Bristol-Myers
Squibb Company (NYSE: BMY) today announced updated survival data
from the advanced melanoma cohort (n=107) of the expanded Phase 1b
dose-ranging study of nivolumab, an investigational PD-1 immune
checkpoint inhibitor, administered as a single agent (Study -003).
Results showed sustained activity in this heavily pre-treated patient
population as defined by two- and three-year survival rates of 48% and
41%, respectively, across dose cohorts. These data, which are based on
Kaplan-Meier estimates, will be featured in an oral presentation at the
50th Annual Meeting of the American Society of Clinical Oncology (ASCO)
in Chicago on June 2 at 3 p.m. CDT (Abstract #9002).
“These Phase 1b results for nivolumab are encouraging in a group of
patients with one of the most aggressive forms of cancer,” said F.
Stephen Hodi, M.D., director of the Melanoma Treatment Center and
director of the Center for Immuno-Oncology at Dana-Farber, and Associate
Professor of Medicine at Harvard Medical School. “They represent the
longest follow up data for survival in pre-treated advanced melanoma
patients who have received an investigational PD-1 immune checkpoint
inhibitor as a single agent.”
“We are committed to improving survival expectations for patients with
advanced melanoma and to leading immuno-oncology research and
development that adds to the treatment options for patients across lines
of therapy and stages of disease,” said Michael Giordano, senior vice
president, Head of Development, Oncology & Immunology. “The updated
results reported in this Phase 1b study help to characterize the
long-term survival of nivolumab in this patient population. We look
forward to presenting additional follow up results at ASCO evaluating
the combination regimen of nivolumab and Yervoy®
(ipilimumab) in this tumor type along with the first reported results
from a Phase 3 trial of Yervoy as an investigational adjuvant
therapy.”
Results from Advanced Melanoma Cohort of Phase
1b Single Agent Study (-003)
Study -003 is a Phase 1b dose escalation study (n=306) evaluating the
safety, antitumor activity and pharmacokinetics of nivolumab as a single
agent in previously-treated patients with advanced melanoma (n=107),
non-small cell lung cancer (NSCLC) (n=129), renal cell carcinoma (n=34),
castration-resistant prostate cancer (n=17) or colorectal cancer (n=19).
Based on an amendment to the protocol, patients were followed for
survival. Eligible patients were administered nivolumab as an
intravenous infusion every two weeks of each eight-week treatment cycle.
Cohorts of three to six patients per dose level (0.1, 0.3, 1.0, 3.0 or
10 mg/kg) were enrolled sequentially. Patients continued treatment ≤2
years (12 cycles), unless they experienced complete response,
unacceptable toxicity, progressive disease or withdrew consent.
Results from this study were initially presented in 2012 at ASCO and
published in the New England Journal of Medicine. The initial and
updated analysis is reflective of 107 previously-treated advanced
melanoma patients who had not received prior treatment with Yervoy.
Updated results reported here show sustained activity in heavily
pre-treated patients as defined by two- and three-year survival rates of
48% and 41%, respectively, across dose cohorts. Of the 32% of patients
with objective responses (based on RECIST criteria), the median duration
of response was 22.9 months.
Safety data from this study published in the Journal of Clinical
Oncology earlier this year, with all patients having greater than or
equal to one year of follow up, demonstrated a spectrum, frequency and
severity of treatment-related adverse events (AEs) that were consistent
with those initially reported in the study in 2012. As reported, common
drug-related AEs included fatigue (32%), rash (23%), diarrhea (18%) and
pruritus (13%). Drug-related select AEs with potential immunologic
etiologies, defined as adverse events that may require more frequent
monitoring and/or unique intervention, included skin (36%),
gastrointestinal (18%), endocrine (13%), hepatic (6.5%), pulmonary
(3.7%) and renal (1.9%).
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 other organs, such
as the lymph nodes, lungs, brain or other areas of the body. The
incidence of melanoma has been increasing for at least 30 years. In
2012, an estimated 232,130 melanoma cases were diagnosed globally.
Melanoma is mostly curable when treated in its early stages. However, in
its late stages, the average survival rate has historically been just
six months with a one-year mortality rate of 75%, making it one of the
most aggressive forms of cancer.
About Bristol-Myers Squibb Immuno-Oncology
Trials in Melanoma
Bristol-Myers Squibb is committed to the research and development of
immuno-oncology as an innovative approach to treating melanoma and has a
broad development program evaluating its approved and investigational
immunotherapies – either as single agents or as part of a regimen -
across lines of therapy, stages of disease and biomarker expression.
Among these are five Phase 3 trials. There are two ongoing Phase 3
trials evaluating nivolumab as a single agent at the 3 mg/kg dose in
treatment-naïve patients (CheckMate -066) as well as in patients who
have been previously treated (CheckMate -037). A Phase 3 trial
evaluating Yervoy 3 mg/kg vs. Yervoy 10 mg/mg in patients
with previously treated or treatment-naïve metastatic melanoma is
ongoing (Study -169) and the first results of a Phase 3 trial evaluating
the use of Yervoy 10 mg/kg as adjuvant therapy among patients
with Stage 3 melanoma who are at high risk of recurrence following
complete surgical resection (Study -029) will be featured in an oral
presentation at ASCO on June 2 at 3 p.m. CDT (Abstract #LBA9008).
Additionally, a Phase 3 trial evaluating the combination regimen of
nivolumab and Yervoy in treatment-naïve patients is ongoing
(CheckMate -067).
About Nivolumab and Yervoy
Cancer cells may exploit “regulatory” pathways, such as checkpoint
pathways, to hide from the immune system and shield the tumor from
immune attack. Nivolumab and Yervoy are both monoclonal
antibodies and immune checkpoint inhibitors, but target different
receptors for distinct T-cell checkpoint pathways.
Nivolumab is an investigational, fully-human PD-1 immune checkpoint
inhibitor that binds to the checkpoint receptor PD-1 (programmed
death-1) expressed on activated T-cells. We are investigating whether by
blocking this pathway, nivolumab would enable the immune system to
resume its ability to recognize, attack and destroy cancer cells.
Bristol-Myers Squibb has a broad, global development program to study
nivolumab in multiple tumor types consisting of more than 35 trials – as
monotherapy or in combination with other therapies – in which more than
7,000 patients have been enrolled worldwide. Among these are several
potentially registrational trials in non-small cell lung cancer (NSCLC)
melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma
and non-Hodgkin lymphoma. In 2013, the FDA granted Fast Track
designation for nivolumab in NSCLC, melanoma and RCC.
Yervoy, which is a recombinant, human monoclonal antibody, blocks
the cytotoxic T- lymphocyte antigen-4 (CTLA-4). CTLA-4 is a negative
regulator of T-cell activation. Ipilimumab binds to CTLA-4
and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.
Blockade of CTLA-4 has been shown to augment T-cell activation and
proliferation. The mechanism of action of ipilimumab’s effect in
patients with melanoma is indirect through T-cell mediated anti-tumor
immune responses. On March 25, 2011, the FDA approved Yervoy 3
mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy
is now approved in more than 40 countries.
YERVOY® (ipilimumab) INDICATION & IMPORTANT
SAFETY INFORMATION
YERVOY (ipilimumab) is indicated for the treatment of unresectable or
metastatic melanoma.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions due to T-cell activation and proliferation. 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) and thyroid function tests at
baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroids for severe immune-mediated reactions.
Recommended Dose Modifications
Withhold dose for any moderate immune-mediated adverse reactions or for
symptomatic endocrinopathy until return to baseline, improvement to mild
severity, or complete resolution, and patient is receiving <7.5 mg
prednisone or equivalent per day.
Permanently discontinue YERVOY for any of the following:
-
Persistent moderate adverse reactions or inability to reduce
corticosteroid dose to 7.5 mg prednisone or equivalent per day
-
Failure to complete full treatment course within 16 weeks from
administration of first dose
-
Severe or life-threatening adverse reactions, including any of the
following:
-
Colitis with abdominal pain, fever, ileus, or peritoneal signs;
increase in stool frequency (≥7 over baseline), stool
incontinence, need for intravenous hydration for >24 hours,
gastrointestinal hemorrhage, and gastrointestinal perforation
-
AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin
>3 × the ULN
-
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full-thickness dermal ulceration or necrotic,
bullous, or hemorrhagic manifestations
-
Severe motor or sensory neuropathy, Guillain-Barré syndrome, or
myasthenia gravis
-
Severe immune-mediated reactions involving any organ system
-
Immune-mediated ocular disease which is unresponsive to topical
immunosuppressive therapy
Immune-mediated Enterocolitis:
-
In the pivotal Phase 3 study in YERVOY-treated patients, 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%) and moderate (diarrhea with up to 6
stools above baseline, abdominal pain, mucus or blood in stool; Grade
2) enterocolitis occurred in 28 (5%) patients
-
Across all YERVOY-treated patients (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis
-
Infliximab was administered to 5 of 62 (8%) patients with moderate,
severe, or life-threatening immune-mediated enterocolitis following
inadequate response to corticosteroids
-
Monitor patients for signs and symptoms of enterocolitis (such as
diarrhea, abdominal pain, mucus or blood in stool, with or without
fever) and of bowel perforation (such as peritoneal signs and ileus).
In symptomatic patients, rule out infectious etiologies and consider
endoscopic evaluation for persistent or severe symptoms
-
Permanently discontinue YERVOY in patients with severe enterocolitis
and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or
equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid
taper and continue over at least 1 month. In clinical trials, rapid
corticosteroid tapering resulted in recurrence or worsening symptoms
of enterocolitis in some patients
-
Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal
treatment and, if persistent for >1 week, initiate systemic
corticosteroids (0.5 mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis:
-
In the pivotal Phase 3 study in YERVOY-treated patients, 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%
-
13 (2.5%) additional YERVOY-treated patients experienced moderate
hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations
>2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the
ULN; Grade 2)
-
Monitor LFTs (hepatic transaminase and bilirubin levels) and assess
patients for signs and symptoms of hepatotoxicity before each dose of
YERVOY. In patients with hepatotoxicity, rule out infectious or
malignant causes and increase frequency of LFT monitoring until
resolution
-
Permanently discontinue YERVOY in patients with Grade 3-5
hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day
of prednisone or equivalent). When LFTs show sustained improvement or
return to baseline, initiate corticosteroid tapering and continue over
1 month. Across the clinical development program for YERVOY,
mycophenolate treatment has been administered in patients with
persistent severe hepatitis despite high-dose corticosteroids
-
Withhold YERVOY in patients with Grade 2 hepatotoxicity
-
In a dose-finding trial, Grade 3 increases in transaminases with or
without concomitant increases in total bilirubin occurred in 6 of 10
patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960
mg BID or 720 mg BID)
Immune-mediated Dermatitis:
-
In the pivotal Phase 3 study in YERVOY-treated patients, severe,
life-threatening, or fatal immune-mediated dermatitis (e.g.,
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
-
There were 63 (12%) YERVOY-treated patients with moderate (Grade 2)
dermatitis
-
Monitor patients for signs and symptoms of dermatitis such as rash and
pruritus. Unless an alternate etiology has been identified, signs or
symptoms of dermatitis should be considered immune-mediated
-
Permanently discontinue YERVOY in patients with severe,
life-threatening, or fatal immune-mediated dermatitis (Grade 3-5).
Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or
equivalent). When dermatitis is controlled, corticosteroid tapering
should occur over a period of at least 1 month. Withhold YERVOY in
patients with moderate to severe signs and symptoms
-
Treat mild to moderate dermatitis (e.g., localized rash and pruritus)
symptomatically. Administer topical or systemic corticosteroids if
there is no improvement within 1 week
Immune-mediated Neuropathies:
-
In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of
fatal Guillain-Barré syndrome and 1 case of severe (Grade 3)
peripheral motor neuropathy were reported
-
Across the clinical development program of YERVOY, myasthenia gravis
and additional cases of Guillain-Barré syndrome have been reported
-
Monitor for symptoms of motor or sensory neuropathy such as unilateral
or bilateral weakness, sensory alterations, or paresthesia.
Permanently discontinue YERVOY in patients with severe neuropathy
(interfering with daily activities) such as Guillain-Barré–like
syndromes
-
Institute medical intervention as appropriate for management of severe
neuropathy. Consider initiation of systemic corticosteroids (1-2
mg/kg/day of prednisone or equivalent) for severe neuropathies.
Withhold YERVOY in patients with moderate neuropathy (not interfering
with daily activities)
Immune-mediated Endocrinopathies:
-
In the pivotal Phase 3 study in YERVOY- treated patients, 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
-
Moderate endocrinopathy (requiring hormone replacement or medical
intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients
and consisted of hypothyroidism, adrenal insufficiency,
hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s
syndrome
-
Median time to onset of moderate to severe immune-mediated
endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the
initiation of YERVOY
-
Monitor patients for clinical signs and symptoms of hypophysitis,
adrenal insufficiency (including adrenal crisis), and hyper- or
hypothyroidism
-
Patients may present with fatigue, headache, mental status
changes, abdominal pain, unusual bowel habits, and hypotension, or
nonspecific symptoms which may resemble other causes such as brain
metastasis or underlying disease. Unless an alternate etiology has
been identified, signs or symptoms should be considered
immune-mediated
-
Monitor thyroid function tests and clinical chemistries at the
start of treatment, before each dose, and as clinically indicated
based on symptoms. In a limited number of patients, hypophysitis
was diagnosed by imaging studies through enlargement of the
pituitary gland
-
Withhold YERVOY in symptomatic patients. Initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and
initiate appropriate hormone replacement therapy. Long-term hormone
replacement therapy may be necessary
Other Immune-mediated Adverse Reactions, Including Ocular
Manifestations:
-
In the pivotal Phase 3 study in YERVOY-treated patients, clinically
significant immune-mediated adverse reactions seen in <1% were:
nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and
hemolytic anemia
-
Across the clinical development program for YERVOY, likely
immune-mediated adverse reactions also reported with <1% incidence
were: myocarditis, angiopathy, temporal arteritis, vasculitis,
polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis,
scleritis, leukocytoclastic vasculitis, erythema multiforme,
psoriasis, pancreatitis, arthritis, autoimmune thyroiditis,
sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy
(encephalitis), myositis, polymyositis, and ocular myositis
-
Permanently discontinue YERVOY for clinically significant or severe
immune-mediated adverse reactions. Initiate systemic corticosteroids
(1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated
adverse reactions
-
Administer corticosteroid eye drops for uveitis, iritis, or
episcleritis. Permanently discontinue YERVOY for immune-mediated
ocular disease unresponsive to local immunosuppressive therapy
Pregnancy & Nursing:
-
YERVOY is classified as pregnancy category C. There are no adequate
and well-controlled studies of YERVOY in pregnant women. Use YERVOY
during pregnancy only if the potential benefit justifies the potential
risk to the fetus
-
Human IgG1 is known to cross the placental barrier and YERVOY is an
IgG1; therefore, YERVOY has the potential to be transmitted from the
mother to the developing fetus
-
It is not known whether YERVOY is secreted in human milk. Because many
drugs are secreted in human milk and because of the potential for
serious adverse reactions in nursing infants from YERVOY, a decision
should be made whether to discontinue nursing or to discontinue YERVOY
Common Adverse Reactions:
-
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 Full Prescribing Information, including Boxed WARNING
regarding immune-mediated adverse reactions, available at www.bms.com.
YERVOY® is a registered trademark of Bristol-Myers Squibb Company.
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the
mainstay of cancer treatment over the last several decades, but
long-term survival and a positive quality of life have remained elusive
for many patients with advanced disease. To address this unmet medical
need, Bristol-Myers Squibb is leading advances in a rapidly evolving
field of cancer research and treatment known as immuno-oncology, which
involves agents whose primary mechanism is to work directly with the
body’s immune system to fight cancer. This includes conducting research
on the potential of combining immuno-oncology agents that target
different and complementary pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of
immuno-oncology, with the goal of changing survival expectations and the
way patients live with cancer.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Partnership
Through a collaboration agreement with Ono Pharmaceutical in 2011,
Bristol-Myers Squibb expanded its territorial rights to develop and
commercialize nivolumab (BMS-936558/ONO-4538) globally except in Japan,
Korea and Taiwan where Ono has retained all rights to the compound.
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, please
visit www.bms.com
or follow us on Twitter at http://twitter.com/bmsnews.
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 product development. 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 nivolumab will receive
regulatory approval, that the combination use of nivolumab and Yervoy
will receive regulatory approval, or that, if approved, they will become
commercially successful. 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, 2013, 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.
Copyright Business Wire 2014