U.S. Food and Drug Administration assigned a
target action date of February 20, 2021
Applications based on pivotal Phase 3
CheckMate -9ER trial, which showed OPDIVO in combination with
CABOMETYX improved overall survival, doubled median
progression-free survival and objective response rate, and
demonstrated a manageable safety profile
Results from CheckMate -9ER recently
presented during a Presidential Symposium at the European Society
for Medical Oncology Virtual Congress 2020
Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ:
EXEL) today announced that the U.S. Food and Drug Administration
(FDA) has accepted the supplemental Biologics License Application
(sBLA) and supplemental New Drug Application (sNDA), respectively,
for OPDIVO® (nivolumab) in combination with
CABOMETYX® (cabozantinib) for patients with advanced renal
cell carcinoma (RCC). The FDA granted Priority Review to both
applications and assigned a Prescription Drug User Fee Act (PDUFA)
goal date, or target action date, of February 20, 2021.
These filings were based on results from the Phase 3 CheckMate
-9ER trial, which evaluated OPDIVO in combination with CABOMETYX in
patients with previously untreated advanced RCC versus sunitinib.
In CheckMate -9ER, OPDIVO in combination with CABOMETYX
demonstrated significant improvements across all efficacy
endpoints, including overall survival (OS), progression-free
survival (PFS) and objective response rate (ORR), versus the
comparator, sunitinib.
“We have witnessed practice-changing advancements in the
treatment of renal cell carcinoma in recent years, but we recognize
the importance of providing patients and physicians with additional
options that can help them take control of the disease,” said Mark
Rutstein, vice president, development program lead, OPDIVO, Bristol
Myers Squibb. “In the CheckMate -9ER trial, combining OPDIVO and
CABOMETYX, two proven agents with strong clinical legacies in
advanced renal cell carcinoma, led to superior efficacy across all
endpoints. We look forward to working with the FDA to bring this
potential treatment option to physicians and their patients who
choose an immunotherapy plus tyrosine kinase inhibitor
regimen.”
“With their complementary mechanisms of action and evidence that
CABOMETYX may promote a more immune-permissive environment, we
believe there is opportunity for additive or synergistic effects
with this potential combination regimen,” said Gisela Schwab, M.D.,
president, product development and medical affairs and chief
medical officer, Exelixis. “Based on strong supporting data from
CheckMate -9ER, the acceptance of our application is important
progress in our efforts to make CABOMETYX in combination with
OPDIVO available to patients with advanced kidney cancer who need
additional treatment options. We look forward to working with the
FDA throughout the ongoing review process.”
The combination of OPDIVO plus CABOMETYX was well tolerated,
with a low rate of treatment-related discontinuations, and
reflected the known safety profiles of the immunotherapy and
tyrosine kinase inhibitor components in patients with previously
untreated advanced RCC. In addition, patient-reported outcomes data
from CheckMate -9ER showed that OPDIVO in combination with
CABOMETYX was associated with statistically significant
improvements in health-related quality of life at most time points
versus sunitinib. On September 19, 2020, results from the trial
were presented as a Proffered Paper during a Presidential Symposium
at the European Society for Medical Oncology (ESMO) Virtual
Congress 2020.
Bristol Myers Squibb and Exelixis thank the patients and
investigators who were 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, Ipsen 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 140,000 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.
The five-year survival rate for those diagnosed with metastatic, or
advanced, kidney cancer is 12.1%.
Bristol Myers Squibb: Advancing Cancer
Research
At Bristol Myers Squibb, patients are at the center of
everything we do. The goal of our cancer research is to increase
patients’ quality of life, long-term survival and make cure a
possibility. We harness our deep scientific experience,
cutting-edge technologies and discovery platforms to discover,
develop and deliver novel treatments for patients.
Building upon our transformative work and legacy in hematology
and Immuno-Oncology that has changed survival expectations for many
cancers, our researchers are advancing a deep and diverse pipeline
across multiple modalities. In the field of immune cell therapy,
this includes registrational CAR T cell agents for numerous
diseases, and a growing early-stage pipeline that expands cell and
gene therapy targets, and technologies. We are developing cancer
treatments directed at key biological pathways using our protein
homeostasis platform, a research capability that has been the basis
of our approved therapies for multiple myeloma and several
promising compounds in early- to mid-stage development. Our
scientists are targeting different immune system pathways to
address interactions between tumors, the microenvironment and the
immune system to further expand upon the progress we have made and
help more patients respond to treatment. Combining these approaches
is key to delivering potential new options for the treatment of
cancer and addressing the growing issue of resistance to
immunotherapy. We source innovation internally, and in
collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of
transformational medicines a reality for patients.
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 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.
About CABOMETYX®
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC and for the treatment of patients with
HCC who have been previously treated with sorafenib. CABOMETYX
tablets have also received regulatory approvals in the European
Union, Japan and additional countries and regions worldwide. In
2016, Exelixis granted Ipsen exclusive rights for the
commercialization and further clinical development of cabozantinib
outside of the United States and Japan. In 2017, Exelixis granted
exclusive rights to Takeda Pharmaceutical Company Limited 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 United
States.
OPDIVO® INDICATIONS
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
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 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 metastatic small cell lung cancer (SCLC) with progression
after platinum-based chemotherapy and at least one other line of
therapy. 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 first-line treatment of adult patients with
unresectable malignant pleural mesothelioma (MPM).
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), 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) 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 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), in combination with YERVOY® (ipilimumab),
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
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 adjuvant treatment of
patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with unresectable advanced, recurrent or metastatic esophageal
squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and
platinum-based chemotherapy.
OPDIVO® IMPORTANT SAFETY
INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not be
inclusive of 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 at any time after starting or discontinuing YERVOY. Early
identification and management are essential to ensure safe use of
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 before each dose. Institute medical management
promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue YERVOY depending on
severity. In general, if YERVOY requires interruption or
discontinuation, administer systemic corticosteroid therapy (1 to 2
mg/kg/day prednisone or equivalent) until improvement to Grade 1 or
less followed by corticosteroid taper for at least 1 month.
Consider administration of other systemic immunosuppressants in
patients whose immune-mediated adverse reaction is not controlled
with corticosteroid therapy. Institute hormone replacement therapy
for endocrinopathies as warranted.
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 melanoma patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in
6% (25/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 10%
(5/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 1.7% (2/119) of patients. In NSCLC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in
9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%),
and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients
(0.7%) died due to pneumonitis. The incidence and severity of
immune-mediated pneumonitis in patients with NSCLC treated with
OPDIVO 360 mg every 3 weeks in combination with YERVOY 1 mg/kg
every 6 weeks and 2 cycles of platinum-doublet chemotherapy were
comparable to treatment with OPDIVO in combination with YERVOY
only. The incidence and severity of immune-mediated pneumonitis in
patients with malignant pleural mesothelioma treated with OPDIVO 3
mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks were similar
to those occurring in NSCLC.
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 melanoma 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 HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated colitis occurred in 10% (5/49) of patients.
In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 10% (52/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated colitis occurred in 7% (8/119) of
patients.
In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated
diarrhea/colitis occurred in 12% (62/511) of patients, including
Grade 3-5 (7%).
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. Addition of an
alternative immunosuppressive agent to the corticosteroid therapy,
or replacement of the corticosteroid therapy, should be considered
in corticosteroid-refractory immune-mediated colitis if other
causes are excluded.
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 melanoma patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407)
of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated hepatitis occurred in 20% (10/49) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119)
of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated
hepatitis occurred in 4.1% (21/511) of patients, including Grade
3-5 (1.6%).
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. Withhold for Grades 2, 3, or 4 endocrinopathies if
not clinically stable. 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 melanoma patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9%
(36/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, hypophysitis occurred in 4% (2/49) of patients. In
RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated hypophysitis occurred in 3.4% (4/119) of patients.
In patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994) of patients. In melanoma patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In HCC patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred
in 18% (9/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547)
of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119)
of patients. In patients receiving OPDIVO monotherapy,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7%
(54/1994) of patients receiving OPDIVO monotherapy. In melanoma
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
HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 22% (11/49) of patients. Hyperthyroidism occurred in 10% (5/49)
of patients receiving this dose of OPDIVO with YERVOY. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 22% (119/547) of patients. Hyperthyroidism occurred in 12%
(66/547) of patients receiving this dose of OPDIVO with YERVOY. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism
occurred in 15% (18/119) of patients. Hyperthyroidism occurred in
12% (14/119) of patients. In patients receiving OPDIVO monotherapy,
diabetes occurred in 0.9% (17/1994) of patients. In melanoma
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes
occurred in 1.5% (6/407) of patients. In RCC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7%
(15/547) of patients.
In a separate Phase 3 trial of YERVOY 3 mg/kg, severe to
life-threatening endocrinopathies occurred in 9 (1.8%) patients.
All 9 patients had hypopituitarism, and some had additional
concomitant endocrinopathies such as adrenal insufficiency,
hypogonadism, and hypothyroidism. Six of the 9 patients were
hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In patients
receiving OPDIVO monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In melanoma
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated nephritis and renal dysfunction occurred in 2.2%
(9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction
occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
nephritis and renal dysfunction occurred in 1.7% (2/119) of
patients.
Immune-Mediated Skin and Dermatologic Adverse
Reactions
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In melanoma patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6%
(92/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated rash occurred in 35% (17/49) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 16% (90/547) of patients.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 14% (17/119) of
patients.
YERVOY can cause immune-mediated rash or dermatitis, including
bullous and exfoliative dermatitis, Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN). Topical emollients and/or
topical corticosteroids may be adequate to treat mild to moderate
non-bullous exfoliative rashes. Withhold YERVOY until specialist
assessment for Grade 2 and permanently discontinue for Grade 3 or 4
exfoliative or bullous dermatologic conditions.
In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated
rash occurred in 15% (76/511) of patients, including Grade 3-5
(2.5%).
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Fatal cases have
been reported. 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 melanoma patient
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7
months of exposure. Encephalitis occurred in one RCC patient
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after
approximately 4 months of exposure. Encephalitis occurred in one
MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg after 15 days of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Dose modifications for YERVOY for adverse reactions that
require management different from these general guidelines are
summarized as follows. Withhold for Grade 2 and permanently
discontinue YERVOY for Grade 3 or 4 neurological toxicities.
Withhold for Grade 2 and permanently discontinue YERVOY for Grade 3
or 4 myocarditis. Permanently discontinue YERVOY for Grade 2, 3, or
4 ophthalmologic adverse reactions that do not improve to Grade 1
within 2 weeks while receiving topical therapy OR that require
systemic 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, myasthenic syndrome, hemophagocytic
lymphohistiocytosis (HLH), and autoimmune hemolytic anemia. 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: autoimmune neuropathy (2%),
meningitis, encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis, nerve paresis, angiopathy, temporal
arteritis, pancreatitis (1.3%), arthritis, polymyositis,
conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema
multiforme, hypersensitivity vasculitis, neurosensory hypoacusis,
psoriasis, blepharitis, episcleritis, orbital myositis, scleritis,
and solid organ transplant rejection. Some cases of ocular IMARs
have been associated with retinal detachment.
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 and
may require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions, which have
been reported in <1.0% of patients in clinical trials.
Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related
reactions. Interrupt or slow the rate of infusion in patients with
Grade 1 or 2. Severe infusion-related reactions can also occur with
YERVOY. Discontinue YERVOY in patients with severe or
life-threatening infusion reactions and interrupt or slow the rate
of infusion in patients with mild or moderate infusion 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, infusion-related reactions occurred in 8% (4/49) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, infusion-related reactions occurred in 5.1% (28/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119)
of patients. 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.
In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg,
infusion-related reactions occurred in 2.9% (28/982).
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 a PD-1 receptor blocking
antibody 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 PD-1 or CTLA-4 receptor blockade and
allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1 receptor blocking antibody or YERVOY
prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on mechanism 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
OPDIVO or 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 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
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 OPDIVO or YERVOY, advise women
not to breastfeed during treatment and for at least 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 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 032, serious
adverse reactions occurred in 45% of patients receiving OPDIVO
(n=245). The most frequent serious adverse reactions reported in
≥2% of patients receiving OPDIVO were pneumonia, dyspnea,
pneumonitis, pleural effusion, and dehydration. 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 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. 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 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 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO with YERVOY, serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and dehydration. In
Checkmate 040, serious adverse reactions occurred in 49% of
patients receiving OPDIVO (n=154). The most frequent serious
adverse reactions reported in ≥2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, pneumonia, and anemia. 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
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 ≥2% of OPDIVO-treated patients were
diarrhea and increased lipase and amylase. Serious adverse
reactions occurred in 18% of OPDIVO-treated patients. 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%).
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 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 032, the most common adverse reactions
(≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%),
decreased appetite (27%), musculoskeletal pain (25%), dyspnea
(22%), nausea (22%), diarrhea (21%), constipation (20%), and cough
(20%). In Checkmate 743, the most common adverse reactions (≥20%)
in patients receiving OPDIVO and 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 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) 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 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 142 in MSI-H/dMMR mCRC
patients receiving OPDIVO as a single agent, the most common
adverse reactions (≥20%) were fatigue (54%), diarrhea (43%),
abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal
pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation
(20%), and upper respiratory tract infection (20%). In Checkmate
142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the
most common adverse reactions (≥20%) were fatigue (49%), diarrhea
(45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain
(30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite
(20%), and vomiting (20%). In 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 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 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 Attraction-3,
the most common adverse reactions occurring in ≥20% of
OPDIVO-treated patients (n=209) were rash (22%) and decreased
appetite (21%).
In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg
were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and
colitis (8%).
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY.
Checkmate Trials and Patient Populations
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 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
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 032–small cell
lung cancer; Checkmate 743 – previously untreated unresectable
malignant pleural mesothelioma, in combination with YERVOY;
Checkmate 025–previously treated renal cell carcinoma; Checkmate
214–previously untreated renal cell carcinoma, in combination with
YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate
141–recurrent or metastatic squamous cell carcinoma of the head and
neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or
dMMR metastatic colorectal cancer, as a single agent or in
combination with YERVOY; Checkmate 040–hepatocellular carcinoma, as
a single agent or in combination with YERVOY; Checkmate
238–adjuvant treatment of melanoma; Attraction-3—esophageal
squamous cell carcinoma
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 and HCC studies. Discontinue CABOMETYX
for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to
patients who have a recent history of hemorrhage, including
hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Fistulas, including fatal cases, occurred in 1% of
CABOMETYX patients. Monitor patients for signs and symptoms of
perforations and fistulas, 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
event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause
hypertension, including hypertensive crisis. Hypertension occurred
in 36% (17% 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. Discontinue CABOMETYX for severe hypertension that
cannot be controlled with anti-hypertensive therapy or for
hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients.
Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold
CABOMETYX until improvement to Grade 1 and resume at a reduced dose
for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be
managed with standard antidiarrheal treatments, or Grade 4
diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
44% 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.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. 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.
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 is observed.
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.
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 commonly reported (≥25%) adverse reactions are:
diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension,
and vomiting.
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. CABOMETYX is not
recommended for use in patients with severe hepatic impairment.
Please see accompanying full Prescribing Information:
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
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.
Celgene and Juno Therapeutics are wholly owned subsidiaries of
Bristol-Myers Squibb Company. In certain countries outside the
U.S., due to local laws, Celgene and Juno Therapeutics are referred
to as, Celgene, a Bristol Myers Squibb company and Juno
Therapeutics, a Bristol Myers Squibb company.
About Exelixis
Founded in 1994, Exelixis, Inc. (NASDAQ: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model system genetics, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. Our discovery efforts have resulted in four commercially
available products, CABOMETYX® (cabozantinib), COMETRIQ®
(cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO®
(esaxerenone), and we have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery — all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer.
Exelixis is a member of the Standard & Poor’s (S&P) MidCap
400 index, which measures the performance of profitable mid-sized
companies. For more information about Exelixis, please visit
www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis,
Inc. on Facebook.
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 historical performance and 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 will be consistent with the
results to date, that Opdivo plus CABOMETYX may not receive
regulatory approval for the indication described in this release
and, if approved, whether such combination treatment for such
indication described in this release will be commercially
successful. 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, 2019, 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
therapeutic potential of the combination of CABOMETYX and Opdivo as
a treatment for patients with advanced kidney cancer; the
regulatory review process, including Exelixis’ and BMS’ plans to
work with the FDA the during the FDA’s review of Exelixis’ and BMS’
respective applications; and Exelixis’ plans to reinvest in its
business to maximize the potential of the company’s pipeline,
including through targeted business development activities and
internal drug discovery. 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: complexities and the unpredictability
of the regulatory review and approval processes in the U.S. and
elsewhere, including the risk that the FDA may not approve the
combination of CABOMETYX and Opdivo as a treatment for advanced RCC
in a timely fashion, if at all; unexpected concerns that may arise
as a result of the occurrence of adverse safety events or
additional data analyses of clinical trials evaluating the
combination of CABOMETYX and Opdivo; Exelixis’ dependence on its
relationships with its collaboration partners, including their
pursuit of regulatory approvals for partnered compounds in new
indications and their adherence to their obligations under relevant
collaboration agreements; the continuing COVID-19 pandemic and its
impact on Exelixis’ product development and commercial activities;
Exelixis’ ability to protect its 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 partners to obtain regulatory approval for
cabozantinib in new indications discussed under the caption “Risk
Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on August 6, 2020, and in
Exelixis’ future filings with the SEC. 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.
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Bristol Myers Squibb Media Inquiries:
Media@BMS.com 609-252-3345 Investors: Tim Power 609-252-7509
timothy.power@bms.com Exelixis Investors: Susan
Hubbard EVP, Public Affairs and Investor Relations (650) 837-8194
shubbard@exelixis.com Media: Lindsay Treadway Senior
Director, Public Affairs and Advocacy Relations (650) 837-7522
ltreadway@exelixis.com
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