– Submission based on the CheckMate -9ER
phase 3 pivotal trial, which showed CABOMETYX in combination with
OPDIVO improved overall survival and doubled median
progression-free survival and objective response rate versus
sunitinib –
Exelixis, Inc. (NASDAQ: EXEL) today announced that Takeda
Pharmaceutical Company Limited (Takeda), its partner responsible
for the clinical development and commercialization of CABOMETYX®
(cabozantinib) in Japan, and Ono Pharmaceutical Co., Ltd. (Ono),
have submitted a supplemental application to the Japanese Ministry
of Health, Labour and Welfare (MHLW) for Manufacturing and
Marketing approval of CABOMETYX in combination with OPDIVO®
(nivolumab) for the treatment of patients with unresectable,
advanced or metastatic renal cell carcinoma (RCC).
Takeda and Ono’s application is based on the results of
CheckMate -9ER, a phase 3 pivotal trial evaluating CABOMETYX in
combination with OPDIVO in previously untreated patients with
advanced or metastatic RCC compared with sunitinib. In CheckMate
-9ER, CABOMETYX in combination with OPDIVO demonstrated superior
overall survival, doubled median progression-free survival and
objective response rate, and demonstrated a favorable safety
profile versus sunitinib. These results were presented as a
Proffered Paper during a Presidential Symposium at the European
Society for Medical Oncology Virtual Congress 2020.
“Following our recent announcement that the U.S. FDA accepted
and granted Priority Review to our supplemental new drug
application for CABOMETYX in combination with OPDIVO for the
treatment of advanced renal cell carcinoma, we’re excited that our
partner Takeda along with Ono have also advanced this combination
regimen toward potential regulatory approval in Japan,” said Gisela
Schwab, M.D., President, Product Development and Medical Affairs
and Chief Medical Officer, Exelixis. “The results of the CheckMate
-9ER trial suggest CABOMETYX in combination with OPDIVO may become
an important new treatment option for patients with advanced kidney
cancer in need of new therapies.”
Per the terms of Exelixis and Takeda’s collaboration and license
agreement, Exelixis is eligible to receive a $10 million milestone
payment from Takeda as a result of this latest submission for RCC.
Following the milestone associated with this regulatory filing,
Exelixis will be eligible to receive a first-sale milestone payment
of $20 million from Takeda related to the combination of CABOMETYX
and OPDIVO for the treatment of RCC. Exelixis continues to be
eligible to receive additional development, regulatory and
first-sale milestones for potential future cabozantinib
indications, and is also eligible for sales revenue milestones and
royalties on net sales of cabozantinib in Japan. Takeda fully funds
cabozantinib development activities that are exclusively for the
benefit of Japan and has the opportunity to share the costs
associated with global cabozantinib clinical trials, providing the
company opts into those trials.
Takeda received approval in March 2020 from the Japanese MHLW to
manufacture and market CABOMETYX as a treatment for patients with
curatively unresectable or metastatic RCC.
About CheckMate -9ER
CheckMate -9ER is an open-label, randomized, multi-national
phase 3 trial evaluating patients with previously untreated
advanced or metastatic 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.
Secondary endpoints include overall survival and objective response
rate. 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 RCC
The American Cancer Society’s 2020 statistics cite kidney cancer
as among the top ten most commonly diagnosed forms of cancer among
both men and women in the U.S.1 Clear cell RCC is the most common
type of kidney cancer in adults.2 If detected in its early stages,
the five-year survival rate for RCC is high; for patients with
advanced or late-stage metastatic RCC, however, the five-year
survival rate is only 12%.2 Approximately 32,000 patients in the
U.S. and 71,000 worldwide will require systemic treatment for
advanced kidney cancer in 2020.3
About 70% of RCC cases are known as “clear cell” carcinomas,
based on histology.4 The majority of clear cell RCC tumors have
below-normal levels of a protein called von Hippel-Lindau, which
leads to higher levels of MET, AXL and VEGF.5,6 These proteins
promote tumor angiogenesis (blood vessel growth), growth,
invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape
pathways that drive resistance to VEGF receptor inhibitors.6,7
About CABOMETYX® (cabozantinib)
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 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.
CABOMETYX in combination with OPDIVO is not indicated for
advanced RCC.
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.
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
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.
Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: Exelixis’
expectation that, if approved, CABOYMETYX in combination with
Opdivo may become an important new treatment option in Japan for
patients with advanced kidney cancer in need of new therapies; the
anticipated timing for receipt of a $10 million milestone payment
from Takeda for Takeda’s regulatory submission in Japan for
CABOMETYX in combination with Opdivo for the treatment for
unresectable, advanced or metastatic RCC; Exelixis’ eligibility for
future development, regulatory and first-sale milestones, plus
sales revenue milestones and royalties on net sales under its
collaboration with Takeda; 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, including the risk
that the Japanese MHLW may not approve CABOMETYX in combination
with Opdivo as a treatment for unresectable, advanced or metastatic
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 CABOMETYX in
combination with 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.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a
Japanese trademark.
OPDIVO® and YERVOY® are registered trademarks
of Bristol-Myers Squibb Company.
1 American Cancer Society: Cancer Facts & Figures 2020.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
Accessed October 2020. 2 Jonasch, E., Gao, J., Rathmell, W., Renal
cell carcinoma. BMJ. 2014; 349:g4797. 3 Decision Resources Report:
Renal Cell Carcinoma. October 2014 (internal data on file). 4
American Cancer Society: What is Kidney Cancer? Available at:
https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html.
Accessed October 2020. 5 Harshman, L., and Choueiri, T. Targeting
the hepatocyte growth factor/c-Met signaling pathway in renal cell
carcinoma. Cancer J. 2013; 19:316-323. 6 Rankin, et al. Direct
regulation of GAS6/AXL signaling by HIF promotes renal metastasis
through SRC and MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.
7 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL
overcomes resistance to sunitinib therapy in renal cell carcinoma.
Oncogene. 2016; 35:2687-2697. 8 Koochekpour, et al. The von
Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth
factor/scatter factor-induced invasion and branching morphogenesis
in renal carcinoma cells. Mol Cell Biol. 1999; 19:5902–5912. 9
Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased
amounts of messenger RNAs for vascular endothelial growth factor
and placenta growth factor in renal cell carcinoma associated with
angiogenesis. Cancer Res. 1994; 54:4233-4237. 10 Nakagawa, M.,
Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by
microvascular endothelial cells is mediated by vascular endothelial
growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997;
79:681-687.
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Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com
Media Contact: Lindsay Treadway Senior Director, Public
Affairs and Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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