Designation based on results of Phase 3 study, CheckMate -141, in which Opdivo met its primary endpoint of overall survival, versus three standard of care options in this patient population
Designation signals the urgent need for new treatment approaches in recurrent or metastatic squamous cell carcinoma of the head and neck after platinum based therapy
Bristol-Myers
Squibb Company (NYSE: BMY) announced today that the U.S. Food and
Drug Administration (FDA) has granted Breakthrough Therapy Designation
to Opdivo for the potential indication of recurrent or metastatic
squamous cell carcinoma of the head and neck (SCCHN) after platinum
based therapy. The Breakthrough Therapy Designation is an FDA program
intended to expedite the development and review of medicines with early
signals of potential clinical benefit in serious diseases to help ensure
patients have access to new therapies as soon as possible.
The designation is based on results of CheckMate -141, a Phase 3,
open-label, randomized trial evaluating Opdivo versus
investigator’s choice of therapy in patients with recurrent or
metastatic SCCHN with tumor progression within six months of platinum
therapies in the adjuvant, primary, recurrent or metastatic setting.
This trial was stopped early in January 2016 because an assessment
conducted by the independent Data Monitoring Committee (DMC) concluded
that the study met its primary endpoint of overall survival.
Jean Viallet, M.D., Global Clinical Research Lead, Oncology,
Bristol-Myers Squibb, commented, “The Breakthrough Therapy Designation
for Opdivo in advanced squamous cell carcinoma of the head and
neck underscores the immediate need for new treatment approaches for
this devastating disease, and reflects our commitment to advancing
Immuno-Oncology research with the goal of addressing hard-to-treat
cancers and changing survival expectations for patients.”
According to the FDA, the criteria for Breakthrough Therapy Designation
requires preliminary clinical evidence that demonstrates the medicine
may have substantial improvement on at least one clinically significant
endpoint over available therapy. This is the fifth Breakthrough Therapy
Designation granted for Opdivo by the FDA, with previous
Breakthrough Therapy Designation indications including patients with
Hodgkin lymphoma after failure of autologous stem cell transplant and
brentuximab, previously treated advanced melanoma, previously treated
non-squamous non-small cell lung cancer, and advanced or metastatic
renal cell carcinoma.
About Head & Neck Cancer
Head and neck cancer is the seventh most common cancer globally, with an
estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000
deaths per year. The five-year survival rate is reported as less than 4%
for metastatic Stage IV disease. Squamous cell carcinoma of the head and
neck (SCCHN) accounts for approximately 90% of all head and neck cancers
with global incidence expected to increase by 17% between 2012 and 2022.
Risk factors for SCCHN include tobacco and alcohol consumption, and the
increasing role of Human Papilloma Virus (HPV) infection leading to
rapid increase in oropharyngeal SCCHN in Europe and North America.
Quality of life is often impacted for SCCHN patients, as physiological
function (breathing, swallowing, eating, drinking), personal
characteristics (appearance, speaking, voice), sensory function (taste,
smell, hearing), and psychological/social function can be affected.
Bristol-Myers Squibb & Immuno-Oncology:
Advancing Oncology Research
At Bristol-Myers Squibb, we have a vision for the future of cancer care
that is focused on Immuno-Oncology, now considered a major treatment
choice alongside surgery, radiation, chemotherapy and targeted therapies
for certain types of cancer.
We have a comprehensive clinical portfolio of investigational and
approved Immuno-Oncology agents, many of which were discovered and
developed by our scientists. Our ongoing Immuno-Oncology clinical
program is looking at broad patient populations, across multiple solid
tumors and hematologic malignancies, and lines of therapy and
histologies, with the intent of powering our trials for overall survival
and other important measures like durability of response. We pioneered
the research leading to the first regulatory approval for the
combination of two Immuno-Oncology agents, and continue to study the
role of combinations in cancer.
We are also investigating other immune system pathways in the treatment
of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO,
and LAG-3. These pathways may lead to potential new treatment options –
in combination or monotherapy – to help patients fight different types
of cancers.
Our collaboration with academia, as well as small and large biotech
companies, to research the potential of Immuno-Oncology and
non-Immuno-Oncology combinations, helps achieve our goal of providing
new treatment options in clinical practice.
At Bristol-Myers Squibb, we are committed to changing survival
expectations in hard-to-treat cancers and the way patients live with
cancer.
About Opdivo
Cancer cells may exploit “regulatory” pathways, such as checkpoint
pathways, to hide from the immune system and shield the tumor from
immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that
binds to the checkpoint receptor PD-1 expressed on activated T-cells,
and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s
suppressive signaling on the immune system, including the interference
with an anti-tumor immune response.
Opdivo’s broad global development program is based on
Bristol-Myers Squibb’s understanding of the biology behind
Immuno-Oncology. Our company is at the forefront of researching the
potential of Immuno-Oncology to extend survival in hard-to-treat
cancers. This scientific expertise serves as the basis for the Opdivo
development program, which includes a broad range of Phase 3 clinical
trials evaluating overall survival as the primary endpoint across a
variety of tumor types. The Opdivo trials have also contributed
toward the clinical and scientific understanding of the role of
biomarkers and how patients may benefit from Opdivo across the
continuum of PD-L1 expression. To date, the Opdivo clinical
development program has enrolled more than 18,000 patients.
Opdivo was the first PD-1 immune checkpoint inhibitor to receive
regulatory approval anywhere in the world in July 2014, and currently
has regulatory approval in 50 countries including the United States,
Japan, and in the European Union.
U.S. FDA APPROVED INDICATIONS
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of
patients with BRAF V600 wild-type unresectable or metastatic melanoma.
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
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.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO
treatment. Across the clinical trial experience with solid tumors, fatal
immune-mediated pneumonitis occurred with OPDIVO. Monitor patients for
signs with radiographic imaging and symptoms of pneumonitis. Administer
corticosteroids for Grade 2 or greater pneumonitis. Permanently
discontinue for Grade 3 or 4 and withhold until resolution for Grade 2.
In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in
1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2
(n=12). In Checkmate 057, immune-mediated pneumonitis, including
interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade
3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025,
pneumonitis, including interstitial lung disease, occurred in 5%
(21/406) of patients receiving OPDIVO and 18% (73/397) of patients
receiving everolimus. Immune-mediated pneumonitis occurred in 4.4%
(18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4),
Grade 2 (n=12), and Grade 1 (n=1).
Immune-Mediated Colitis
Immune-mediated colitis can occur with OPDIVO treatment. Monitor
patients for signs and symptoms of colitis. Administer corticosteroids
for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single
agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for
Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037,
066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients
receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of
patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In
Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients
receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of
patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate
025, diarrhea or colitis occurred in 25% (100/406) of patients receiving
OPDIVO and 32% (126/397) of patients receiving everolimus.
Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of
patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1
(n=1).
Immune-Mediated Hepatitis
Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor
patients for abnormal liver tests prior to and periodically during
treatment. Administer corticosteroids for Grade 2 or greater
transaminase elevations. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate
037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787)
of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2
(n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated
hepatitis. In Checkmate 025, there was an increased incidence of liver
test abnormalities compared to baseline in AST (33% vs 39%), alkaline
phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs
3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated
hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406)
of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1
diabetes mellitus can occur with OPDIVO treatment. Monitor patients for
signs and symptoms of hypophysitis, signs and symptoms of adrenal
insufficiency during and after treatment, thyroid function prior to and
periodically during treatment, and hyperglycemia. Administer
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. Administer insulin for type 1 diabetes. Withhold OPDIVO
for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.
In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of
patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1
(n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate
037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of
patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1
(n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients
developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency
occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3),
Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, 066, and 067,
hypothyroidism or thyroiditis occurred in 9% (73/787) of patients
receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35).
Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO:
Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057,
Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7%
(20/287) and elevated thyroid stimulating hormone occurred in 17% of
patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4%
(4/287) of patients. In Checkmate 025, thyroid disease occurred in 11%
(43/406) of patients receiving OPDIVO, including one Grade 3 event, and
in 3.0% (12/397) of patients receiving everolimus.
Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving
OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14).
Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO:
Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 037, 066, and 067,
diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of
patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1
(n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9%
(37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred
in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2
(n=2), and Grade 1 (n=1).
Immune-Mediated Nephritis and Renal Dysfunction
Immune-mediated nephritis can occur with OPDIVO treatment. Monitor
patients for elevated serum creatinine prior to and periodically during
treatment. For Grade 2 or 3 increased serum creatinine, withhold and
administer corticosteroids; if worsening or no improvement occurs,
permanently discontinue. Administer corticosteroids for Grade 4 serum
creatinine elevation and permanently discontinue. In Checkmate 037, 066,
and 067, nephritis and renal dysfunction of any grade occurred in 5%
(40/787) of patients receiving OPDIVO. Immune-mediated nephritis and
renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4)
and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal
dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In
Checkmate 025, renal injury occurred in 7% (27/406) of patients
receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus.
Immune-mediated nephritis and renal dysfunction occurred in 3.2%
(13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1),
Grade 3 (n=5), and Grade 2 (n=6).
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Severe rash
(including rare cases of fatal toxic epidermal necrolysis) occurred in
the clinical program of OPDIVO. Monitor patients for rash. Administer
corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and
permanently discontinue for Grade 4. In Checkmate 037, 066, and 067,
immune-mediated rash occurred in 9% (72/787) of patients receiving
OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate
057, immune-mediated rash occurred in 6% (17/287) of patients receiving
OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in
28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients
receiving everolimus. Immune-mediated rash, defined as a rash treated
with systemic or topical corticosteroids, occurred in 7% (30/406) of
patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1
(n=19).
Immune-Mediated Encephalitis
Immune-mediated encephalitis can occur with OPDIVO treatment. 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 Checkmate 057, fatal limbic
encephalitis occurred in one patient (0.3%) receiving OPDIVO.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or
withhold treatment, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. In < 1.0% of patients
receiving OPDIVO, the following clinically significant, immune-mediated
adverse reactions occurred: uveitis, pancreatitis, facial and abducens
nerve paresis, demyelination, polymyalgia rheumatica, autoimmune
neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic
inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis.
Across clinical trials of OPDIVO as a single agent administered at doses
of 3 mg/kg and 10 mg/kg, additional clinically significant,
immune-mediated adverse reactions were identified: motor dysfunction,
vasculitis, and myasthenic syndrome.
Infusion Reactions
Severe infusion reactions have been reported in <1.0% of patients in
clinical trials of OPDIVO. 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 Checkmate 037, 066, and 067, Grade 2
infusion related reactions occurred in 2.7% (21/787) of patients
receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In
Checkmate 057, Grade 2 infusion reactions requiring corticosteroids
occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025,
hypersensitivity/infusion-related reactions occurred in 6% (25/406) of
patients receiving OPDIVO and 1.0% (4/397) of patients receiving
everolimus.
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 067, serious adverse reactions (37%), adverse reactions
leading to permanent discontinuation (14%) or to dosing delays (28%),
and Grade 3 or 4 adverse reactions (44%) occurred in the OPDIVO arm. The
most frequent (≥10%) serious adverse reactions in the OPDIVO arm were
diarrhea (2.6%), colitis (1.6%), and pyrexia (0.6%). In Checkmate 037,
serious adverse reactions occurred in 41% of patients receiving OPDIVO.
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. 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 057, serious adverse reactions occurred in 47% of patients
receiving OPDIVO. The most frequent serious adverse reactions reported
in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural
effusion, and respiratory failure. In Checkmate 025, serious adverse
reactions occurred in 47% of patients receiving OPDIVO. The most
frequent serious adverse reactions reported in ≥2% of patients were
acute kidney injury, pleural effusion, pneumonia, diarrhea, and
hypercalcemia.
Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO
arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In
Checkmate 037, the most common adverse reaction (≥20%) reported with
OPDIVO was rash (21%). In Checkmate 066, the most common adverse
reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49%
vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and
pruritus (23% vs 12%). In Checkmate 057, the most common adverse
reactions (≥20%) reported with OPDIVO were fatigue (49%),
musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and
constipation (23%). In Checkmate 025, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic
conditions (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%).
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co.,
Ltd (Ono) 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, Bristol-Myers Squibb and Ono 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 www.BMS.com
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and YouTube.
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.
Among other risks, there can be no guarantee that Opdivo will receive
regulatory approval for an additional indication in SCCHN.
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, 2015 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.

Bristol-Myers SquibbMedia:Audrey Abernathy, 609-419-5375, Cell: 919-605-4521, audrey.abernathy@bms.comorInvestors:Ranya Dajani, 609-252-5330, ranya.dajani@bms.comBill Szablewski, 609-252-5894, william.szablewski@bms.com