Interim results show favorable safety
profile of Opdivo, and durable responses in
previously-treated patients
Overall survival rate of 62% at 12 months
observed at this interim analysis
Hepatocellular carcinoma is the second most
frequent cause of cancer-related death worldwide and remains an
area of significant unmet medical need
Patients with hepatocellular carcinoma who
have relapsed or have disease progression, following standard of
care, have a median survival with best supportive care of ~7 to 8
months
Bristol-Myers Squibb Company (NYSE:BMY) today announced results
from an interim analysis of CA209-040, a Phase I/II dose-ranging
trial evaluating the safety and anti-tumor activity of Opdivo
(nivolumab) in previously-treated patients with hepatocellular
carcinoma (HCC) or advanced liver cancer. Initial findings
demonstrated that the estimated survival rate in evaluable patients
(n=47) was 62% at 12 months. Results also show the safety profile
of Opdivo is generally consistent with that previously-reported for
Opdivo in other tumor types. These data will be featured today, May
29, during the 51st Annual Meeting of the American Society of
Clinical Oncology (ASCO) press briefing at 1:00 – 2:00 p.m. CDT and
presented on Saturday, May 30 from 8:27 a.m. – 8:39 a.m. CDT (Late
Breaking Abstract #101).
“Hepatocellular carcinoma is an aggressive and fatal cancer,
comprising 90 percent of all liver cancer in adults worldwide with
limited therapeutic options for patients with advanced stage
disease; no treatment advances have been made for patients who fail
to respond or progress on the current standard of care,” said
Anthony B. El-Khoueiry, MD, lead study author and associate
professor of clinical medicine and phase I program director at the
University of Southern California Norris Comprehensive Cancer
Center. “These preliminary data are encouraging and support the
ongoing evaluation of nivolumab in this patient population, as they
show promising preliminary survival data, and durable partial or
complete response in one out of five nivolumab-treated patients,
with many others experiencing stable disease.”
More than 700,000 people around the world are diagnosed with HCC
each year with a majority of all HCC cases caused by infection with
the hepatitis B virus (HBV) or hepatitis C virus (HCV), making
HBV/HCV the most common risk factor for liver cancer worldwide.
Patients with advanced HCC receiving the current standard of care
have a median overall survival of less than 1 year. For patients
who have relapsed or have disease progression, median survival with
best supportive care is approximately 7 to 8 months.
“Bristol-Myers Squibb’s experience in hepatitis and
Immuno-Oncology make us poised as leaders to advance Opdivo into
additional studies of hepatocellular carcinoma,” said Michael
Giordano, senior vice president, Head of Development, Oncology,
Bristol-Myers Squibb. “Opdivo has demonstrated improvements in
survival in a number of different tumor types. We are excited that
this trial has shown the potential that this may extend to advanced
liver cancer and hope to confirm these findings in future
trials.”
About the CA209-040
CA209-040 is a Phase I/II dose-ranging trial that evaluated the
safety and anti-tumor activity of Opdivo in patients with HCC, the
majority of whom had received prior treatment. The trial included
47 HCC patients who were enrolled into one of three treatment arms
depending on whether or not they were infected with HCV or HBV.
Patients enrolled in the trial received Opdivo doses ranging from
0.1 – 10 mg/kg intravenously every 2 weeks for up to 2 years. The
primary objective was safety, tolerability, dose limiting
toxicities, and maximum tolerated dose. Anti-tumor activity was a
secondary objective (using RECIST 1.1 criteria), and overall
survival was an exploratory objective.
As of this interim analysis, 62% of patients in the study were
still alive after 12 months. Eight (19%) patients (of 42 evaluable
patients) achieved a complete or partial response, meaning that the
size of their tumors measured at baseline decreased by 30–100% with
Opdivo treatment. In patients with response, duration of response
ranged from more than 1.4 – 12.5 months. Seventeen patients
remained on study treatment and 30 discontinued treatment due to
progressive disease (n=26), complete response (n=2), or adverse
events (n=2).
CA209-040 is the first trial to characterize the safety profile
of Opdivo monotherapy in patients with HCC, including those with
HCV and HBV infections. In the trial, safety and tolerability were
well-characterized, with the frequency and intensity of
treatment-related adverse events (AEs) being consistent across
Opdivo dose levels. The majority of side effects were mild to
moderate in nature with abnormal liver enzymes (19% AST and 15%
ALT), rash (17%) and elevation of amylase (15%) and lipase (17%)
being the most common; the abnormal liver enzymes and elevated
amylase and lipase were not accompanied by any significant clinical
symptoms. Grade 3–4 treatment-related AEs were infrequent (19%).
There were no treatment-related deaths reported.
About Opdivo
Bristol-Myers Squibb has a broad, global development program to
study Opdivo in multiple tumor types consisting of more than 50
trials – as monotherapy or in combination with other therapies – in
which more than 8,000 patients have been enrolled worldwide.
Opdivo became the first PD-1 immune checkpoint inhibitor to
receive regulatory approval anywhere in the world on July 4, 2014
when Ono Pharmaceutical Co. announced that it received
manufacturing and marketing approval in Japan for the treatment of
patients with unresectable melanoma. In the U.S., the U.S. Food and
Drug Administration (FDA) granted its first approval for Opdivo for
the treatment of patients with unresectable or metastatic melanoma
and disease progression following Yervoy (ipilimumab) and, if BRAF
V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo
received its second FDA approval for the treatment of patients with
metastatic squamous non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
- Severe pneumonitis or interstitial lung
disease, including fatal cases, occurred with OPDIVO treatment.
Across the clinical trial experience in 691 patients with solid
tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691)
of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial
3. In Trial 1, pneumonitis, including interstitial lung disease,
occurred in 3.4% (9/268) of patients receiving OPDIVO and none of
the 102 patients receiving chemotherapy. Immune-mediated
pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO;
one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated
pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO,
including, five Grade 3 and two Grade 2 cases. Monitor patients for
signs and symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for
Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
- In Trial 1, diarrhea or colitis
occurred in 21% (57/268) of patients receiving OPDIVO and 18%
(18/102) of patients receiving chemotherapy. Immune-mediated
colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five
with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in
21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated
colitis occurred in 0.9% (1/117) of patients. Monitor patients for
immune-mediated colitis. Administer corticosteroids for Grade 2 (of
more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for
Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or
recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
- In Trial 1, there was an increased
incidence of liver test abnormalities in the OPDIVO-treated group
as compared to the chemotherapy-treated group, with increases in
AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs
5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis
occurred in 1.1% (3/268) of patients receiving OPDIVO; two with
Grade 3 and one with Grade 2. In Trial 3, the incidences of
increased liver test values were AST (16%), alkaline phosphatase
(14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. Withhold OPDIVO for Grade 2 and permanently discontinue
OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
- In Trial 1, there was an increased
incidence of elevated creatinine in the OPDIVO-treated group as
compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or
3 immune-mediated nephritis or renal dysfunction occurred in 0.7%
(2/268) of patients. In Trial 3, the incidence of elevated
creatinine was 22%. Immune-mediated renal dysfunction (Grade 2)
occurred in 0.9% (1/117) of patients. Monitor patients for elevated
serum creatinine prior to and periodically during treatment. For
Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and
administer corticosteroids; if worsening or no improvement occurs,
permanently discontinue OPDIVO. Administer corticosteroids for
Grade 4 serum creatinine elevation and permanently discontinue
OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
- In Trial 1, Grade 1 or 2 hypothyroidism
occurred in 8% (21/268) of patients receiving OPDIVO and none of
the 102 patients receiving chemotherapy. Grade 1 or 2
hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO
and 1% (1/102) of patients receiving chemotherapy. In Trial 3,
hypothyroidism occurred in 4.3% (5/117) of patients receiving
OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients,
including one Grade 2 case. Monitor thyroid function prior to and
periodically during treatment. Administer hormone replacement
therapy for hypothyroidism. Initiate medical management for control
of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
- In Trial 1 and 3 (n=385), the following
clinically significant immune-mediated adverse reactions occurred
in <2% of OPDIVO-treated patients: adrenal insufficiency,
uveitis, pancreatitis, facial and abducens nerve paresis,
demyeliniation, autoimmune neuropathy, motor dysfunction, and
vasculitis. Across clinical trials of OPDIVO administered at doses
3 mg/kg and 10 mg/kg, additional clinically significant,
immune-mediated adverse reactions were identified: hypophysitis,
diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome,
and myasthenic syndrome. Based on the severity of adverse reaction,
withhold OPDIVO, administer high-dose corticosteroids, and, if
appropriate, initiate hormone- replacement therapy.
Embryofetal 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 OPDIVO 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 OPDIVO, advise women to
discontinue breastfeeding during treatment.
Serious Adverse Reactions
- In Trial 1, 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 Trial 3, serious adverse reactions
occurred in 59% of patients receiving OPDIVO. The most frequent
serious adverse drug reactions reported in ≥2% of patients were
dyspnea, pneumonia, chronic obstructive pulmonary disease
exacerbation, pneumonitis, hypercalcemia, pleural effusion,
hemoptysis, and pain.
Common Adverse Reactions
- The most common adverse reactions
(≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial
3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%),
decreased appetite (35%), cough (32%), nausea (29%), and
constipation (24%).
Please see U.S. Full Prescribing Information for OPDIVO.
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 research in an innovative 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. The company is exploring a variety of compounds
and immunotherapeutic approaches for patients with different types
of cancer, including researching the potential of combining
Immuno-Oncology agents that target different 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 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 http://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 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
Opdivo will receive regulatory approval for an additional
indication in hepatocellular carcinoma or advanced liver cancer.
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, 2014 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20150529005942/en/
Bristol-Myers Squibb CompanyMedia:Carrie
Fernandez, 215-859-2605carrie.fernandez@bms.comorPriyanka Shah,
908-447-6134priyanka.shah1@bms.comorInvestors:Ranya Dajani,
609-252-5330ranya.dajani@bms.comorBill Szablewski,
609-252-5864william.szablewski@bms.com
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