First combination of two Immuno-Oncology agents in advanced melanoma to receive positive CHMP opinion, based on efficacy and safety data from two trials, CheckMate -067 and CheckMate -069
Bristol-Myers
Squibb Company (NYSE: BMY) announced today that the Committee for
Medicinal Products for Human Use (CHMP) has recommended the approval of Opdivo
in combination with Yervoy for the treatment of advanced
(unresectable or metastatic) melanoma in adults. The CHMP also added an
informative statement to the broad indication that relative to Opdivo
monotherapy, an increase in progression-free survival (PFS) for the
combination of Opdivo with Yervoy is established only in
patients with low tumor PD-L1 expression. This CHMP recommendation will
now be reviewed by the European Commission (EC), which has the authority
to approve medicines for the European Union. Opdivo monotherapy
is already approved by the EC for advanced melanoma and previously
treated advanced squamous non-small cell lung cancer (NSCLC), and was
recommended for approval by the CHMP in February for previously treated
advanced or metastatic non-squamous NSCLC and renal cell carcinoma (RCC).
Jean Viallet, M.D., Global Clinical Research Lead, Oncology,
Bristol-Myers Squibb, commented, “Our pioneering Immuno-Oncology science
began with the study of Yervoy in advanced melanoma. This
scientific knowledge led to the development of Opdivo, which is
now an important treatment option for patients with advanced melanoma.
Now, we continue our progress in finding new treatment options for this
devastating disease through the study of the combination of these two
Immuno-Oncology agents. We are pleased the CHMP has recommended approval
of Opdivo in combination with Yervoy in a broad melanoma
patient population, and look forward to the European Commission’s
decision.”
The CHMP adopted the positive opinion based on data from two trials,
CheckMate -067 and CheckMate -069, in addition to supportive data from
CA209-004, a Phase 1b study which evaluated the combination of Opdivo
and Yervoy in patients with advanced melanoma. CheckMate -067 is
a Phase 3, double-blind trial which evaluated Opdivo in
combination with Yervoy or Opdivo monotherapy vs. Yervoy
monotherapy in patients with previously untreated advanced melanoma,
and included patients with both BRAF V600 mutation-positive and
wild-type advanced melanoma. The co-primary endpoints were PFS and
overall survival (OS).
CheckMate -069 is a Phase 2, double-blind, randomized study which
evaluated Opdivo in combination with Yervoy vs. Yervoy monotherapy
in patients with previously untreated unresectable or metastatic
melanoma, and included patients with both BRAF wild-type and BRAF
V600 mutation-positive melanoma. The primary endpoint was objective
response rate (ORR) in patients with BRAF wild-type tumors.
Secondary endpoints included PFS in patients with BRAF wild-type
tumors, ORR in patients with BRAF V600 mutation positive tumors,
and safety. Overall survival was an exploratory endpoint.
About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled
growth of pigment-producing cells (melanocytes) located in the skin.
Metastatic melanoma is the deadliest form of the disease, and occurs
when cancer spreads beyond the surface of the skin to the other organs,
such as the lymph nodes, lungs, brain or other areas of the body.
Melanoma is the ninth most common cancer in Europe, with an estimated
100,000 new cases diagnosed annually and more than 20,000 deaths.
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 48 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), 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
confirmatory trials.
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
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. In addition, in
Checkmate -069, there were six patients who died without resolution of
abnormal respiratory findings. 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 -069 and -067, immune-mediated pneumonitis occurred in 6%
(25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3
(n=6), Grade 2 (n=17), and Grade 1 (n=1). 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).
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. When administered
with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate
-069 and -067, diarrhea or colitis occurred in 56% (228/407) of patients
receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26%
(107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32),
and Grade 1 (n=13). 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 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
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
-069 and -067, immune-mediated hepatitis occurred in 13% (51/407) of
patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37),
Grade 2 (n=5), and Grade 1 (n=1). 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 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 Dermatitis
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 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
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 -069 and -067, hypophysitis occurred in 9% (36/407) of
patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25),
and Grade 1 (n=3). 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 -069 and -067, adrenal
insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with
YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2).
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 -069 and -067, hypothyroidism or thyroiditis
occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade
3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in
8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1
(n=13). 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 -069 and -067, diabetes mellitus or
diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4
(n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). 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 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
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 -069 and
-067, immune-mediated nephritis and renal dysfunction occurred in 2.2%
(9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). 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).
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 -069 and -067,
immune-mediated rash occurred in 22.6% (92/407) of patients receiving
OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46).
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).
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 -067, encephalitis was
identified in one patient (0.2%) receiving OPDIVO with YERVOY.
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 -069 and -067, infusion-
related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO
with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). 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).
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 nursing
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 relative
to the OPDIVO arm. 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 -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%).
Common Adverse Reactions
In Checkmate -067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm 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 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 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 for YERVOY regarding immune-mediated adverse reactions.
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 BMS.com
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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 the Opdivo and Yervoy
combination therapy will receive regulatory approval in the European
Union for the indication described in this release. 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: 919-605-4521audrey.abernathy@bms.comorInvestors:Ranya Dajani, 609-252-5330, cell: 215-666-1515ranya.dajani@bms.comorBill Szablewski, 609-252-5894, cell: 215-801-0906william.szablewski@bms.com