– First phase 3 trial in a global clinical development program to explore the combination of these agents –
– Exelixis, Bristol-Myers Squibb and Ipsen to co-fund this trial –
Exelixis,
Inc. (NASDAQ:EXEL) and Bristol-Myers
Squibb Company (NYSE:BMY) today announced the initiation of the
phase 3 CheckMate 9ER trial to evaluate Opdivo® (nivolumab)
in combination with CABOMETYX™ (cabozantinib) tablets, a small molecule
inhibitor of receptor tyrosine kinases, or Opdivo and Yervoy®
(ipilimumab) in combination with CABOMETYX versus sunitinib in patients
with previously untreated, advanced or metastatic renal cell carcinoma
(RCC). The primary endpoint for the trial is progression-free survival
(PFS).
“There is strong scientific evidence showing that CABOMETYX results in a
more immune permissive tumor environment, and we are eager to determine
if combining these active agents with complementary and potentially
cooperative mechanisms of action has the potential to further improve
patient outcomes,” said Gisela Schwab, M.D., President, Product
Development and Medical Affairs and Chief Medical Officer, Exelixis. “We
are excited to initiate this first clinical trial from our broad
development program with Bristol-Myers Squibb looking at the potential
of Opdivo in combination with CABOMETYX, with or without Yervoy, in a
variety of tumor types.”
“While existing therapies have improved outcomes for some patients with
advanced or metastatic kidney cancer, high rates of relapse and disease
progression demonstrate a need for additional therapeutic options,
especially among poor and intermediate risk patients,” said Fouad
Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb.
“Combination therapy with agents that target different and complementary
pathways—in this case, the combination of immune checkpoint inhibitors
and tyrosine kinase inhibitors—may be a potential new approach for these
patients.”
CheckMate 9ER is an open-label, randomized, multi-national phase 3 trial
that aims to enroll approximately 1,014 patients with previously
untreated advanced or metastatic RCC. Patients will be randomized 1:1:1
to one of three arms: CABOMETYX and Opdivo; CABOMETYX, Opdivo and
Yervoy; or sunitinib. The primary efficacy analysis will compare the
doublet combination versus sunitinib and the triplet combination versus
sunitinib in intermediate/poor risk patients with RCC.
More information about this trial is available at ClinicalTrials.gov.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2017 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 percent, with no identified cure for the disease.3
Approximately 30,000 patients in the U.S. and 68,000 globally require
treatment.4
The majority of clear cell RCC tumors have lower than 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.7-10
MET and AXL may provide escape pathways that drive resistance to VEGF
receptor inhibitors.6,7
About CABOMETYX
CABOMETYX is the tablet formulation of cabozantinib. Its targets
include MET, AXL and VEGFR-1, -2 and -3. In preclinical models,
cabozantinib has been shown to inhibit the activity of these receptors,
which are involved in normal cellular function and pathologic processes
such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended
dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment
of patients with advanced renal cell carcinoma who have received prior
anti-angiogenic therapy. On September 9, 2016, the European Commission
approved CABOMETYX tablets for the treatment of advanced renal cell
carcinoma in adults who have received prior vascular endothelial growth
factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.
About OPDIVO
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that
is designed to uniquely harness the body’s own immune system to help
restore anti-tumor immune response. By harnessing the body’s own immune
system to fight cancer, Opdivo has become an important treatment option
across multiple cancers.
Opdivo’s leading global development program is based on Bristol-Myers
Squibb’s scientific expertise in the field of Immuno-Oncology and
includes a broad range of clinical trials across all phases, including
Phase 3, in a variety of tumor types. To date, the Opdivo clinical
development program has enrolled more than 25,000 patients. The Opdivo
trials have contributed to gaining a deeper understanding of the
potential role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of PD-L1
expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to
receive regulatory approval anywhere in the world. Opdivo is currently
approved in more than 60 countries, including the United States, the
European Union and Japan. In October 2015, the company’s Opdivo and
Yervoy combination regimen was the first Immuno-Oncology combination to
receive regulatory approval for the treatment of metastatic melanoma and
is currently approved in more than 50 countries, including the United
States and the European Union.
CABOMETYX U.S. Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The
incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated
patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also
occurred in the cabozantinib clinical program. Do not administer
CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas were
reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated
patients and 0% of everolimus-treated patients. GI perforations were
reported in 0.9% of CABOMETYX-treated patients and 0.6% of
everolimus-treated patients. Fatal perforations occurred in the
cabozantinib clinical program. Monitor patients for symptoms of
fistulas and perforations. Discontinue CABOMETYX in patients who
experience a fistula that cannot be appropriately managed or a GI
perforation.
Thrombotic Events: CABOMETYX treatment results in an increased
incidence of thrombotic events. Venous thromboembolism was reported in
7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated
patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated
patients and 0.3% of everolimus-treated patients. Events of arterial
thromboembolism were reported in 0.9% of CABOMETYX-treated patients and
0.3% of everolimus-treated patients. Fatal thrombotic events occurred in
the cabozantinib clinical program. Discontinue CABOMETYX in patients who
develop an acute myocardial infarction or any other arterial
thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results
in an increased incidence of treatment-emergent hypertension.
Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated
patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients.
Monitor blood pressure prior to initiation and regularly during
CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not
adequately controlled with medical management; when controlled, resume
CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe
hypertension that cannot be controlled with anti-hypertensive therapy.
Discontinue CABOMETYX if there is evidence of hypertensive crisis or
severe hypertension despite optimal medical management.
Diarrhea: Diarrhea occurred in 74% of patients treated with
CABOMETYX and in 28% of patients treated with everolimus. Grade 3
diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of
everolimus-treated patients. Withhold CABOMETYX in patients who develop
intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be
managed with standard antidiarrheal treatments until improvement to
Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to
diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar
erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated
with CABOMETYX and in 6% of patients treated with everolimus. Grade 3
PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of
everolimus-treated patients. Withhold CABOMETYX in patients who develop
intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1;
resume CABOMETYX at a reduced dose. Dose modification due to PPES
occurred in 16% of patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a
syndrome of subcortical vasogenic edema diagnosed by characteristic
finding on MRI, occurred in the cabozantinib clinical program. Perform
an evaluation for RPLS in any patient 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 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 CABOMETYX and for 4 months
after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse
reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES,
hypertension, vomiting, weight decreased, and constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce
the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors
cannot be avoided. Increase the dosage of CABOMETYX if concomitant use
with strong CYP3A4 inducers cannot be avoided.
Lactation: Advise a lactating woman not to breastfeed during
treatment with CABOMETYX and for 4 months after the final dose.
Reproductive Potential: Contraception―Advise females of
reproductive potential to use effective contraception during treatment
with CABOMETYX and for 4 months after the final dose. Infertility―CABOMETYX
may impair fertility in females and males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients with
mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment.
CABOMETYX is not recommended for use in patients with severe hepatic
impairment.
Please see full Prescribing Information at
https://cabometyx.com/downloads/cabometyxuspi.pdf
.
OPDIVO AND YERVOY INDICATIONS & IMPORTANT
SAFETY INFORMATION
INDICATIONS
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY®
(ipilimumab), is indicated for the treatment of patients with
unresectable or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with EGFR
or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of
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.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ system;
however, the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal
necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation of
YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests (LFTs), adrenocorticotropic hormone
(ACTH) level, and thyroid function tests at baseline and before each
dose.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been
reported. Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more
severe pneumonitis. Permanently discontinue for Grade 3 or 4 and
withhold until resolution for Grade 2. In patients receiving OPDIVO
monotherapy, fatal cases of immune-mediated pneumonitis have occurred.
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In
patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis
occurred in 6% (25/407) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial lung
disease, occurred in 6.0% (16/266) of patients receiving OPDIVO.
Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients
receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 (of more
than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent
colitis upon re-initiation of OPDIVO. When administered with YERVOY,
withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO
monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of
patients. In patients receiving OPDIVO with YERVOY, immune-mediated
colitis occurred in 26% (107/407) of patients including three fatal
cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%)
patients. Across all YERVOY-treated patients in that study (n=511), 5
(1%) developed intestinal perforation, 4 (0.8%) died as a result of
complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. Withhold for Grade 2 and permanently discontinue for Grade 3
or 4 immune-mediated hepatitis. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of
patients. In patients receiving OPDIVO with YERVOY, immune-mediated
hepatitis occurred in 13% (51/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total
bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with
fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor
neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal
insufficiency, autoimmune thyroid disorders, and Type 1 diabetes
mellitus. Monitor patients for signs and symptoms of hypophysitis, signs
and symptoms of adrenal insufficiency, thyroid function prior to and
periodically during treatment, and hyperglycemia. Administer hormone
replacement as clinically indicated and corticosteroids for Grade 2 or
greater hypophysitis. Withhold for Grade 2 or 3 and permanently
discontinue for Grade 4 hypophysitis. Administer corticosteroids for
Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 adrenal insufficiency. Administer
hormone-replacement therapy for hypothyroidism. Initiate medical
management for control of hyperthyroidism. Withhold OPDIVO for Grade 3
and permanently discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6%
(12/1994) of patients. In patients receiving OPDIVO with YERVOY,
hypophysitis occurred in 9% (36/407) of patients. In patients receiving
OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of
patients. In patients receiving OPDIVO with YERVOY, adrenal
insufficiency occurred in 5% (21/407) of patients. In patients receiving
OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism
occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In
patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis
resulting in hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO
with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred
in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY,
diabetes occurred in 1.5% (6/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients.
All 9 patients had hypopituitarism, and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and
hypothyroidism. 6 of the 9 patients were hospitalized for severe
endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum creatinine.
Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4
increased serum creatinine. In patients receiving OPDIVO monotherapy,
immune-mediated nephritis and renal dysfunction occurred in 1.2%
(23/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407)
of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with
fatal outcome. Administer corticosteroids for Grade 3 or 4 rash.
Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For
symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient
for specialized care for assessment and treatment; if confirmed,
permanently discontinue. In patients receiving OPDIVO monotherapy,
immune-mediated rash occurred in 9% (171/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6%
(92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome,
toxic epidermal necrolysis, or rash complicated by full thickness dermal
ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade
3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result
of toxic epidermal necrolysis. 1 additional patient required
hospitalization for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of patients
with neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold OPDIVO in patients with new-onset moderate to severe neurologic
signs or symptoms and evaluate to rule out other causes. If other
etiologies are ruled out, administer corticosteroids and permanently
discontinue OPDIVO for immune-mediated encephalitis. In patients
receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of
patients. Fatal limbic encephalitis occurred in one patient after 7.2
months of exposure despite discontinuation of OPDIVO and administration
of corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or
withhold treatment, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. Across clinical
trials of OPDIVO the following clinically significant immune-mediated
adverse reactions occurred in <1.0% of patients receiving OPDIVO:
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), myositis, myocarditis,
rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been reported in
<1.0% of patients in clinical trials. Discontinue OPDIVO in patients
with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of
infusion in patients with Grade 1 or 2. In patients receiving OPDIVO
monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of
patients. In patients receiving OPDIVO with YERVOY, infusion-related
reactions occurred in 2.5% (10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who received
allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients
from Checkmate 205 and 039, who underwent allogeneic HSCT after
discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with
myeloablative conditioning). Thirty-five percent (6/17) of patients died
from complications of allogeneic HSCT after OPDIVO. Five deaths occurred
in the setting of severe or refractory GVHD. Grade 3 or higher acute
GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was
reported in 20% (n=2) of patients. A
steroid-requiring febrile syndrome, without an identified infectious
cause, was reported in 35% (n=6) of patients. Two cases of encephalitis
were reported: Grade 3 (n=1) lymphocytic encephalitis without an
identified infectious cause, and Grade 3 (n=1) suspected viral
encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one
patient, who received reduced-intensity conditioned allogeneic HSCT and
died of GVHD and multi-organ failure. Other cases of hepatic VOD after
reduced-intensity conditioned allogeneic HSCT have also been reported in
patients with lymphoma who received a PD-1 receptor blocking antibody
before transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal
harm when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to
use effective contraception during treatment with an OPDIVO- or YERVOY-
containing regimen and for at least 5 months after the last dose of
OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human milk.
Because many drugs, including antibodies, are excreted in human milk and
because of the potential for serious adverse reactions in nursing
infants from an OPDIVO-containing regimen, advise women to discontinue
breastfeeding during treatment. Advise women to discontinue nursing
during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients
receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in
42% of patients receiving OPDIVO. The most frequent Grade 3 and 4
adverse drug reactions reported in 2% to <5% of patients receiving
OPDIVO were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase. In Checkmate 066, serious
adverse reactions occurred in 36% of patients receiving OPDIVO (n=206).
Grade 3 and 4 adverse reactions occurred in 41% of patients receiving
OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in
≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase
(3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions
(73% and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The
most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY
arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%),
colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and
057, serious adverse reactions occurred in 46% of patients receiving
OPDIVO (n=418). The most frequent serious adverse reactions reported in
at least 2% of patients receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and
respiratory failure. In Checkmate 025, serious adverse reactions
occurred in 47% of patients receiving OPDIVO (n=406). The most frequent
serious adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In
Checkmate 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. The most frequent serious adverse reactions reported
in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea,
respiratory failure, respiratory tract infections, and sepsis. In
Checkmate 275, serious adverse reactions occurred in 54% of patients
receiving OPDIVO (n=270). The most frequent serious adverse reactions
reported in at least 2% of patients receiving OPDIVO were urinary tract
infection, sepsis, diarrhea, small intestine obstruction, and general
physical health deterioration.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with
OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse
reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205)
were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28%
vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common
(≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were
fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%),
vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse
reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%),
diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most
common adverse reactions (≥20%) in patients receiving OPDIVO (n=418)
were fatigue, musculoskeletal pain, cough, dyspnea, and decreased
appetite. In Checkmate 025, the most common adverse reactions (≥20%)
reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were
asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs
29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%),
constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain
(21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue
(39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain
(26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141,
the most common adverse reactions (≥10%) in patients receiving OPDIVO
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 a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse
reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue
(41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
Checkmate Trials and Patient Populations
Checkmate 067 - advanced melanoma alone or in combination with
YERVOY; Checkmate 037 and 066 - advanced melanoma; Checkmate
017 - squamous non-small cell lung cancer (NSCLC); Checkmate 057
- non-squamous NSCLC; Checkmate 025 - renal cell carcinoma; Checkmate
205/039 - classical Hodgkin lymphoma; Checkmate 141 –
squamous cell carcinoma of the head and neck; Checkmate 275 -
urothelial carcinoma.
Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY,
including Boxed WARNING regarding immune-mediated adverse reactions
for YERVOY.
About Exelixis
Exelixis, Inc. (Nasdaq: EXEL) is a biopharmaceutical company committed
to the discovery, development and commercialization of new medicines to
improve care and outcomes for people with cancer. Since its founding in
1994, three products discovered at Exelixis have progressed through
clinical development, received regulatory approval, and entered the
marketplace. Two are derived from cabozantinib, an inhibitor of multiple
tyrosine kinases including MET, AXL and VEGF receptors: CABOMETYX™
tablets approved for previously treated advanced kidney cancer and
COMETRIQ® capsules approved for progressive, metastatic medullary
thyroid cancer. The third product, COTELLIC®, is a formulation of
cobimetinib, a selective inhibitor of MEK, is marketed under a
collaboration with Genentech (a member of the Roche Group), and is
approved as part of a combination regimen to treat advanced melanoma.
Both cabozantinib and cobimetinib have shown potential in a variety of
forms of cancer and are the subjects of broad clinical development
programs. For more information about Exelixis, please visit www.exelixis.com
or follow @ExelixisInc on Twitter.
About Exelixis’ Collaboration with Ipsen
On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive
licensing agreement for the commercialization and further development of
cabozantinib indications outside of the United States, Canada and Japan.
On December 21, 2016, this agreement was amended to include
commercialization rights for Ipsen in Canada. Ipsen, Exelixis’ global
partner for cabozantinib in all geographies outside the United States
and Japan, has opted in to participate in the phase 3 pivotal trial in
first-line RCC and will have access to the results to support potential
future regulatory submissions. They may also participate in future
studies at their choosing.
About Exelixis’ Collaboration with Takeda
On January 30, 2017, Exelixis and Takeda jointly announced an exclusive
licensing agreement for the commercialization and further development of
cabozantinib indications in Japan. Takeda may also participate in this
trial and future studies and will have access to the results to support
potential future regulatory submissions in their territories, if they
opt into their funding obligations under the respective collaboration
agreements.
Exelixis holds the exclusive rights to develop and commercialize
cabozantinib in the United States.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information about
Bristol-Myers Squibb, visit us at BMS.com
or follow us on LinkedIn,
Twitter,
YouTube
and Facebook.
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 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.
Exelixis Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the potential of CABOMETYX in
combination with Opdivo, with or without Yervoy to improve patient
outcomes; Exelixis' commitment to the discovery, development and
commercialization of new medicines with the potential to improve care
and outcomes for people with cancer; the therapeutic potential and
continued development of cabozantinib and cobimetinib; the potential for
Ipsen’s participation in future studies under the collaboration; and the
potential for Takeda’s participation in the phase 3 first-line RCC and
in future studies under the collaboration and to have access to the
results to support potential future regulatory submissions in their
territories. Words such as “potential,” “committed,” “may,” or other
similar expressions identify forward-looking statements, but the absence
of these words does not necessarily mean that a statement is not
forward-looking. In addition, any statements that refer to expectations,
projections or other characterizations of future events or circumstances
are forward-looking statements. These forward-looking statements 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: Exelixis’ ability and the ability of its collaborators to
conduct clinical trials of CABOMETYX in combination with Opdivo, with or
without Yervoy, sufficient to achieve a positive completion; risks
related to the potential failure of the combination of these compounds
to demonstrate safety and efficacy in clinical testing; Exelixis’
dependence on its collaboration partners, including, the level of their
investment in the resources necessary to successfully develop CABOMETYX
in combination with Opdivo, with or without Yervoy; the complexities and
challenges associated with regulatory review and approval processes; the
degree of market acceptance of CABOMETYX and the availability of
coverage and reimbursement for CABOMETYX; the risk that unanticipated
developments could adversely affect the commercialization of CABOMETYX;
Exelixis’ dependence on third-party vendors; Exelixis’ ability to
protect the company’s intellectual property rights; market competition;
changes in economic and business conditions, and other factors discussed
under the caption “Risk Factors” in Exelixis’ quarterly report on Form
10-Q filed with the Securities and Exchange Commission (SEC) on May 1,
2017, and in Exelixis’ future filings with the SEC. The forward-looking
statements made in this press release speak only as of the date of this
press release. Exelixis expressly disclaims any duty, obligation or
undertaking to release publicly any updates or revisions to any
forward-looking statements contained herein to reflect any change in
Exelixis’ expectations with regard thereto or any change in events,
conditions or circumstances on which any such statements are based.
Bristol-Myers Squibb Company Forward-Looking Statements
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based on
current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Among other risks, there can be no guarantee that cabozantinib in
combination with Opdivo or the Opdivo+Yervoy regimen will be
successfully developed or approved for any of the indications described
in this release. Forward-looking statements in this press release should
be evaluated together with the many uncertainties that affect
Bristol-Myers Squibb's business, particularly those identified in the
cautionary factors discussion in Bristol-Myers Squibb's Annual Report on
Form 10-K for the year ended December 31, 2016, in our Quarterly Reports
on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb
undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise.
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References
|
1.
|
|
American Cancer Society. Cancer Facts & Figures 2017. Atlanta:
American Cancer Society; 2017.
|
2.
|
|
Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ. 2014;
349:g4797.
|
3.
|
|
Ko, J. J., Choueiri, T.K., et al. First-, second- third-line therapy
for mRCC: benchmarks for trial design from the IMDC. British Journal
of Cancer. 2014; 110: 1917-1922.
|
4.
|
|
Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file).
|
5.
|
|
Harshman, L.C. and Choueiri, T.K., Targeting the hepatocyte growth
factor/c-Met signaling pathway in renal cell carcinoma. Cancer J.
2013; 19(4):316-23.
|
6.
|
|
Rankin et al., Direct regulation of GAS6/AXL signaling by HIF
promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U
S A. 2014; 111(37):13373-8.
|
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(21):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(9):5902–5912.
|
9.
|
|
Takahashi A, Sasaki H, Kim SJ, 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.
|
|
|
|
Exelixis: Investors: Susan Hubbard, 650-837-8194EVP, Public Affairs & Investor Relations shubbard@exelixis.com or Media: Lindsay Treadway, 650-837-7522Director, Public Affairs & Advocacy Relations ltreadway@exelixis.com or Bristol-Myers Squibb: Media: Ken Dominski, 609-252-5251 ken.dominski@bms.com orLisa McCormick Lavery, 609-252-7602 lisa.mccormicklavery@bms.com or Investors: Tim Power, 609-252-7509 timothy.power@bms.com orBill Szablewski, 609-252-5894 william.szablewski@bms.com