- Opdivo is the first and only
Immuno-Oncology agent to receive this FDA approval; this
accelerated approval is based on tumor response rate and durability
of response in these patients
- The CheckMate -040 pivotal study
evaluated Opdivo in patients with and without active
Hepatitis B or C infection, and across PD-L1 expression levels
1,2
- HCC is the most common type of liver
cancer and incidence rates are increasing3,4
Bristol-Myers Squibb Company (NYSE:BMY) today announced the U.S.
Food and Drug Administration (FDA) has approved Opdivo (nivolumab)
injection for intravenous use for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. Approval for this indication has been granted 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.1 In the CheckMate -040 trial, 14.3%* (95% CI:
9.2-20.8; 22/154) of patients responded to treatment with Opdivo.
The percentage of patients with a complete response was 1.9%
(3/154) and the percentage of patients with a partial response was
12.3% (19/154).1 Among responders (n=22), responses ranged from 3.2
to 38.2+ months; 91% of those patients had responses of six months
or longer and 55% had responses of 12 months or longer.1
Opdivo is associated with the following Warnings and Precautions
including: immune-mediated pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, skin adverse
reactions, encephalitis, other adverse reactions; infusion
reactions; and embryo-fetal toxicity.1 Please see the Important
Safety Information section below.
“We are proud to bring the potential for clinically meaningful
responses with Immuno-Oncology therapy to these advanced-stage HCC
patients, who have had limited treatment options for years,” said
Chris Boerner, president, U.S. Commercial, Bristol-Myers Squibb.
“Today’s approval marks an important step toward our mission of
delivering transformational medicines to treat conditions with a
high unmet need.”
The burden of liver cancer in the U.S. is significant and is
expected to increase in the decades to come.5,6 A recently-released
American Cancer Society (ACS) report published in CA: A Cancer
Journal for Clinicians notes that death rates for liver cancer are
increasing at a faster pace than any other cancer, doubling since
the mid-1980s.5
“Unfortunately, the majority of HCC patients are diagnosed with
advanced-stage disease and are not candidates for potentially
curative surgical interventions,” said Adrian M. Di Bisceglie,
M.D., co-director, Saint Louis University Liver Center, Chief of
Hepatology. “More options are needed for advanced-stage HCC
patients who have failed prior systemic therapy.”
Hepatocellular carcinoma is often diagnosed in the
advanced-stage where treatment options are limited and there is a
high unmet need for patients who are intolerant to or who have
progressed on sorafenib therapy.5,7,8
“In recent years, there has been growing interest in leveraging
immuno-oncology knowledge and discoveries to add to the treatment
options available for patients with advanced-stage liver cancer,”
said Anthony B. El-Khoueiry, M.D., lead investigator and associate
professor of clinical medicine and phase I program director at the
Keck School of Medicine of University of Southern California (USC)
and the USC Norris Comprehensive Cancer Center. “The approval of
Opdivo provides us with an encouraging approach and a new treatment
option for appropriate patients with HCC following prior systemic
therapy.”
Approval Based on Notable Overall
Response Rate and Duration of Response
CheckMate -040 included a Phase 1/2, open-label, multicenter
study evaluating Opdivo in patients with HCC who progressed on or
were intolerant to sorafenib.1,9 In this study, 154 patients
received Opdivo 3 mg/kg administered intravenously every two weeks.
The recommended dose is 240 milligrams administered as an
intravenous infusion over 60 minutes every two weeks until disease
progression or unacceptable toxicity.1 Efficacy outcome measures
included confirmed overall response rate (as assessed by blinded
independent central review using RECIST v1.1 and modified RECIST
for HCC) and duration of response.1 The median age of patients
participating in the study was 63 (range: 19-81), all patients had
received prior sorafenib therapy and 19% of patients had received
two or more prior systemic therapies.1 Patients were enrolled
regardless of PD-L1 expression level and whether or not they were
infected with active Hepatitis B virus (HBV) or active Hepatitis C
virus (HCV).1,2 Data from CheckMate -040 were presented at the
American Society of Clinical Oncology 2017 Annual Meeting in
June.
In the CheckMate -040 trial, 14.3%* (95% CI: 9.2-20.8; 22/154)
of patients responded to treatment with Opdivo. The percentage of
patients with a complete response was 1.9% (3/154) and the
percentage of patients with a partial response was 12.3% (19/154).
Among responders (n=22), responses ranged from 3.2 to 38.2+ months;
91% of those patients had responses of six months or longer and 55%
had responses of 12 months or longer.1 The median time to response
was 2.8 months (range: 1.2-7.0).2 The overall response rate based
on modified RECIST was 18.2% (95% CI: 12.4-25.2; 28/154). Complete
response rate was 3.2% (5/154); partial response rate was 14.9%
(23/154).1 Responses were observed across PD-L1 expression
levels.2
“I advocate for others because I know firsthand the terrible
toll cancers of the liver take on a patient and their loved ones.
In my opinion, HCC is an example of a cancer where awareness is out
of sync with the impact of the disease,” said Suzanne Lindley,
Co-Founder, Yes! Beat Liver Tumors. “Today’s approval shines a
light of awareness and hope on a disease with a high unmet medical
need.”
Select Safety Profile
The safety of Opdivo was evaluated in a 154-patient subgroup of
patients with HCC and Child-Pugh A cirrhosis who progressed on or
were intolerant to sorafenib in the CheckMate -040 study. Patients
were required to have an aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) of no more than five times the upper
limit of normal and total bilirubin of less than 3 mg/dL. The
median duration of exposure to Opdivo was six months. Treatment
with Opdivo resulted in treatment-emergent Grade 3 or 4 AST in 18%
(27/154) of patients, Grade 3 or 4 ALT in 11% (16/154) of patients,
and Grade 3 or 4 bilirubin in 7% (11/154) of patients.
Immune-mediated hepatitis requiring systemic corticosteroids
occurred in 5% (8/154) of patients.1 Serious adverse reactions
occurred in 49% of patients. The most frequent serious adverse
reactions reported in at least 2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia. The most common adverse reactions
(≥20%) in patients receiving Opdivo (n=154) were fatigue (38%),
musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%),
diarrhea (27%), rash (26%), cough (23%), and decreased appetite
(22%). Opdivo was discontinued due to adverse reactions in 11% of
patients and 32% of patients had a dose delay for an adverse
reaction.2
About Hepatocellular
Carcinoma
Hepatocellular carcinoma (HCC) is the most common type of liver
cancer and the fastest-growing cause of cancer death in the
U.S.3,5,10 The incidence of liver cancer in the U.S. has more than
tripled since 1980.3 It is estimated that there will be
approximately 41,000 new cases of liver and intrahepatic bile duct
cancer and 29,000 deaths from these diseases in the U.S. this
year.4 The majority of these cases are caused by Hepatitis B virus
(HBV) or Hepatitis C virus (HCV) infections, making chronic
infection with HBV or HCV the most common risk factor for liver
cancer.10,11 However, the increasing prevalence of metabolic
syndrome and nonalcoholic steatohepatitis (NASH) is expected to
contribute to increased rates of HCC in the U.S. in the foreseeable
future.12,13
INDICATION
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.
IMPORTANT SAFETY
INFORMATION
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.
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. In patients
receiving OPDIVO monotherapy, immune-mediated colitis occurred in
2.9% (58/1994) of patients.
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 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 Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
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
monotherapy, adrenal insufficiency occurred in 1% (20/1994) 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 monotherapy, diabetes occurred in 0.9% (17/1994) of
patients.
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.
Immune-Mediated Skin Adverse Reactions
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.
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.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO, the following clinically
significant immune-mediated adverse reactions, some with fatal
outcome, occurred in <1.0% of patients receiving OPDIVO:
myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination,
polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré
syndrome, hypopituitarism, systemic inflammatory response syndrome,
gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), motor dysfunction,
vasculitis, and myasthenic syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. 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
patients receiving OPDIVO monotherapy, infusion-related reactions
occurred in 6.4% (127/1994) of patients.
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 040, serious adverse reactions occurred in 49% of
patients (n=154). The most frequent serious adverse reactions
reported in at least 2% of patients were pyrexia, ascites, back
pain, general physical health deterioration, abdominal pain, and
pneumonia.
Common Adverse Reactions
In Checkmate 040, the most common adverse reactions (≥20%) in
patients receiving OPDIVO (n=154) were fatigue (38%),
musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%),
diarrhea (27%), rash (26%), cough (23%), and decreased appetite
(22%).
Please see U.S. Full Prescribing Information for OPDIVO.
About the Opdivo Clinical
Development Program
Bristol-Myers Squibb’s global development program is founded on
scientific expertise in the field of Immuno-Oncology and includes a
broad range of clinical trials studying Opdivo, 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.
About Bristol-Myers Squibb’s Patient
Access Support
Bristol-Myers Squibb remains committed to providing assistance
so that cancer patients who need our medicines can access them and
expedite time to therapy.
BMS Access Support®, the Bristol-Myers Squibb patient access and
reimbursement services program, is designed to help appropriate
patients initiate and maintain access to BMS medicines during their
treatment journey. BMS Access Support offers benefit investigation,
prior authorization assistance and co-pay assistance for eligible,
commercially insured patients. More information about our access
and reimbursement support services can be obtained by calling BMS
Access Support® at 1-800-861-0048 or by visiting
www.bmsaccesssupport.com.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., 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, Ono and
Bristol-Myers Squibb 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 or
follow us on LinkedIn, Twitter, YouTube and Facebook.
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. 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,
2016 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.
* BICR-assessed based on RECIST v1.1
References
- Opdivo Prescribing Information. Opdivo
U.S. Product Information. Last updated: September 22, 2017.
Princeton, NJ: Bristol-Myers Squibb Company.
- Data on file. NIVO 314. Princeton, NJ:
Bristol-Myers Squibb.
- American Cancer Society. Cancer Facts
& Figures. 2017. Atlanta: American Cancer Society; 2017.
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Surveillance, Epidemiology, and End Results Program Stat Fact
Sheets: Liver and Intrahepatic Bile Duct Cancer.
https://seer.cancer.gov/statfacts/html/livibd.html. Accessed July
31, 2017.
- Islami F, Miller K, Siegel R, et al.
Disparities in Liver Cancer Occurrence in the United States by
Race/Ethnicity and State. Ca Cancer J Clin 2017 Jul
8;67(4):273–289.
- Wang S, Sun H, Xie Z, et al. Improved
survival of patients with hepatocellular carcinoma and disparities
by age, race, and socioeconomic status by decade, 1983-2012.
Oncotarget. 2016 Sep 13;7(37):59820-59833.
- Allaire M and Nault JC. Advances in
management of hepatocellular carcinoma. Curr Opin Oncol. 2017
Jul;29(4):288-295.
- Mlynarsky L, Menachem Y and Shibolet O.
Treatment of hepatocellular carcinoma: Steps forward but still a
long way to go. World J Hepatol. 2015 Mar 27;7(3):566-74.
- Clinicaltrials.gov. “An Immuno-therapy
Study to Evaluate the Effectiveness, Safety and Tolerability of
Nivolumab or Nivolumab in Combination With Other Agents in Patients
With Advanced Liver Cancer (CheckMate040). Available at:
https://clinicaltrials.gov/ct2/show/NCT01658878
- Mittal S and El-Serag HB. Epidemiology
of hepatocellular carcinoma: consider the population. J Clin
Gastroenterol. 2013 Jul; 47 Suppl:S2-6.
- American Cancer Society. Liver Cancer
Risk Factors.
https://www.cancer.org/cancer/liver-cancer/causes-risks-prevention/risk-factors.html.
Accessed August 8, 2017.
- Dhanasekaran R, Limaye A and Cabrera R.
Hepatocellular carcinoma: current trends in worldwide epidemiology,
risk factors, diagnosis, and therapeutics. Hepat Med. 2012 May
8;4:19-37.
- Yang JD and Roberts LR. Hepatocellular
carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010 Aug;
7(8):448-58.
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Bristol-Myers Squibb CompanyMedia:Laurel Sacks,
609-302-5456laurel.sacks@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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