is an ongoing, multi-part, open-label global Phase 3
trial evaluating Opdivo-based regimens versus platinum-doublet
chemotherapy in patients with first-line advanced non-small cell lung
cancer across squamous and non-squamous tumor histologies.

  • 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 or tumor mutational burden (TMB) status

There are two co-primary endpoints in Part 1 for Opdivo plus
low-dose Yervoy versus chemotherapy: overall survival (OS) in
patients whose tumors express PD-L1 (assessed in patients enrolled in
Part 1a, which continues to final analysis) 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). TMB status was
assessed using the validated assay, FoundationOne CDx.

The primary endpoint in Part 2 is OS, and the study is ongoing.

Opdivo and Yervoy are dosed as follows in this study: Opdivo
3 mg/kg every two weeks with low-dose Yervoy (1 mg/kg) every six
weeks.

About Tumor Mutational Burden (TMB)

Over time, cancer cells accumulate mutations that are not seen in normal
cells of the body. Tumor mutational burden, or TMB, is a quantitative
biomarker that reflects the total number of mutations carried by tumor
cells. Tumor cells with high TMB have higher levels of neoantigens,
which are thought to help the immune system recognize tumors and incite
an increase in cancer-fighting T cells and an anti-tumor response. TMB
is one type of biomarker that may help predict the likelihood a patient
responds to immunotherapies.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in
nearly 1.7 million deaths each year, according to the World Health
Organization. It is estimated that more than 234,000 new cases of lung
cancer will be diagnosed in the United States this year and that the
disease will cause more than 154,000 deaths, or approximately 1 in 4
cancer deaths.

Non-small cell lung cancer (NSCLC) is one of the most common types of
lung cancer and accounts for approximately 85% of diagnoses. About 25%
to 30% of all lung cancers are squamous cell carcinomas, and
non-squamous NSCLC accounts for approximately 50% to 65% of all lung
cancer 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 less than 5%.

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 Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor
that is designed to uniquely harness the body's own immune system to
help restore anti-tumor immune response. By harnessing the body's own
immune system to fight cancer, Opdivo has become an
important treatment option across multiple cancers.

Opdivo's leading global development program is based on
Bristol-Myers Squibb's scientific expertise in the field of
Immuno-Oncology, and includes a broad range of clinical trials across
all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical
development program has enrolled more than 25,000 patients. The Opdivo trials
have contributed to gaining a deeper understanding of the potential role
of biomarkers in patient care, particularly regarding how patients may
benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world. Opdivo is
currently approved in more than 60 countries, including the United
States, the European Union and Japan. In October 2015, the company's Opdivo and Yervoy combination
regimen was the first Immuno-Oncology combination to receive regulatory
approval for the treatment of metastatic melanoma and is currently
approved in more than 50 countries, including the United States and the
European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.

OPDIVO® (nivolumab), in combination with YERVOY®
(ipilimumab), is indicated for the treatment of patients with
unresectable or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with EGFR
or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.

OPDIVO® (nivolumab), 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) 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) 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.

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 patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 4.4% (24/547) 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 patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated colitis occurred in 10% (52/547) 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
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 7% (38/547) 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 patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in
4.6% (25/547) 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 patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547)
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 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 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 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. 6 of the 9 patients were hospitalized for severe
endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum creatinine.
Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4
increased serum creatinine. In patients receiving OPDIVO monotherapy,
immune-mediated nephritis and renal dysfunction occurred in 1.2%
(23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY
3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in
2.2% (9/407) of patients. In 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.

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 patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6%
(91/547) 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

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