Bristol-Myers Squibb’s Opdivo®
(nivolumab) + Low-Dose Yervoy® (ipilimumab) is the
First Immuno-Oncology Combination Approved for MSI-H/dMMR mCRC
Patients Who Progressed Following Treatment with a
Fluoropyrimidine, Oxaliplatin and Irinotecan
- In the CheckMate -142 trial,
Opdivo + Yervoy demonstrated an overall response rate of 46%
(95% CI: 35-58; n = 38/82)1
- Opdivo + Yervoy is now approved in
three tumor types, dosing and administration varies by
tumor1
Bristol-Myers Squibb Company (NYSE: BMY) today announced Opdivo
(nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab) 1 mg/kg
(injections for intravenous use) received approval from the U.S.
Food and Drug Administration (FDA) for the treatment of adult and
pediatric patients 12 years and older 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.1
Approval for this indication has been granted under accelerated
approval based on overall response rate (ORR) and duration of
response (DOR).1 Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
“Bristol-Myers Squibb is pleased to bring forward Opdivo plus
Yervoy as the first I-O/I-O combination therapy to be approved in
this type of colorectal cancer,” said Ian M. Waxman, M.D.,
development lead, gastrointestinal cancers, Bristol-Myers Squibb.
“Our commitment to studying Opdivo plus Yervoy, which target
distinct but complementary immune pathways, results from our strong
belief that rational combinations in biomarker-selected populations
may improve clinical benefit for patients.”
Opdivo + Yervoy is associated with the following Warnings and
Precautions: immune-mediated pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, skin adverse
reactions, encephalitis, other adverse reactions; infusion
reactions; and embryo-fetal toxicity. Please see the Important
Safety Information section below, including Boxed WARNING for
Yervoy regarding immune-mediated adverse reactions, as well as
additional information on CheckMate -142.1,2
Today’s approved indication was based on data from the ongoing
Phase 2 CheckMate -142 study evaluating the Opdivo + Yervoy
combination in patients with MSI-H or dMMR mCRC previously treated
with a fluoropyrimidine-, oxaliplatin- or irinotecan-based
chemotherapy.1,3,4 The application was granted Priority Review and
Breakthrough Therapy Designation by the FDA.
The Opdivo + Yervoy cohort of the CheckMate -142 trial enrolled
MSI-H/dMMR mCRC patients who had received at least one prior line
of therapy for metastatic disease, and efficacy was analyzed for
both patients who had received prior treatment with a
fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119
patients) as well as for all enrolled patients.1
- Among the 82 patients who received
prior treatment with a fluoropyrimidine, oxaliplatin and
irinotecan, 46% (95% CI: 35-58; n = 38/82) responded to treatment
with Opdivo + Yervoy as assessed by Independent Radiographic Review
Committee (IRRC).1
- The percentage of these patients with a
complete response was 3.7% (n = 3/82), and the percentage of
patients with a partial response was 43% (n = 35/82).1 Among these
38 responders, the median DOR was not reached (range: 1.9-23.2+
months); 89% of those patients had responses of six months or
longer, and 21% had responses of 12 months or longer.1,5,6 This
trial is ongoing.3
- Among all enrolled patients, 49% (95%
CI: 39-58; n = 58/119) responded to treatment with Opdivo + Yervoy;
4.2% (n = 5/119) experienced a complete response, while 45% (n =
53/119) experienced a partial response.1 Among these 58 responders,
the median DOR was not reached (range: 1.9-23.2+ months)5,6; 83% of
those patients had responses of six months or longer, and 19% had
responses of 12 months or longer.1 In the combination cohort, 51 of
58 responders were ongoing at the time of database lock; 78% of
these ongoing responders had not reached 12 months of follow-up
from the date of onset of response.1
The recommended dosing schedule includes the Opdivo + low-dose
Yervoy combination (Opdivo 3 mg/kg, administered as an I.V.
infusion over 30 minutes, followed by Yervoy 1 mg/kg, administered
as an I.V. infusion over 30 minutes, on the same day, every three
weeks for four doses), followed by Opdivo maintenance therapy (240
mg, administered as an I.V. infusion over 30 minutes, every two
weeks) after completion of four doses of the combination until
disease progression or unacceptable toxicity.1 Please review the
U.S. Full Prescribing Information for Yervoy prior to
initiation.
In the Opdivo + Yervoy cohort of CheckMate -142, 86% of patients
received all four doses of Opdivo + Yervoy.7 Opdivo was
discontinued in 13% of patients and delayed in 45% of patients due
to an adverse reaction.1 Serious adverse reactions occurred in 47%
of patients.1
“Metastatic colorectal cancers with dMMR or MSI-H biomarkers can
be difficult to treat and some patients may need additional
options,” said Heinz-Josef Lenz, M.D., FACP, L. Terrence Lanni
Chair in Gastrointestinal Cancer Research, Keck School of Medicine
of University of Southern California and principal investigator of
the study at USC Norris Comprehensive Cancer Center. “The FDA’s
approval of an I-O/I-O combination provides us with an encouraging
approach to address this challenging disease in patients who have
progressed following treatment with three standard chemotherapy
options.”
The Opdivo + Yervoy combination is also approved in two other
tumor types. The Opdivo (3 mg/kg) + low-dose Yervoy (1 mg/kg)
combination is approved for previously untreated patients with
intermediate- or poor-risk advanced renal cell carcinoma. Opdivo (1
mg/kg) + Yervoy (3 mg/kg) is approved for patients with
unresectable or metastatic melanoma under accelerated approval
based on progression-free survival. Opdivo as a single agent is
approved for the treatment of adult and pediatric (12 years and
older) patients with MSI-H or dMMR metastatic colorectal cancer
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin and irinotecan under accelerated approval based on ORR
and DOR. Continued approval for these accelerated approval
indications may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The infusion time for
each indication differs, please see U.S. Full Prescribing
Information for Opdivo and Yervoy for details.1
Approval Based on CheckMate -142
Trial
CheckMate -142 included a multicenter, non-randomized,
multiple-parallel cohort, open-label study investigating Opdivo +
Yervoy in patients with locally determined dMMR or MSI-H mCRC whose
disease had progressed during or after prior treatment with a
fluoropyrimidine-, oxaliplatin- or irinotecan-based
chemotherapy.1,8 In the combination cohort, patients received
Opdivo 3 mg/kg with Yervoy 1 mg/kg every three weeks for four
doses, followed by Opdivo 3 mg/kg as a single agent every two
weeks.1 Treatment continued until unacceptable toxicity or
radiographic progression.1 Tumor assessments were conducted every
six weeks for the first 24 weeks and every 12 weeks thereafter.1
Efficacy outcome measures included ORR as assessed by IRRC using
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and
DOR.1 Data from this study were presented in January at the 2018
Gastrointestinal Cancers Symposium and published simultaneously in
the Journal of Clinical Oncology.
Select Safety Profile for the CheckMate
-142 Trial
The most frequent serious adverse reactions reported in at least
2% of patients were colitis/diarrhea, hepatic events, abdominal
pain, acute kidney injury, pyrexia, and dehydration.1 The most
common adverse reactions (reported in at least 20% of patients)
were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal
pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%),
rash (25%), decreased appetite (20%), and vomiting (20%).1
About MSI-H or dMMR 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.10 In the United States, CRC is the third
most common cancer.10 In 2018, it is estimated that there will be
approximately 140,000 new cases of the disease and that it will be
the third leading cause of cancer-related deaths among men and
women combined.10
DNA mismatch repair deficiency (dMMR) occurs when the proteins
that repair mismatch errors in DNA replication are missing or
non-functional, leading to microsatellite instability-high (MSI-H)
tumors.11,12 Approximately 5% of metastatic CRC patients have dMMR
or MSI-H tumors.13 Patients with these biomarkers are less likely
to benefit from conventional chemotherapy and typically have a poor
prognosis.11,13,14
INDICATIONS
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with intermediate or
poor risk, previously untreated advanced renal cell carcinoma
(RCC).
OPDIVO® (nivolumab), as a single agent, is indicated 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 (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.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adults and pediatric patients 12
years and older 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 approved 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.
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for
intravenous use.
IMPORTANT SAFETY
INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. 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),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests, at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
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. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6%
(25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 1.7% (2/119) 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. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent colitis.
In patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis
occurred in 26% (107/407) of patients including three fatal cases.
In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 10% (52/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated colitis occurred in 7% (8/119) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
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 OPDIVO for Grade 2 and permanently discontinue
OPDIVO for Grade 3 or 4. In patients receiving OPDIVO monotherapy,
immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated hepatitis occurred in 13% (51/407) of patients. In
RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated hepatitis occurred in 7% (38/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
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 1 mg/kg
with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of
patients. In patients receiving OPDIVO monotherapy, adrenal
insufficiency occurred in 1% (20/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In RCC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 5.9% (7/119) 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 1 mg/kg with
YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving this
dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 22% (119/547) of patients.
Hyperthyroidism occurred in 12% (66/547) of patients receiving this
dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis
resulting in hypothyroidism occurred in 15% (18/119) of patients.
Hyperthyroidism occurred in 12% (14/119) of patients. In patients
receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994)
of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes
occurred in 2.7% (15/547) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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. Six of the 9
patients were hospitalized for severe endocrinopathies.
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. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated
nephritis and renal dysfunction occurred in 2.2% (9/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and
renal dysfunction occurred in 1.7% (2/119) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
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. In patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 14% (17/119) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
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.
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. Encephalitis occurred in one patient receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of
exposure. Encephalitis occurred in one RCC patient receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of
exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient
(0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days
of exposure.
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 monotherapy or in
combination with YERVOY, 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, aplastic anemia,
pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
which has been observed in patients receiving OPDIVO and may
require treatment with systemic steroids to reduce the risk of
permanent vision loss.
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 as a
60-minute infusion, infusion-related reactions occurred
in 6.4% (127/1994) of patients. In a separate study in which
patients received OPDIVO monotherapy as a 60-minute infusion or a
30-minute infusion, infusion-related reactions occurred in 2.2%
(8/368) and 2.7% (10/369) of patients, respectively. Additionally,
0.5% (2/368) and 1.4% (5/369) of patients, respectively,
experienced adverse reactions within 48 hours of infusion that led
to dose delay, permanent discontinuation or withholding of OPDIVO.
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3
weeks, infusion-related reactions occurred in
2.5% (10/407) of patients. In RCC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions
occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related
reactions occurred in 4.2% (5/119) of patients.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY 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- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY 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. Advise
women to discontinue breastfeeding during treatment with YERVOY and
for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 067, serious adverse reactions (73% and 37%),
adverse reactions leading to permanent discontinuation (43% and
14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse
reactions (72% and 44%) all occurred more frequently in the OPDIVO
plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The
most frequent (≥10%) serious adverse reactions in the OPDIVO plus
YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and
2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In
Checkmate 214, serious adverse reactions occurred in 59% of
patients receiving OPDIVO plus YERVOY and in 43% of patients
receiving sunitinib. The most frequent serious adverse reactions
reported in ≥2% of patients were diarrhea, pyrexia, pneumonia,
pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal
insufficiency, and colitis; in patients treated with sunitinib,
they were pneumonia, pleural effusion, and dyspnea. In Checkmate
142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY,
serious adverse reactions occurred in 47% of patients. The most
frequent serious adverse reactions reported in ≥2% of patients were
colitis/diarrhea, hepatic events, abdominal pain, acute kidney
injury, pyrexia, and dehydration.
Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in
the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%),
diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and
dyspnea (20%). The most common (≥20%) adverse reactions in the
OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%),
and nausea (28%). In Checkmate 214, the most common adverse
reactions (≥20%) reported in patients treated with OPDIVO plus
YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash
(39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs
40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs
25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and decreased
appetite (21% vs 29%). In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO as a single agent, the most common adverse
reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain
(34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%),
cough (26%), pyrexia (24%), rash (23%), constipation (20%), and
upper respiratory tract infection (20%). In Checkmate 142 in
MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most
common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%),
pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%),
pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%),
and vomiting (20%).
In a separate Phase 3 study of YERVOY 3 mg/kg, 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 U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. Our vision for the future of cancer care is
focused on researching and developing transformational
Immuno-Oncology (I-O) medicines for hard-to-treat cancers that
could potentially improve outcomes for these patients.
We are advancing the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved
agents. Our differentiated clinical development program is studying
broad patient populations across more than 50 types of cancers with
24 clinical-stage molecules designed to target different immune
system pathways. Our deep expertise and innovative clinical trial
designs position us to advance I-O/I-O, I-O/chemotherapy,
I-O/targeted therapies and I-O/radiation therapies across multiple
tumors and potentially deliver the next wave of therapies with a
sense of urgency. Through our leading translational capabilities,
we are pioneering immune biology research and identifying a number
of potentially predictive biomarkers, including PD-L1, TMB,
MSI-H/dMMR and LAG-3, advancing the possibility of precision
medicine for more patients with cancer.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
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 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 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,
2017 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.
References
1. Opdivo Prescribing Information. Opdivo U.S. Product
Information. Last Updated: July 2018. Princeton, NJ: Bristol-Myers
Squibb Company.
2. Yervoy Prescribing Information. Yervoy U.S. Product
Information. Last Updated: July 2018. Princeton, NJ: Bristol-Myers
Squibb Company.
3. ClinicalTrials.gov. An investigational immune-therapy study
of nivolumab, and nivolumab in combination with other anti-cancer
drugs, in colon cancer that has come back or has spread
(CheckMate142).
https://clinicaltrials.gov/ct2/show/NCT02060188?term=NCT02060188&rank=11.
Published November 22, 2017. Updated January 23, 2018. Accessed
April 23, 2018.
4. The ASCO Post. FDA accepts sBLA for nivolumab plus ipilimumab
in previously treated MSI-H or dMMR metastatic colorectal cancer.
http://www.ascopost.com/News/58676. Published March 30, 2018.
Accessed April 23, 2018.
5. Overman M, Lonardi S, Yeung KYM, et al. Durable clinical
benefit with nivolumab plus ipilimumab in DNA mismatch
repair-deficient/microsatellite instability-high metastatic
colorectal cancer. J Clin Oncol. 2018;36(8):773-779.
6. Data on file. NIVO 319, Princeton, NJ: Bristol-Myers
Squibb.
7. Data on file. NIVO 377, Princeton, NJ: Bristol-Myers
Squibb.
8. Bever K, Le D. An expanding role for immunotherapy in
colorectal cancer. J Natl Compr Canc Netw. 2017;15(3):410-410.
9. McLean J, Rho YS, Kuruba G, et al. Clinical practice patterns
in chemotherapeutic treatment regimens for metastatic colorectal
cancer. Clin Colorectal Cancer. 2016;15(2):135-140.
10. American Cancer Society. About Colorectal Cancer.
https://www.cancer.org/content/dam/CRC/PDF/Public/8604.00.pdf.
Updated February 21, 2018. Accessed May 18, 2018.
11. 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.
12. Yacoub G, Nagalla S, Aklilu M. Oncologic Management of
Hereditary Colorectal Cancer. Clin Colon Rectal Surg.
2012;25:118–122.
13. 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.
14. 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.
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Bristol-Myers Squibb CompanyMedia Inquiries: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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