Patients treated with Opdivo
experienced a 32% reduction in the risk of death after two years
minimum follow-up
Opdivo remains the only PD-1 inhibitor to
demonstrate statistically significant OS versus standard
chemotherapy in the primary analysis of a Phase 3 trial in these
patients, with benefit maintained with long-term follow-up
Bristol-Myers Squibb Company (NYSE: BMY) announced today
two-year overall survival (OS) data from CheckMate -141, a Phase 3
open-label, randomized trial evaluating Opdivo (nivolumab) compared
with investigator’s choice chemotherapy (cetuximab, docetaxel or
methotrexate) in patients with recurrent or metastatic squamous
cell carcinoma of the head and neck (SCCHN) after failure on
platinum-based therapy. Patients treated with Opdivo experienced a
32% reduction in the risk of death after a minimum two years of
follow-up (HR 0.68; 95% CI: 0.54 to 0.86), with a median OS of 7.7
months (95% CI: 5.7 to 8.8) compared with 5.1 months (95% CI: 4.0
to 6.2) for standard chemotherapy. The two-year survival rate for
Opdivo was 16.9% (95% CI: 12.4 to 22.0) versus 6.0% (95% CI: 2.7 to
11.3) for standard chemotherapy. The safety profile for Opdivo at
two-year follow-up was consistent with previous analyses from the
study.
These data will be presented today as an oral presentation
(Abstract #CT116) at 4:35 PM CDT, N Hall C (Level 1) during the
Updates in Immuno-Oncology Trials session at the 2018 American
Association for Cancer Research (AACR) Annual Meeting in
Chicago.
“The introduction of Immuno-Oncology has the potential to change
the treatment landscape of squamous cell carcinoma of the head and
neck, compared with the standard of care,” said Robert L. Ferris,
M.D., Ph.D., a cancer immunotherapist and Director, UPMC Hillman
Cancer Center, Pittsburgh, PA. “The sustained overall survival
benefit demonstrated by nivolumab in this study is encouraging in
SCCHN, which historically has a median survival of less than six
months.”
The sustained Opdivo OS benefit was observed across PD-L1
expressors and non-expressors in patients with recurrent or
metastatic SCCHN. At the two-year follow-up in patients treated
with Opdivo whose tumors had PD-L1 expression ≥ 1%, risk of death
was reduced by 45% (HR 0.55; 95% CI: 0.39 to 0.78). For patients
treated with Opdivo whose tumors had PD-L1 expression
<1%, risk of death at two years was reduced by 27% (HR 0.73; 95%
CI: 0.49 to 1.09) versus standard chemotherapy.
“Opdivo is the only I-O treatment for squamous cell carcinoma of
the head and neck to have shown a significant overall survival
benefit versus chemotherapy at the primary analysis. These two-year
follow-up data show a sustained long-term overall survival benefit
for patients, across PD-L1 expression levels and regardless of HPV
status,” said Shinta Cheng, M.D., Ph.D., development lead,
Bristol-Myers Squibb. “These data showing the durability of this
benefit reinforce our ongoing commitment to continuing research
with the hope of delivering what matters most to patients fighting
cancer: long-term survival.”
There were no statistically significant differences between the
two arms for PFS (HR 0.87; 95% CI: 0.68 to 1.11)
for Opdivo and investigator’s choice,
respectively. The safety profile of Opdivo with a
two-year follow-up was consistent with previous analyses and with
prior studies of Opdivo in patients with melanoma and non-small
cell lung cancer. Grade 3-4 treatment-related adverse
reactions occurred in 15.3% of patients receiving Opdivo
versus 36.9% of patients receiving investigator’s choice.
About CheckMate -141 (Abstract
#CT116)
CheckMate -141 is a global phase 3, open-label, randomized trial
evaluating Opdivo versus investigator’s choice chemotherapy in
patients with recurrent or metastatic SCCHN who had tumor
progression during or within six months of receiving platinum-based
therapy administered in the adjuvant, neo-adjuvant, primary
(unresectable locally advanced) or metastatic setting. Patients
were included regardless of their HPV or PD-L1
status. Patients were randomized 2:1 to
receive Opdivo 3 mg/kg intravenously over 60 minutes
every two weeks (n=240), or investigator’s choice (n=121) of
methotrexate 40 to 60 mg/m2 intravenously weekly, docetaxel 30
to 40 mg/m2 intravenously weekly, or cetuximab 400
mg/m2 intravenously once then 250 mg/m2 weekly. The
primary endpoint is OS. The trial’s secondary endpoints
include progression-free survival (PFS) and objective response rate
(ORR).
About Head & Neck
Cancer
Cancers that are known as head and neck cancers usually begin in
the squamous cells that line the moist mucosal surfaces inside the
head and neck, such as inside the mouth, the nose and the throat.
Head and neck cancer is the seventh most common cancer globally,
with an estimated 400,000 to 600,000 new cases per year and 223,000
to 300,000 deaths per year. The five-year survival rate is reported
as less than 4% for metastatic Stage IV disease. Squamous cell
carcinoma of the head and neck (SCCHN) accounts for approximately
90% of all head and neck cancers, with global incidence expected to
increase by 17% between 2012 and 2022. Risk factors for SCCHN
include tobacco and alcohol consumption. The human papillomavirus
(HPV) infection is also a risk factor leading to rapid increase in
oropharyngeal SCCHN in Europe and North America. Quality of life is
often impacted for SCCHN patients, as physiological function
(breathing, swallowing, eating, drinking), personal characteristics
(appearance, speaking, voice), sensory function (smell and
hearing), and psychological/social function can be affected.
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 Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight cancer, Opdivo has
become an important treatment option across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
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. The Opdivo trials have contributed to gaining
a deeper understanding of the potential role of biomarkers in
patient care, particularly regarding how patients may benefit from
Opdivo across the continuum of PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world.
Opdivo is currently approved in more than 60 countries, including
the United States, the European Union and Japan. In October 2015,
the Company’s Opdivo and Yervoy combination regimen was the first
Immuno-Oncology combination to receive regulatory approval for the
treatment of metastatic melanoma and is currently approved in more
than 50 countries, including the United States and the European
Union.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive 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) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
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) is indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) with progression
on or after platinum-based chemotherapy. Patients with EGFR or ALK
genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
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) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. This indication is approved
under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy. This indication is approved under accelerated
approval based on tumor 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) 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) 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.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
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 patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
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 patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 10% (52/547) 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. For patients without HCC, withhold OPDIVO for Grade 2
and permanently discontinue OPDIVO for Grade 3 or 4. 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 patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of
patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated hepatitis occurred in 7% (38/547) of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
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 patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
hypophysitis occurred in 4.6% (25/547) 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 patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
adrenal insufficiency occurred in 7% (41/547) 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 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 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 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. 6 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 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.
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 patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated rash occurred in 16.6% (91/547) 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 patient receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months 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 ipilimumab 3 mg/kg every
3 weeks, infusion-related reactions occurred in
2.5% (10/407) of patients. In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in
5.1% (28/547) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
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 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions
occurred in 42% of patients receiving OPDIVO . The most frequent
Grade 3 and 4 adverse drug reactions reported in 2% to <5% of
patients receiving OPDIVO were abdominal pain, hyponatremia,
increased aspartate aminotransferase, and increased lipase. In
Checkmate 066, serious adverse reactions occurred in 36% of
patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions
occurred in 41% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse reactions reported in ≥2% of patients
receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). 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 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia,
pleural effusion, pneumonitis, and respiratory failure. In
Checkmate 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO (n=406). The most frequent serious
adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.
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 at least 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 205 and 039, adverse reactions leading to discontinuation
occurred in 7% and dose delays due to adverse reactions occurred in
34% of patients (n=266). Serious adverse reactions occurred in 26%
of patients. The most frequent serious adverse reactions reported
in ≥1% of patients were pneumonia, infusion-related reaction,
pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and
rash. Eleven patients died from causes other than disease
progression: 3 from adverse reactions within 30 days of the last
OPDIVO dose, 2 from infection 8 to 9 months after completing
OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate
141, serious adverse reactions occurred in 49% of patients
receiving OPDIVO (n=236). The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. In Checkmate 275, serious adverse reactions
occurred in 54% of patients receiving OPDIVO (n=270). The most
frequent serious adverse reactions reported in at least 2% of
patients receiving OPDIVO were urinary tract infection, sepsis,
diarrhea, small intestine obstruction, and general physical health
deterioration. 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. In Checkmate 238, Grade 3 or 4
adverse reactions occurred in 25% of OPDIVO-treated patients
(n=452). The most frequent Grade 3 and 4 adverse reactions reported
in at least 2% of OPDIVO-treated patients were diarrhea and
increased lipase and amylase. Serious adverse reactions occurred in
18% of OPDIVO-treated patients.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). 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 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite. In
Checkmate 025, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=406) vs everolimus (n=397) were
fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash
(28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%),
constipation (23% vs 18%), decreased appetite (23% vs 30%), back
pain (21% vs 16%), and arthralgia (20% vs 14%). 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 205
and 039, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%),
pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%)
and pruritus (20%). In Checkmate 141, the most common adverse
reactions (≥10%) in patients receiving OPDIVO (n=236) were cough
and dyspnea at a higher incidence than investigator’s choice. In
Checkmate 275, the most common adverse reactions (≥ 20%) reported
in patients receiving OPDIVO (n=270) were fatigue (46%),
musculoskeletal pain (30%), nausea (22%), and decreased appetite
(22%). 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%). In Checkmate 238, the most common adverse reactions (≥20%)
reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated
patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%),
rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28%
vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper
respiratory infection (22% vs 15%), and abdominal pain (21% vs
23%). The most common immune-mediated adverse reactions were rash
(16%), diarrhea/colitis (6%), and hepatitis (3%). 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, headache, and abdominal pain.
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%).
Checkmate Trials and Patient Populations
Checkmate 067–advanced melanoma alone or in combination
with YERVOY® (ipilimumab); Checkmate 037
and 066–advanced melanoma; Checkmate
017–squamous non-small cell lung
cancer (NSCLC); Checkmate 057–non-squamous
NSCLC; Checkmate 025–renal cell
carcinoma; Checkmate 205/039–classical Hodgkin
lymphoma; Checkmate 141–squamous cell carcinoma of the
head and neck; Checkmate
275–urothelial carcinoma; Checkmate
040–hepatocellular carcinoma, Checkmate 238–adjuvant
treatment of melanoma.
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Ltd. (Ono), 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, Bristol-Myers
Squibb and Ono 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20180416006326/en/
Bristol-Myers SquibbMedia:Audrey Abernathy,
919-605-4521audrey.abernathy@bms.comorInvestor:Tim Power,
609-252-7509timothy.power@bms.comBill Szablewski,
609-252-5894william.szablewski@bms.com
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