- Approval based on CheckMate -142, in
which Opdivo demonstrated an objective response rate of 28%
(95% CI: 17-42; 15/53) among patients who received prior treatment
with a fluoropyrimidine, oxaliplatin, and
irinotecan1,2
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 adult and
pediatric (12 years and older) patients with microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR)
metastatic colorectal cancer (mCRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.2
Approval for this indication has been granted under accelerated
approval based on overall response rate (ORR) and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials. The recommended dose is 240 milligrams
administered as an intravenous infusion over 60 minutes every two
weeks until disease progression or unacceptable toxicity.2 In the
CheckMate -142 trial, among patients (53/74) who received prior
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, 28%
(95% CI: 17-42; 15/53) responded to treatment with Opdivo. The
percentage of patients with a complete response was 1.9% (1/53) and
the percentage of patients with a partial response was 26% (14/53).
Among these responders, the median duration of response was not
reached (range: 2.8+-22.1+ months).2 Among all enrolled patients,
32% (95% CI: 22-44; 24/74) responded to treatment with Opdivo; 2.7%
(2/74) experienced a complete response, 30% (22/74) experienced a
partial response.2
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.2 Please see the Important
Safety Information section below.
“As part of our commitment to address hard-to-treat cancers,
with today’s approval, Opdivo provides a new treatment option for
these patients who have historically faced a poor prognosis,”3,4,5
said Chris Boerner, president, U.S. Commercial, Bristol-Myers
Squibb. “This approval is one example of how our commitment to
translational medicine and investigating predictive biomarkers may
help us discover treatment approaches to address different
patients’ unique needs.”
“Patients with metastatic colorectal cancer who have dMMR or
MSI-H tumors are less likely to respond to conventional
chemotherapy,”3,4,5 said Heinz-Josef Lenz, M.D., FACP, J. Terrence
Lanni Chair in Gastrointestinal Cancer Research, University of
Southern California. “While the challenges of treating these
patients have been significant, tumors characterized by these
biomarkers are immunogenic.3,6 Therefore, advances in immunotherapy
research are encouraging in presenting new treatment options for
appropriate patients with MSI-H metastatic colorectal cancer.”
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
recommend universal MMR or MSI testing for all patients with a
personal history of colon or rectal cancer to inform use of
immunotherapy in patients with metastatic disease. The National
Comprehensive Cancer Network® (NCCN®) panel recommends nivolumab
(OPDIVO) as a category 2A treatment option in patients with
metastatic deficient mismatch repair (dMMR) or microsatellite
instability-high (MSI-H) colorectal cancer in second- or third-line
therapy.7
Approval Based on Notable Tumor
Response Rate and Duration of Response
CheckMate -142 is a Phase 2, multicenter, open-label, single-arm
study evaluating Opdivo in patients with locally determined dMMR or
MSI-H mCRC whose disease had progressed during, after, or were
intolerant to, prior treatment with fluoropyrimidine-,
oxaliplatin-, or irinotecan-based chemotherapy.1,2 In this study,
74 patients received Opdivo 3 mg/kg administered intravenously
every two weeks.2 The recommended dose is 240 mg administered as an
intravenous infusion over 60 minutes every two weeks until disease
progression or unacceptable toxicity.2 Across the 74 patients, 72%
received prior treatment with a fluoropyrimidine, oxaliplatin, and
irinotecan.2 Efficacy outcome measures included independent
radiographic review committee-assessed confirmed ORR per RECIST
1.1, and duration of response.2 More than half of patients (51%)
had a BRAF (16%) or KRAS (35%) mutation.1
In this trial, Opdivo demonstrated an ORR of 28% (95% CI: 17-42;
15/53) in patients who received prior treatment with a
fluoropyrimidine, oxaliplatin, and irinotecan, including a 1.9%
complete response rate (1/53) and a 26% partial response rate
(14/53). Median duration of response in these patients was not
reached (range: 2.8+-22.1+ months).2 Among all enrolled patients,
32% (95% CI: 22-44; 24/74) responded to treatment with Opdivo,
including a 2.7% complete response rate (2/74) and a 30% partial
response rate (22/74). The median duration of response was not
reached (range: 1.4+-26.5+ months).2 Data from CheckMate -142 were
published in The Lancet Oncology in July.
“As the third most common type of cancer in the United States,
our view is that colorectal cancer – particularly for those with
dMMR or MSI-H metastatic disease – has been in need of new research
and treatments.8 The approval of Opdivo for appropriate patients
with this disease gives the community more hope,” said Michael
Sapienza, chief executive officer of the Colon Cancer Alliance.
Select Safety Profile
The most common adverse reactions (≥20%) in patients who
received Opdivo as a single agent were fatigue, rash,
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough,
dyspnea, constipation, decreased appetite, back pain, arthralgia,
upper respiratory tract infection, pyrexia.2 Please see additional
Important Safety Information below.
About dMMR or MSI-H Colorectal
Cancer
Colorectal cancer (CRC) is cancer that develops in the colon or
the rectum, which are part of the body’s digestive or
gastrointestinal system.9 In the United States, CRC is the third
most common cancer, in 2017 it is estimated that there will be
approximately 135,000 new cases of the disease and that it will be
the second leading cause of cancer-related deaths among men and
women combined.8,10 Approximately 5% of metastatic CRC patients
have mismatch repair deficient (dMMR) or microsatellite
instability-high (MSI-H) tumors.3
Mismatch repair deficiency occurs when the proteins that repair
mismatch errors in DNA replication are missing or non-functional,
which leads to MSI-H tumors in certain types of cancer, including
CRC.5,11 Patients with dMMR or MSI-H metastatic CRC are less likely
to benefit from conventional chemotherapy and typically have a poor
prognosis.3,4,5 Routine testing to confirm dMMR or MSI-H status
should be conducted for all metastatic CRC patients.7
INDICATION
OPDIVO® (nivolumab) is indicated for the treatment of adults and
pediatric (12 years and older) patients with microsatellite
instability high (MSI-H) or mismatch repair deficient (dMMR)
metastatic colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
overall response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in 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. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 immune-mediated hepatitis.. In patients receiving
OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8%
(35/1994) of patients.
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 adverse reaction, permanently
discontinue or withhold treatment, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO the following clinically
significant immune-mediated adverse reactions occurred in <1.0%
of patients receiving OPDIVO: 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), myositis, myocarditis, rhabdomyolysis, 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.
Common Adverse Reactions
The most common adverse reactions (≥20%) in patients who
received OPDIVO as a single agent were fatigue, rash,
musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough,
dyspnea, constipation, decreased appetite, back pain, arthralgia,
upper respiratory tract infection, pyrexia.2
Please see U.S. Full Prescribing Information for OPDIVO
About the Opdivo Clinical
Development Program
Bristol-Myers Squibb’s global development program founded on
scientific expertise in the field of Immuno-Oncology 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 a
comprehensive set of programs and services 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 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.
The National Comprehensive Cancer Network makes no warranties of
any kind whatsoever regarding their content, use or application and
disclaims any responsibility for their application or use in any
way.
References
1. Data on file. NIVO 287. Princeton, NJ: Bristol-Myers
Squibb.2. Opdivo Prescribing Information. Opdivo U.S. Product
Information. Last updated: July 31, 2017. Princeton, NJ:
Bristol-Myers Squibb Company.3. Venderbosch S, Nagteagaal ID,
Maughan TS, et al. Mismatch repair status and BRAF mutation status
in metastatic colorectal cancer patients: A pooled analysis of the
CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res.
2014;20:5322-5330.4. Müller CI, Schulmann K, Reinacher-Schick A, et
al. Predictive and prognostic value of microsatellite instability
in patients with advanced colorectal cancer treated with a
fluoropyrimidine and oxaliplatin containing first-line
chemotherapy. A report of the AIO Colorectal Study Group. Int J
Colorectal Dis. 2008;23:1033-10395. Koopman M, Kortman G, Mekenkamp
L, et al. Deficient mismatch repair system in patients with
sporadic advanced colorectal cancer. Brit J Cancer.
2009;100:266-273.6. Llosa NJ, Cruise M, Tam A, et al. The vigorous
immune microenvironment of microsatellite instable colon cancer is
balanced by multiple counter-inhibitory checkpoints. Cancer Discov.
2015;5(1):43-517. Benson AB 3rd, Venook AP, Cederquist L, et al.
Colon Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in
Oncology. J Natl Compr Canc Netw. 2017;15(3):370-398.8. American
Cancer Society. Colorectal Cancer Facts & Figures 2017-2019.
Atlanta: American Cancer Society; 2017.9. American Cancer Society.
Key Statistics for Colorectal Cancer.
https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html.
Accessed March 9, 2017.10. National Cancer Institute. Cancer Stat
Facts: Colon and Rectum Cancer. Surveillance, Epidemiology, and End
Results Program.
https://seer.cancer.gov/statfacts/html/colorect.html. Accessed
March 9, 2017.11. Yacoub, George, Srikanth Nagalla, Mebea Aklilu.
Oncologic Management of Hereditary Colorectal Cancer. Clin Colon
Rectal Surg. 2012;25:118–122.
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Bristol-Myers Squibb CompanyMedia Inquiries:Carrie
Fernandez,
609-897-4957carrie.fernandez@bms.comorInvestors:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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