- Companies intend to initiate pivotal
trial evaluating CABOMETYX™ (cabozantinib) with Opdivo® (nivolumab)
alone or in combination with Yervoy® (ipilimumab) in first-line
renal cell carcinoma
- Planning additional studies in bladder
cancer and hepatocellular carcinoma
Exelixis, Inc. (Nasdaq:EXEL) and Bristol-Myers Squibb Company
(NYSE:BMY) today announced the companies have entered into a
clinical development collaboration to evaluate CABOMETYX™
(cabozantinib), Exelixis’ small molecule inhibitor of receptor
tyrosine kinases, with Opdivo (nivolumab), Bristol-Myers Squibb’s
PD-1 immune checkpoint inhibitor, either alone or in combination
with Yervoy (ipilimumab). The clinical development program, which
will be co-funded by the companies, is expected to include a phase
3 pivotal trial in first-line renal cell carcinoma, with additional
trials planned in bladder cancer, hepatocellular carcinoma (HCC),
and potentially other tumor types.
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“The safety and efficacy data from the phase 1 clinical trial
evaluating CABOMETYX in combination with Opdivo are consistent with
the preclinical scientific rationale for combining these two
therapeutic modalities,” said Michael M. Morrissey, Ph.D.,
President and Chief Executive Officer of Exelixis. “This clinical
development collaboration will provide the resources and
collaborative framework to fully evaluate the potential for this
combination, with and without Yervoy, in both late-stage pivotal
and exploratory trials in a variety of forms of cancer. We look
forward to working with Bristol-Myers Squibb to further understand
the role these combination therapies may play in helping patients
on a global basis.”
“Combining our Immuno-Oncology portfolio with promising agents
which target different and complementary pathways is a key
component of our strategy to improve treatment outcomes for
patients,” said Fouad Namouni, M.D., head of Development, Oncology,
Bristol-Myers Squibb. “We look forward to working with Exelixis,
bringing together our knowledge and experience in oncology, to
evaluate the potential clinical value of combining these therapies
to treat multiple tumors.”
The clinical development collaboration builds upon previously
published preclinical and clinical data that provide a scientific
rationale for combining CABOMETYX with immunotherapies, including
phase 1 data of CABOMETYX in combination with Opdivo in patients
with previously treated genitourinary tumors that were presented at
the European Society for Medical Oncology (ESMO) 2016 Congress.
Updated results from this part of the study as well as results from
a second part evaluating the combination of CABOMETYX, Opdivo and
Yervoy were presented during the poster discussion session
(Abstract #293) on February 17 at the American Society of Clinical
Oncology 2017 Genitourinary Cancers Symposium, which was held in
Orlando, Florida, February 16 – 18, 2017.
CABOMETYX and Opdivo have both received approval in the United
States and European Union for specific uses in previously treated
renal cell carcinoma, and both compounds are the subject of
ongoing, global phase 3 pivotal trials in hepatocellular carcinoma.
Opdivo is approved in the United States for previously treated
bladder cancer.
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 renal cell carcinoma 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 these and future studies and 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 CABOMETYX™
(cabozantinib)
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 the Opdivo Clinical
Development Program
Bristol-Myers Squibb’s global development program founded on
scientific expertise in the field of Immuno-Oncology includes a
broad range of clinical trials studying Opdivo, 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.
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.
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 post-transplantation brentuximab vedotin. 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 4.9% (13/263) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).
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 (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. Withhold OPDIVO in patients with new-onset moderate to
severe neurologic signs or symptoms and evaluate to rule out other
causes. If other etiologies are ruled out, administer
corticosteroids and permanently discontinue OPDIVO for
immune-mediated encephalitis. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO 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, among all patients (safety population
[n=263]), adverse reactions leading to discontinuation (4.2%) or to
dosing delays (23%) occurred. The most frequent serious adverse
reactions reported in ≥1% of patients were infusion-related
reaction, pneumonia, pleural effusion, pyrexia, rash and
pneumonitis. Ten patients died from causes other than disease
progression, including 6 who died from complications of allogeneic
HSCT. Serious adverse reactions occurred in 21% of patients in the
safety population (n=263) and 27% of patients in the subset of
patients evaluated for efficacy (efficacy population [n=95]). 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, among all patients (safety population [n=263]) and the
subset of patients in the efficacy population (n=95), respectively,
the most common adverse reactions (≥20%) were fatigue (32% and
43%), upper respiratory tract infection (28% and 48%), pyrexia (24%
and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the
subset of patients in the efficacy population (n=95), the most
common adverse reactions also included rash (31%), musculoskeletal
pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and
peripheral neuropathy (21%). 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 on Exelixis, please visit www.exelixis.com or
follow @ExelixisInc on Twitter.
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.
Exelixis Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the
expectation that the clinical development program will include a
phase 3 pivotal trial in first-line renal cell carcinoma, with
additional trials planned in bladder cancer, HCC and potentially
other tumor types; the clinical potential for the combination of
CABOMETYX and Opdivo, with and without Yervoy, in both late-stage
pivotal and exploratory trials in a variety of forms of cancer;
Exelixis’ plan to work with Bristol-Myers Squibb to further
understand the role these combination therapies may play in helping
patients on a global basis; Ipsen’s rights to access the results
from the phase 3 pivotal trial in first-line renal cell cancer to
support potential regulatory submissions; the potential for Ipsen
and Takeda to participate in future studies under the clinical
collaboration; Exelixis' commitment to the discovery, development
and commercialization of new medicines with the potential to
improve care and outcomes for people with cancer; Exelixis’ focus
on advancing cabozantinib; and the continued development of
cobimetinib. Words such as “expected,” “planned,” “potential,”
“look forward,” “may,” “will,” “committed,” “focused,” 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 and 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 and Yervoy; the complexities and challenges associated with
regulatory review and approval processes; the availability of data
at the referenced time; 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
November 3, 2016, 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 the compound discussed in this release, either
alone or in combination with Opdivo or Yervey, 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20170227005356/en/
Exelixis:Investors:Exelixis, Inc.Susan Hubbard,
650-837-8194EVP, Public Affairs & Investor
Relationsshubbard@exelixis.comorMedia:For
Exelixis, Inc.:Hal Mackins,
415-994-0040hal@torchcomllc.comorBristol-Myers
Squibb:Media:Ken Dominski,
609-252-5251ken.dominski@bms.comorLisa McCormick Lavery,
609-252-7602lisa.mccormicklavery@bms.comorInvestors:Tim
Power, 609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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