Opdivo in combination with CABOMETYX reduced
the risk of death by 23% in the first-line treatment of advanced
renal cell carcinoma vs. sunitinib
Four-year results demonstrating continued
benefits with immunotherapy-tyrosine kinase inhibitor combination
to be shared in an oral presentation at ASCO GU 2024
Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ:
EXEL) today announced four-year follow-up results from the
CheckMate -9ER trial evaluating Opdivo® (nivolumab) in combination
with CABOMETYX® (cabozantinib) vs. sunitinib in patients with
previously untreated advanced or metastatic renal cell carcinoma
(RCC). Results continued to show superior progression-free survival
(PFS) and objective response rates (ORR) in patients treated with
Opdivo plus CABOMETYX over sunitinib, regardless of risk
classification based on International Metastatic Renal Cell
Carcinoma Database Consortium (IMDC) scores. Superior overall
survival (OS) was also observed in patients treated with the
combination. These updated results, including data showing
health-related quality-of-life benefits with Opdivo in combination
with CABOMETYX vs. sunitinib, will be featured in an oral
presentation (Abstract #362) at the American Society of Clinical
Oncology (ASCO) 2024 Genitourinary Cancers Symposium from January
25-27, 2024.
“Renal cell carcinoma can be very challenging to treat and
patients who are diagnosed with advanced disease or develop
metastasis often face poor outcomes,” said Maria Teresa Bourlon,
Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, Mexico. “These updated results from the
CheckMate -9ER trial continue to support the role of nivolumab in
combination with cabozantinib as an important first-line treatment
option for this devastating disease, demonstrating durable efficacy
across its multiple study endpoints, including a 23% reduction in
the risk of death.”
At a median follow-up of 55.6 months (48.1 months minimum), all
patients randomized to the Opdivo plus CABOMETYX treatment arm
(n=323) continued to experience benefits over those who received
sunitinib (n=328) across efficacy endpoints:
- PFS (primary endpoint): PFS continued to favor Opdivo plus
CABOMETYX, with median PFS nearly doubled with the combination
regimen at 16.4 months vs. 8.4 months with sunitinib (Hazard Ratio
[HR] 0.58; 95% Confidence Interval [CI]: 0.49 to 0.70).
- OS (secondary endpoint): Treatment with Opdivo in combination
with CABOMETYX elicited durable survival benefit over sunitinib,
with a median OS of 46.5 months compared to 36.0 months with
sunitinib (HR 0.77; 95% CI: 0.63 to 0.95).
- ORR (secondary endpoint): The combination regimen showed
durable response improvements, doubling the ORR compared to
sunitinib (55.7% vs. 27.7%, respectively).
- Complete response (CR): Patients who received Opdivo plus
CABOMETYX continued to show CR benefit, with triple the number of
patients achieving CR vs. sunitinib (13.6% vs. 4.6%).
- Duration of response (DOR): Opdivo plus CABOMETYX was
associated with a longer median DOR of 22.0 months vs. 15.2 months
in the sunitinib group.
- Safety: No new safety concerns were identified in this
follow-up analysis. Among all treated patients, any-grade
treatment-related adverse events (TRAEs) occurred in 97.5% in the
Opdivo plus CABOMETYX group compared to 93.1% in the sunitinib
group. Grade ≥3 TRAEs occurred in 67.5% of Opdivo plus
CABOMETYX-treated patients vs. 55.3% in sunitinib-treated
patients.
Additionally, in exploratory analyses, durable and clinically
meaningful benefits were observed in patient subgroups across risk
groups, including within the favorable-risk and intermediate- and
poor-risk groups:
- OS: Among patients with intermediate-/poor-risk, median OS was
43.9 months for those treated with Opdivo plus CABOMETYX vs. 29.3
months with sunitinib (HR 0.73; 95% CI: 0.58 to 0.91). In patients
with favorable risk, median OS was similar across treatment arms at
52.9 months with the combination regimen and 58.9 months with
sunitinib (HR 1.10; 95% CI: 0.69 to 1.75).
- PFS: PFS was improved with the combination regimen in patients
with intermediate-/poor-risk with a median PFS of 15.4 months
compared to 7.1 months with sunitinib (HR 0.56; 95% CI: 0.45 to
0.68), as well as in those with favorable risk at 21.4 months vs.
12.8 months (HR 0.69; 95% CI: 0.48 to 1.00).
- ORR: In patients with intermediate-/ poor-risk, ORR was more
than doubled at 52.6% with Opdivo and CABOMETYX vs. 23.0% with
sunitinib. In those with favorable risk, ORR was 66.2% vs. 44.4%,
respectively.
- CR: Among those with intermediate-/poor-risk profiles, the
number of patients who achieved CR more than tripled (12.9% vs.
3.5%) with the combination regimen compared to sunitinib. In those
with favorable risk profiles, the number of patients who achieved
CR was doubled (16.2% vs. 8.3%) with the combination regimen.
- DOR: Median DOR was also improved with Opdivo and CABOMETYX
across both groups. Among the intermediate- and poor-risk group,
those treated with the combination regimen had a median DOR of 23.1
months vs. 13.8 months with sunitinib. Among the favorable risk
group, median DOR was 18.7 months vs. 17.8 months,
respectively.
“There has been an ongoing need for therapeutic options that can
provide patients with previously untreated advanced or metastatic
renal cell carcinoma with the potential for disease control and
extended survival. By combining the power of these two unique
modalities, we established a new standard of care with Opdivo and
CABOMETYX, building on our commitment to improving outcomes for
patients with advanced cancers, including but not limited to
genitourinary cancers,” said Dana Walker, M.D., M.S.C.E., vice
president, global program lead, gastrointestinal and genitourinary
cancers, Bristol Myers Squibb. “Now, after more than four years of
follow up, the data continue to underscore the value of
Opdivo-based combinations in the GU cancer treatment paradigm with
the potential to help patients diagnosed with advanced RCC live
longer, regardless of risk classification.”
“These results from CheckMate -9ER provide hope that patients
with previously untreated advanced kidney cancer may experience a
long-term survival benefit. We are pleased to see that the
combination of CABOMETYX and Opdivo continues to demonstrate
durable and clinically meaningful efficacy after four years of
follow-up in this patient population across risk groups,
reinforcing the value of this regimen as a standard of care in this
setting,” said Amy Peterson, M.D., executive vice president,
product development & medical affairs, and chief medical
officer, Exelixis. “It is also encouraging that CABOMETYX in
combination with Opdivo demonstrated superior PFS and OS benefits
in patients who had disease burdens in often challenging-to-treat
areas, including bone, liver and lung metastases. The totality of
these encouraging findings, achieved in partnership with Bristol
Myers Squibb, underscore our commitment to collaborating with the
scientific community to advance treatment regimens for patients
with advanced cancers.”
Bristol Myers Squibb and Exelixis thank the patients and
investigators involved in the CheckMate -9ER clinical trial.
About CheckMate -9ER
CheckMate -9ER is an open-label, randomized, multi-national
Phase 3 trial evaluating patients with previously untreated
advanced or metastatic renal cell carcinoma (RCC). A total of 651
patients (23% favorable risk, 58% intermediate risk, 20% poor risk;
25% PD-L1≥1%) were randomized to receive Opdivo plus CABOMETYX
(n=323) vs. sunitinib (n=328). The primary endpoint is
progression-free survival (PFS). Secondary endpoints include
overall survival (OS) and objective response rate (ORR). The
primary efficacy analysis is comparing the doublet combination vs.
sunitinib in all randomized patients. The trial is sponsored by
Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by
Exelixis, Inc., Ipsen Pharma SAS and Takeda Pharmaceutical Company
Limited.
About Renal Cell
Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney
cancer in adults, accounting for more than 431,000 new cases and
179,000 deaths worldwide each year. RCC is approximately twice as
common in men as in women, with the highest rates of the disease in
North America and Europe. At diagnosis, up to 30% of patients
present with advanced or metastatic RCC.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming patients’ lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine
and, through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep understanding of causal
human biology, cutting-edge capabilities and differentiated
research platforms uniquely position the company to approach cancer
from every angle.
Cancer can have a relentless grasp on many parts of a patient’s
life, and Bristol Myers Squibb is committed to taking actions to
address all aspects of care, from diagnosis to survivorship. As a
leader in cancer care, Bristol Myers Squibb is working to empower
all people with cancer to have a better future.
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 treated more than 35,000 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 65 countries, including
the United States, the European Union, Japan and China. In
September 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.
INDICATIONS
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult and pediatric patients 12 years of age and older
with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adult and pediatric patients 12
years of age and older with unresectable or metastatic
melanoma.
OPDIVO® is indicated for the adjuvant treatment of adult and
pediatric patients 12 years and older with completely resected
Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
OPDIVO® (nivolumab), in combination with platinum-doublet
chemotherapy, is indicated as neoadjuvant treatment of adult
patients with resectable (tumors ≥4 cm or node positive) non-small
cell lung cancer (NSCLC).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or
ALK genomic tumor aberrations.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab)
and 2 cycles of platinum-doublet chemotherapy, is indicated for the
first-line treatment of adult patients with metastatic or recurrent
non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic
tumor aberrations.
OPDIVO® (nivolumab) is indicated for the treatment of adult
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), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
unresectable malignant pleural mesothelioma (MPM).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab), in combination with cabozantinib, is
indicated for the first-line treatment of adult patients with
advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
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 adult
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 adult
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.
OPDIVO® (nivolumab), as a single agent, is indicated for the
adjuvant treatment of adult patients with urothelial carcinoma (UC)
who are at high risk of recurrence after undergoing radical
resection of UC.
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 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 adult patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. 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 the
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with unresectable advanced, recurrent or metastatic
esophageal squamous cell carcinoma (ESCC) after prior
fluoropyrimidine- and platinum-based chemotherapy.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
completely resected esophageal or gastroesophageal junction cancer
with residual pathologic disease in adult patients who have
received neoadjuvant chemoradiotherapy (CRT).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of adult patients with unresectable advanced or
metastatic esophageal squamous cell carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
unresectable advanced or metastatic esophageal squamous cell
carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and
platinum- containing chemotherapy, is indicated for the treatment
of adult patients with advanced or metastatic gastric cancer,
gastroesophageal junction cancer, and esophageal
adenocarcinoma.
IMPORTANT SAFETY
INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include
all possible severe and fatal immune- mediated adverse
reactions.
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue. While immune-mediated
adverse reactions usually manifest during treatment, they can also
occur after discontinuation of OPDIVO or YERVOY. Early
identification and management are essential to ensure safe use of
OPDIVO and YERVOY. Monitor for signs and symptoms that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Evaluate clinical chemistries including liver enzymes,
creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid
function at baseline and periodically during treatment with OPDIVO
and before each dose of YERVOY. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). In general, if OPDIVO
or YERVOY interruption or discontinuation is required, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose immune-mediated
adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not
necessarily require systemic steroids (e.g., endocrinopathies and
dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The
incidence of pneumonitis is higher in patients who have received
prior thoracic radiation. In patients receiving OPDIVO monotherapy,
immune- mediated pneumonitis occurred in 3.1% (61/1994) of
patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2
(2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, immune- mediated pneumonitis occurred in 7% (31/456)
of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2
(4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg
every 3 weeks, immune- mediated pneumonitis occurred in 3.9%
(26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).
In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with
YERVOY 1 mg/kg every 6 weeks, immune- mediated pneumonitis occurred
in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3
(3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to
pneumonitis.
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, including Grade 3 (n=1) and Grade 2
(n=12).
Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may
be fatal. A common symptom included in the definition of colitis
was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been
reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider
repeating infectious workup to exclude alternative etiologies. In
patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%)
and Grade 2 (1%).
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3
weeks, immune-mediated colitis occurred in 25% (115/456) of
patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated colitis occurred in 9% (60/666) of patients,
including Grade 3 (4.4%) and Grade 2 (3.7%).
Immune-Mediated Hepatitis and
Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In
patients receiving OPDIVO monotherapy, immune-mediated hepatitis
occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%),
Grade 3 (1.3%), and Grade 2 (0.4%).
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3
weeks, immune-mediated hepatitis occurred in 15% (70/456) of
patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2
(1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg
every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of
patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2
(0.4%).
OPDIVO in combination with cabozantinib can cause hepatic
toxicity with higher frequencies of Grade 3 and 4 ALT and AST
elevations compared to OPDIVO alone. Consider more frequent
monitoring of liver enzymes as compared to when the drugs are
administered as single agents. In patients receiving OPDIVO and
cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11%
of patients.
Immune-Mediated
Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal
insufficiency, immune-mediated hypophysitis, immune-mediated
thyroid disorders, and Type 1 diabetes mellitus, which can present
with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Hypophysitis can
present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism; initiate hormone replacement as clinically
indicated. Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism; initiate hormone
replacement or medical management as clinically indicated. Monitor
patients for hyperglycemia or other signs and symptoms of diabetes;
initiate treatment with insulin as clinically indicated.
In patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2
(0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, adrenal insufficiency occurred in 8% (35/456),
including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, adrenal insufficiency occurred in 7% (48/666) of patients,
including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In
patients receiving OPDIVO and cabozantinib, adrenal insufficiency
occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and
Grade 2 (1.9%).
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2
(0.3%).
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3
weeks, hypophysitis occurred in 9% (42/456), including Grade 3
(2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4%
(29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and
Grade 2 (0.9%).
In patients receiving OPDIVO monotherapy, thyroiditis occurred
in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, thyroiditis occurred in 2.7% (22/666) of patients, including
Grade 3 (4.5%) and Grade 2 (2.2%).
In patients receiving OPDIVO monotherapy, hyperthyroidism
occurred in 2.7% (54/1994) of patients, including Grade 3
(<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9%
(42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, hyperthyroidism occurred in 12% (80/666) of patients,
including Grade 3 (0.6%) and Grade 2 (4.5%).
In patients receiving OPDIVO monotherapy, hypothyroidism
occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and
Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of
patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks,
hypothyroidism occurred in 18% (122/666) of patients, including
Grade 3 (0.6%) and Grade 2 (11%).
In patients receiving OPDIVO monotherapy, diabetes occurred in
0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2
(0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred
in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3
(0.3%), and Grade 2 (0.9%).
Immune-Mediated Nephritis with Renal
Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In
patients receiving OPDIVO monotherapy, immune-mediated nephritis
and renal dysfunction occurred in 1.2% (23/1994) of patients,
including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated nephritis with renal dysfunction occurred in
4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3
(1.1%), and Grade 2 (2.2%).
Immune-Mediated Dermatologic Adverse
Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative
dermatitis, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), and drug rash with eosinophilia and
systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking
antibodies. Topical emollients and/or topical corticosteroids may
be adequate to treat mild to moderate nonexfoliative rashes.
YERVOY can cause immune-mediated rash or dermatitis, including
bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate non-bullous/exfoliative rashes.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
In patients receiving OPDIVO monotherapy, immune-mediated rash
occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and
Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456)
of patients, including Grade 3 (4.8%) and Grade 2 (10%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated rash occurred in 16% (108/666) of patients,
including Grade 3 (3.5%) and Grade 2 (4.2%).
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received OPDIVO monotherapy or OPDIVO in
combination with YERVOY or were reported with the use of other
PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been
reported for some of these adverse reactions: cardiac/vascular:
myocarditis, pericarditis, vasculitis; nervous system: meningitis,
encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis (including exacerbation), Guillain-Barré
syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis,
iritis, and other ocular inflammatory toxicities can occur;
gastrointestinal: pancreatitis to include increases in serum
amylase and lipase levels, gastritis, duodenitis; musculoskeletal
and connective tissue: myositis/polymyositis, rhabdomyolysis, and
associated sequelae including renal failure, arthritis, polymyalgia
rheumatica; endocrine: hypoparathyroidism; other
(hematologic/immune): hemolytic anemia, aplastic anemia,
hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection.
In addition to the immune-mediated adverse reactions listed
above, across clinical trials of YERVOY monotherapy or in
combination with OPDIVO, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1% of patients unless otherwise specified: nervous
system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia
gravis, motor dysfunction; cardiovascular: angiopathy, temporal
arteritis; ocular: blepharitis, episcleritis, orbital myositis,
scleritis; gastrointestinal: pancreatitis (1.3%); other
(hematologic/immune): conjunctivitis, cytopenias (2.5%),
eosinophilia (2.1%), erythema multiforme, hypersensitivity
vasculitis, neurosensory hypoacusis, psoriasis.
Some ocular IMAR cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. 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 YERVOY, as this may require treatment
with systemic corticosteroids to reduce the risk of permanent
vision loss.
Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions.
Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or
life-threatening (Grade 4) infusion-related reactions. Interrupt or
slow the rate of infusion in patients with mild (Grade 1) or
moderate (Grade 2) infusion-related reactions. In patients
receiving OPDIVO monotherapy as a 60-minute infusion,
infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a separate trial 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 melanoma 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 HCC patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks,
infusion-related reactions occurred in 8% (4/49) of patients. In
RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, 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 every 3 weeks, infusion-related reactions occurred
in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3
mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks,
infusion-related reactions occurred in 12% (37/300) of
patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with OPDIVO or YERVOY.
Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between OPDIVO or YERVOY and allogeneic
HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with OPDIVO and YERVOY prior to or after an
allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal
studies, OPDIVO and YERVOY can cause fetal harm when administered
to a pregnant woman. The effects of YERVOY are likely to be greater
during the second and third trimesters of pregnancy. Advise
pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with OPDIVO and YERVOY and for at least 5 months after
the last dose.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma,
the addition of OPDIVO to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with
multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
Lactation
There are no data on the presence of OPDIVO or YERVOY in human
milk, the effects on the breastfed child, or the effects on milk
production. Because of the potential for serious adverse reactions
in breastfed children, advise women not to breastfeed during
treatment and for 5 months after the last 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 (74%
and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4
adverse reactions (72% and 51%) 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 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).
In Checkmate 238, serious adverse reactions occurred in 18% of
patients receiving OPDIVO (n=452). 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 ≥2% of
OPDIVO-treated patients were diarrhea and increased lipase and
amylase. In Checkmate 816, serious adverse reactions occurred in
30% of patients (n=176) who were treated with OPDIVO in combination
with platinum-doublet chemotherapy. Serious adverse reactions in
>2% included pneumonia and vomiting. No fatal adverse reactions
occurred in patients who received OPDIVO in combination with
platinum-doublet chemotherapy. In Checkmate 227, serious adverse
reactions occurred in 58% of patients (n=576). The most frequent
(≥2%) serious adverse reactions were pneumonia, diarrhea/colitis,
pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency,
and hypophysitis. Fatal adverse reactions occurred in 1.7% of
patients; these included events of pneumonitis (4 patients),
myocarditis, acute kidney injury, shock, hyperglycemia,
multi-system organ failure, and renal failure. In Checkmate 9LA,
serious adverse reactions occurred in 57% of patients (n=358). The
most frequent (>2%) serious adverse reactions were pneumonia,
diarrhea, febrile neutropenia, anemia, acute kidney injury,
musculoskeletal pain, dyspnea, pneumonitis, and respiratory
failure. Fatal adverse reactions occurred in 7 (2%) patients, and
included hepatic toxicity, acute renal failure, sepsis,
pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in
the setting of thrombocytopenia. 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
≥2% of patients receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and
respiratory failure. In Checkmate 057, fatal adverse reactions
occurred; these included events of infection (7 patients, including
one case of Pneumocystis jirovecii pneumonia), pulmonary embolism
(4 patients), and limbic encephalitis (1 patient). In Checkmate
743, serious adverse reactions occurred in 54% of patients
receiving OPDIVO plus YERVOY. The most frequent serious adverse
reactions reported in ≥2% of patients were pneumonia, pyrexia,
diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney
injury, infusion-related reaction, musculoskeletal pain, and
pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%)
patients and included pneumonitis, acute heart failure, sepsis, and
encephalitis. In Checkmate 214, serious adverse reactions occurred
in 59% of patients receiving OPDIVO plus YERVOY (n=547). 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
Checkmate 9ER, serious adverse reactions occurred in 48% of
patients receiving OPDIVO and cabozantinib (n=320). The most
frequent serious adverse reactions reported in ≥2% of patients were
diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract
infection, and hyponatremia. Fatal intestinal perforations occurred
in 3 (0.9%) patients. 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 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 ≥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 ≥2% of patients
receiving OPDIVO were urinary tract infection, sepsis, diarrhea,
small intestine obstruction, and general physical health
deterioration. In Checkmate 274, serious adverse reactions occurred
in 30% of patients receiving OPDIVO (n=351). The most frequent
serious adverse reaction reported in ≥2% of patients receiving
OPDIVO was urinary tract infection. Fatal adverse reactions
occurred in 1% of patients; these included events of pneumonitis
(0.6%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving
OPDIVO with YERVOY (n=119), 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. In
Checkmate 040, serious adverse reactions occurred in 59% of
patients receiving OPDIVO with YERVOY (n=49). Serious adverse
reactions reported in ≥4% of patients were pyrexia, diarrhea,
anemia, increased AST, adrenal insufficiency, ascites, esophageal
varices hemorrhage, hyponatremia, increased blood bilirubin, and
pneumonitis. In Attraction-3, serious adverse reactions occurred in
38% of patients receiving OPDIVO (n=209). Serious adverse reactions
reported in ≥2% of patients who received OPDIVO were pneumonia,
esophageal fistula, interstitial lung disease, and pyrexia. The
following fatal adverse reactions occurred in patients who received
OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia
(1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and
sudden death (0.5%). In Checkmate 577, serious adverse reactions
occurred in 33% of patients receiving OPDIVO (n=532). A serious
adverse reaction reported in ≥2% of patients who received OPDIVO
was pneumonitis. A fatal reaction of myocardial infarction occurred
in one patient who received OPDIVO. In Checkmate 648, serious
adverse reactions occurred in 62% of patients receiving OPDIVO in
combination with chemotherapy (n=310). The most frequent serious
adverse reactions reported in ≥2% of patients who received OPDIVO
with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal
stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received
OPDIVO in combination with chemotherapy; these included
pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney
injury. In Checkmate 648, serious adverse reactions occurred in 69%
of patients receiving OPDIVO in combination with YERVOY (n=322).
The most frequent serious adverse reactions reported in ≥2% who
received OPDIVO in combination with YERVOY were pneumonia (10%),
pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%),
dysphagia (3.7%), hepatic function abnormal (2.8%), decreased
appetite (2.8%), adrenal insufficiency (2.5%), and dehydration
(2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who
received OPDIVO in combination with YERVOY; these included
pneumonitis, interstitial lung disease, pulmonary embolism, and
acute respiratory distress syndrome. In Checkmate 649, serious
adverse reactions occurred in 52% of patients treated with OPDIVO
in combination with chemotherapy (n=782). The most frequent serious
adverse reactions reported in ≥2% of patients treated with OPDIVO
in combination with chemotherapy were vomiting (3.7%), pneumonia
(3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile
neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions
occurred in 16 (2.0%) patients who were treated with OPDIVO in
combination with chemotherapy; these included pneumonitis (4
patients), febrile neutropenia (2 patients), stroke (2 patients),
gastrointestinal toxicity, intestinal mucositis, septic shock,
pneumonia, infection, gastrointestinal bleeding, mesenteric vessel
thrombosis, and disseminated intravascular coagulation. In
Checkmate 76K, serious adverse reactions occurred in 18% of
patients receiving OPDIVO (n=524). Adverse reactions which resulted
in permanent discontinuation of OPDIVO in >1% of patients
included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A
fatal adverse reaction occurred in 1 (0.2%) patient (heart failure
and acute kidney injury). The most frequent Grade 3-4 lab
abnormalities reported in ≥1% of OPDIVO-treated patients were
increased lipase (2.9%), increased AST (2.2%), increased ALT
(2.1%), lymphopenia (1.1%), and decreased potassium (1.0%).
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 (62%), diarrhea (54%),
rash (53%), nausea (44%), pyrexia (40%), pruritus (39%),
musculoskeletal pain (32%), vomiting (31%), decreased appetite
(29%), cough (27%), headache (26%), dyspnea (24%), upper
respiratory tract infection (23%), arthralgia (21%), and increased
transaminases (25%). In Checkmate 067, the most common (≥20%)
adverse reactions in the OPDIVO arm (n=313) were fatigue (59%),
rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea
(30%), cough (28%), pruritus (27%), upper respiratory tract
infection (22%), decreased appetite (22%), headache (22%),
constipation (21%), arthralgia (21%), and vomiting (20%). 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%). In Checkmate 816, the
most common (>20%) adverse reactions in the OPDIVO plus
chemotherapy arm (n=176) were nausea (38%), constipation (34%),
fatigue (26%), decreased appetite (20%), and rash (20%). In
Checkmate 227, the most common (≥20%) adverse reactions were
fatigue (44%), rash (34%), decreased appetite (31%),
musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%),
cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In
Checkmate 9LA, the most common (>20%) adverse reactions were
fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea
(31%), rash (30%), decreased appetite (28%), constipation (21%),
and pruritus (21%). 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 743, the most common adverse reactions
(≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%),
musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea
(27%), nausea (24%), decreased appetite (24%), cough (23%), and
pruritus (21%). In Checkmate 214, the most common adverse reactions
(≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547)
were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal
pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia
(25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%),
and vomiting (20%). In Checkmate 9ER, the most common adverse
reactions (≥20%) in patients receiving OPDIVO and cabozantinib
(n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%),
palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis
(37%), rash (36%), hypertension (36%), hypothyroidism (34%),
musculoskeletal pain (33%), decreased appetite (28%), nausea (27%),
dysgeusia (24%), abdominal pain (22%), cough (20%) and upper
respiratory tract infection (20%). 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 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 (14%) and dyspnea (14%) 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 274, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%),
pruritus (30%), musculoskeletal pain (28%), and urinary tract
infection (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO as a single agent (n=74), 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 (n=119), 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 Checkmate 040, the most common
adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY
(n=49), were rash (53%), pruritus (53%), musculoskeletal pain
(41%), diarrhea (39%), cough (37%), decreased appetite (35%),
fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%),
nausea (20%), dizziness (20%), hypothyroidism (20%), and weight
decreased (20%). In Attraction-3, the most common adverse reactions
(≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and
decreased appetite (21%). In Checkmate 577, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue
(34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal
pain (21%), and cough (20%). In Checkmate 648, the most common
adverse reactions (≥20%) in patients treated with OPDIVO in
combination with chemotherapy (n=310) were nausea (65%), decreased
appetite (51%), fatigue (47%), constipation (44%), stomatitis
(44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the
most common adverse reactions reported in ≥20% of patients treated
with OPDIVO in combination with YERVOY were rash (31%), fatigue
(28%), pyrexia (23%), nausea (22%), diarrhea (22%), and
constipation (20%). In Checkmate 649, the most common adverse
reactions (≥20%) in patients treated with OPDIVO in combination
with chemotherapy (n=782) were peripheral neuropathy (53%), nausea
(48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased
appetite (29%), abdominal pain (27%), constipation (25%), and
musculoskeletal pain (20%). In Checkmate 76K, the most common
adverse reactions (≥20%) reported with OPDIVO (n=524) were fatigue
(36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and
pruritis (20%).
Please see US Full Prescribing Information for OPDIVO and
YERVOY.
Clinical Trials and Patient Populations
Checkmate 227–previously untreated metastatic non-small cell
lung cancer, in combination with YERVOY; Checkmate 9LA–previously
untreated recurrent or metastatic non-small cell lung cancer in
combination with YERVOY and 2 cycles of platinum-doublet
chemotherapy by histology; Checkmate 649–previously untreated
advanced or metastatic gastric cancer, gastroesophageal junction
and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of
esophageal or gastroesophageal junction cancer; Checkmate
238–adjuvant treatment of patients with completely resected Stage
III or Stage IV melanoma; Checkmate 76K–adjuvant treatment of
patients 12 years of age and older with completely resected Stage
IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of
urothelial carcinoma; Checkmate 275–previously treated advanced or
metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR
metastatic colorectal cancer, as a single agent or in combination
with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal
cancer, as a single agent or in combination with YERVOY;
Attraction-3–esophageal squamous cell carcinoma; Checkmate
648—previously untreated, unresectable advanced recurrent or
metastatic esophageal squamous cell carcinoma; Checkmate
648-previously untreated, unresectable advanced recurrent or
metastatic esophageal squamous cell carcinoma; Checkmate
040–hepatocellular carcinoma, in combination with YERVOY; Checkmate
743–previously untreated unresectable malignant pleural
mesothelioma, in combination with YERVOY; Checkmate 037–previously
treated metastatic melanoma; Checkmate 066-previously untreated
metastatic melanoma; Checkmate 067–previously untreated metastatic
melanoma, as a single agent or in combination with YERVOY;
Checkmate 017–second-line treatment of metastatic squamous
non-small cell lung cancer; Checkmate 057–second-line treatment of
metastatic non-squamous non-small cell lung cancer; Checkmate
816–neoadjuvant non-small cell lung cancer, in combination with
platinum-doublet chemotherapy; Checkmate 141–recurrent or
metastatic squamous cell carcinoma of the head and neck; Checkmate
025–previously treated renal cell carcinoma; Checkmate
214–previously untreated renal cell carcinoma, in combination with
YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in
combination with cabozantinib; Checkmate 205/039–classical Hodgkin
lymphoma.
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC; for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib; for patients with advanced RCC as a first-line
treatment in combination with nivolumab; and for adult and
pediatric patients 12 years of age and older with locally advanced
or metastatic differentiated thyroid cancer (DTC) that has
progressed following prior VEGFR-targeted therapy and who are
radioactive iodine-refractory or ineligible. CABOMETYX tablets have
also received regulatory approvals in the European Union and
additional countries and regions worldwide. In 2016, Exelixis
granted Ipsen Pharma SAS exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
U.S. and Japan. In 2017, Exelixis granted exclusive rights to
Takeda for the commercialization and further clinical development
of cabozantinib for all future indications in Japan. Exelixis holds
the exclusive rights to develop and commercialize cabozantinib in
the U.S.
CABOMETYX IMPORTANT SAFETY
INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue
CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as
recommended. Do not administer CABOMETYX to patients who have a
recent history of hemorrhage, including hemoptysis, hematemesis, or
melena.
Perforations and Fistulas: Fistulas, including fatal
cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Monitor patients for signs and symptoms of fistulas and
perforations, including abscess and sepsis. Discontinue CABOMETYX
in patients who experience a Grade 4 fistula or a GI
perforation.
Thrombotic Events: CABOMETYX increased the risk of
thrombotic events. Venous thromboembolism occurred in 7% (including
4% pulmonary embolism) and arterial thromboembolism in 2% of
CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX
patients. Discontinue CABOMETYX in patients who develop an acute
myocardial infarction or serious arterial or venous thromboembolic
events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause
hypertension, including hypertensive crisis. Hypertension was
reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX
patients. Do not initiate CABOMETYX in patients with uncontrolled
hypertension. Monitor blood pressure regularly during CABOMETYX
treatment. Withhold CABOMETYX for hypertension that is not
adequately controlled with medical management; when controlled,
resume at a reduced dose. Permanently discontinue CABOMETYX for
severe hypertension that cannot be controlled with
anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients.
Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and
manage patients using antidiarrheals as indicated. Withhold
CABOMETYX until improvement to ≤ Grade 1, resume at a reduced
dose.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX
patients. Withhold CABOMETYX until improvement to Grade 1 and
resume at a reduced dose for intolerable Grade 2 PPE or Grade 3
PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab
can cause hepatic toxicity with higher frequencies of Grades 3 and
4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically
throughout treatment. Consider more frequent monitoring of liver
enzymes than when the drugs are administered as single agents. For
elevated liver enzymes, interrupt CABOMETYX and nivolumab and
consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4
increased ALT or AST were seen in 11% of patients. ALT or AST >3
times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%)
received systemic corticosteroids; ALT or AST resolved to Grades
0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT
or AST who were rechallenged with either CABOMETYX (n=9) or
nivolumab (n=11) as a single agent or with both (n=24), recurrence
of Grade ≥2 increased ALT or AST was observed in 2 patients
receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients
receiving both CABOMETYX and nivolumab. Withhold and resume at a
reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with
nivolumab can cause primary or secondary adrenal insufficiency. For
Grade 2 or higher adrenal insufficiency, initiate symptomatic
treatment, including hormone replacement as clinically indicated.
Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a
reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with
RCC who received CABOMETYX with nivolumab, including Grade 3
(2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency
led to permanent discontinuation of CABOMETYX and nivolumab in 0.9%
and withholding of CABOMETYX and nivolumab in 2.8% of patients with
RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency
received hormone replacement therapy, including systemic
corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the
15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was
withheld for adrenal insufficiency, 6 reinstated treatment after
symptom improvement; of these, all (n=6) received hormone
replacement therapy and 2 had recurrence of adrenal
insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until
improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced
dose. Discontinue CABOMETYX in patients who develop nephrotic
syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of
CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis,
osteitis, bone erosion, tooth or periodontal infection, toothache,
gingival ulceration or erosion, persistent jaw pain, or slow
healing of the mouth or jaw after dental surgery. Perform an oral
examination prior to CABOMETYX initiation and periodically during
treatment. Advise patients regarding good oral hygiene practices.
Withhold CABOMETYX for at least 3 weeks prior to scheduled dental
surgery or invasive dental procedures, if possible. Withhold
CABOMETYX for development of ONJ until complete resolution, resume
at a reduced dose.
Impaired Wound Healing: Wound complications occurred with
CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to
elective surgery. Do not administer CABOMETYX for at least 2 weeks
after major surgery and until adequate wound healing. The safety of
resumption of CABOMETYX after resolution of wound healing
complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
RPLS, a syndrome of subcortical vasogenic edema diagnosed by
characteristic findings on MRI, can occur with CABOMETYX. Evaluate
for RPLS in patients presenting with seizures, headache, visual
disturbances, confusion, or altered mental function. Discontinue
CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily
hypothyroidism, has been observed with CABOMETYX. Based on the
safety population, thyroid dysfunction occurred in 19% of patients
treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction
prior to the initiation of CABOMETYX and monitored for signs and
symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid
function testing and management of dysfunction should be performed
as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on
the safety population, hypocalcemia occurred in 13% of patients
treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1%
of patients. Laboratory abnormality data were not collected in
CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated
with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of
patients.
Monitor blood calcium levels and replace calcium as necessary
during treatment. Withhold and resume at reduced dose upon recovery
or permanently discontinue CABOMETYX depending on severity.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm.
Advise pregnant women and females of reproductive potential of the
potential risk to a fetus. Verify the pregnancy status of females
of reproductive potential prior to initiating CABOMETYX and advise
them to use effective contraception during treatment and for 4
months after the last dose.
ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased
appetite, hypertension, nausea, vomiting, weight decreased, and
constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue,
hepatotoxicity, PPE, stomatitis, rash, hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong
CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong
CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Avoid St. John’s wort.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during
CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic
impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in
patients with severe hepatic impairment.
Please see accompanying full Prescribing Information
https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.
You are encouraged to report negative side effects of
prescription drugs to the FDA. Visit
www.FDA.gov/medwatch or call 1-800-FDA-1088.
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, Facebook and
Instagram.
About Exelixis
Exelixis is a globally ambitious oncology company innovating
next-generation medicines and regimens at the forefront of cancer
care. Powered by drug discovery and development excellence, we are
rapidly evolving our product portfolio to target an expanding range
of tumor types and indications with our clinically differentiated
pipeline of small molecules, antibody-drug conjugates and other
biotherapeutics. This comprehensive approach harnesses decades of
robust investment in our science and partnerships to advance our
investigational programs and extend the impact of our flagship
commercial product, CABOMETYX® (cabozantinib). Exelixis is driven
by a bold scientific pursuit to create transformational treatments
that give more patients hope for the future. For information about
the company and its mission to help cancer patients recover
stronger and live longer, visit www.exelixis.com, follow
@ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and
follow Exelixis on LinkedIn.
Bristol Myers Squibb Cautionary
Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on current expectations and projections about our future
financial results, goals, plans and objectives and involve inherent
risks, assumptions and uncertainties, including internal or
external factors that could delay, divert or change any of them in
the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
that future study results may not be consistent with the results to
date, that Opdivo® (nivolumab) in combination with CABOMETYX®
(cabozantinib) for the indication described in this release will be
commercially successful, that any marketing approvals, if granted,
may have significant limitations on their use, and, that continued
approval of such combination treatment for such indication
described in this release may be contingent upon verification and
description of clinical benefit in additional confirmatory trials.
No forward-looking statement can be guaranteed. Forward-looking
statements in this press release should be evaluated together with
the many risks and uncertainties that affect Bristol Myers Squibb’s
business and market, particularly those identified in the
cautionary statement and risk factors discussion in Bristol Myers
Squibb’s Annual Report on Form 10-K for the year ended December 31,
2022, as updated by our subsequent Quarterly Reports on Form 10-Q,
Current Reports on Form 8-K and other filings with the Securities
and Exchange Commission. The forward-looking statements included in
this document are made only as of the date of this document and
except as otherwise required by applicable law, Bristol Myers
Squibb undertakes no obligation to publicly update or revise any
forward-looking statement, whether as a result of new information,
future events, changed circumstances or otherwise.
Exelixis Forward-Looking
Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the
presentation of updated results from the CheckMate -9ER trial at
ASCO GU 2024; the therapeutic potential of cabozantinib in
combination with nivolumab and Exelixis’ belief that the regimen
may provide a long-term survival benefit for patients with
previously untreated advanced kidney cancer, regardless of risk
classification; Exelixis’ commitment to collaborating with the
scientific community to advance treatment regimens for patients
with advanced cancers; and Exelixis’ scientific pursuit to create
transformational treatments that give more patients hope for the
future. Any statements that refer to expectations, projections or
other characterizations of future events or circumstances are
forward-looking statements and are based upon Exelixis’ current
plans, assumptions, beliefs, expectations, estimates and
projections. Forward-looking statements involve risks and
uncertainties. Actual results and the timing of events could differ
materially from those anticipated in the forward-looking statements
as a result of these risks and uncertainties, which include,
without limitation: the availability of data at the referenced
times; complexities and the unpredictability of the regulatory
review and approval processes in the U.S. and elsewhere; Exelixis’
and Bristol Myers Squibb’s continuing compliance with applicable
legal and regulatory requirements; the potential failure of
cabozantinib in combination with nivolumab to demonstrate safety
and/or efficacy in future clinical testing; unexpected concerns
that may arise as a result of the occurrence of adverse safety
events or additional data analyses of clinical trials evaluating
cabozantinib; the costs of conducting clinical trials; Exelixis’
dependence on third-party vendors for the development, manufacture
and supply of cabozantinib; Exelixis’ and Bristol Myers Squibb’s
ability to protect their respective intellectual property rights;
market competition, including the potential for competitors to
obtain approval for generic versions of CABOMETYX; changes in
economic and business conditions; and other factors affecting
Exelixis and its development programs detailed from time to time
under the caption “Risk Factors” in Exelixis’ most recent Annual
Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q,
and in Exelixis’ future filings with the Securities and Exchange
Commission. All forward-looking statements in this press release
are based on information available to Exelixis as of the date of
this press release, and Exelixis undertakes no obligation to update
or revise any forward-looking statements contained herein, except
as required by law.
Exelixis, the Exelixis logo and CABOMETYX are registered U.S.
trademarks of Exelixis.
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Bristol Myers Squibb Media Inquiries:
media@bms.com Investors: investor.relations@bms.com
Exelixis Investors: Susan Hubbard EVP, Public Affairs
and Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com Media: Claire McConnaughey Senior
Director, Public Affairs Exelixis, Inc. (650) 837-7052
cmcconn@exelixis.com
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