-
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
PRINCETON, N.J.--(BUSINESS WIRE)--
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,
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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;23:1033-1039
5. 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):43-51
7.
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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