Exelixis and Bristol-Myers Squibb Enter Clinical Collaboration for Late-Stage Combination Trial in First-Line Renal Cell Carcinoma

SOUTH SAN FRANCISCO, Calif. & NEW YORK–(BUSINESS WIRE)– 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.

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