Market Overview

Ipsen and Exelixis Announce Results from Phase 2 CABOSUN Trial of Cabozantinib versus Sunitinib in Previously Untreated Advanced Renal Cell Carcinoma at ESMO 2017

  • Independent Radiology Review Committee confirms primary endpoint
    analysis per investigator: cabozantinib provided statistically
    significant improvement of progression-free survival, with a 52
    percent reduction in the rate of progression or death compared to
  • Exelixis and Ipsen will host an investor and media webcast from
    Madrid to discuss the data on Sunday, September 10 starting at 18h45

Regulatory News:

Ipsen ((Euronext: IPN, OTCMKTS:IPSEY) and Exelixis,
(NASDAQ:EXEL) today announced updated results from the CABOSUN
randomized phase 2 trial of cabozantinib in patients with previously
untreated advanced renal cell carcinoma (RCC) with intermediate- or
poor-risk disease per the International Metastatic Renal Cell Carcinoma
Database Consortium (IMDC). Principal investigator Toni K. Choueiri,
M.D., will present detailed data from late-breaking CABOSUN abstract
[#LBA38_PD] today in the Genitourinary Tumors, Non-Prostate poster
discussion session, starting at 2:45 p.m. CEST (local Madrid time) /
8:45 a.m. EDT / 5:45 a.m. PDT at the European Society for Medical
Oncology (ESMO) 2017 congress, which is being held September 8-12, 2017
in Madrid, Spain.

CABOSUN is being conducted by The Alliance for Clinical Trials in
Oncology as part of Exelixis' collaboration with the National Cancer
Institute's Cancer Therapy Evaluation Program (NCI-CTEP). The data
presented at ESMO 2017 included the analysis from a blinded independent
radiology review committee (IRC), which confirmed the primary efficacy
endpoint results of investigator-assessed progression-free survival
(PFS), as well as an updated investigator-assessed analysis. Per the IRC
analysis, cabozantinib demonstrated a clinically meaningful and
statistically significant 52 percent reduction in the rate of disease
progression or death (HR 0.48, 95% CI 0.31-0.74, two-sided P=0.0008).
The median PFS for cabozantinib was 8.6 months versus 5.3 months for
sunitinib, corresponding to a 3.3 month (62 percent) improvement
favoring cabozantinib over sunitinib.

"These updated analyses from CABOSUN consistently show that
cabozantinib provided a statistically significant decrease in the rate
of disease progression or death compared to sunitinib, a current
standard of care – potentially offering a new treatment option for
physicians to treat patients in the first-line advanced renal cell
carcinoma setting,"
said Toni K. Choueiri, M.D., Director, Lank
Center for Genitourinary Oncology, Dana-Farber Cancer Institute.
CABOSUN trial included patients with intermediate or poor prognostic
factors per the IMDC criteria; in addition, patients had a notable
number of other independent adverse prognostic risk factors. These
included a high rate of bone metastases, two or more sites of metastatic
disease, ECOG 2 performance status, and lack of prior nephrectomy. This
patient population fares poorly and is in need of new therapies to
better control their disease."

The following chart outlines data from the CABOSUN trial presented today
at ESMO 2017, as compared to the data previously published in the Journal
of Clinical Oncology
(JCO) in October 2016:


(April 11, 2016 Cut-off)

  ESMO 2017

(Sept 15, 2016 Cut-off)

  ESMO 2017

IRC Review

(Sept 15, 2016 Cut-off)

N = 79
N = 78
N = 79
N = 78
N = 79
N = 78
Progression-free survival
Median PFS, months   8.2   5.6   8.3   5.4   8.6   5.3
Stratified HR
(95% CI)
  0.66 (0.46-0.95)   0.56 (0.37-0.83)   0.48 (0.31-0.74)
P value   0.012 (1-sided)   0.0042 (2-sided)   0.0008 (2-sided)
Tumor Response
Objective response rate (95% CI),a %   46 (34-57)   18 (10-28)   33 (23-44)   12 (5-21)   20 (12-31)   9 (4-18)
Disease control rate,b %   78   54   76   49   75   47
Progressive disease,c %   18   26   18   24   18   29
Not evaluable or missing, %   4   21   6   27   8   23
Any reduction in target lesions, %   87   44   85   38   80   50

a One complete response was observed with cabozantinib for
both investigator assessments, and one complete response was observed
with sunitinib for the original investigator assessment, all other
responses were partial responses; b Complete response +
partial response + stable disease; c Progressive disease as
best overall response.

The updated 2017 data sets and methods differ from the initial
investigator analyses presented in 2016. The comprehensive image
collection for IRC review used a later cut-off point (5 months) than the
initial investigator analysis and followed a rigorous IRC review
process. The analysis of IRC data applied U.S. Food and Drug
Administration (FDA) guidance for PFS analyses in oncology studies,
including recommended censoring rules (i.e., censoring at the last
adequate tumor assessment prior to initiation of subsequent anti-cancer
therapy, and censoring for events that occur after two or more missing
adequate tumor assessments).1 Both the updated investigator
assessment and IRC analysis demonstrated consistent and statistically
significant improvement of PFS with cabozantinib as compared to

The updated overall survival (OS) analysis had a data cut-off of July 1,
2017, and showed a favorable trend for patients randomized to
cabozantinib compared to sunitinib that was not statistically
significant. Median overall survival was 26.6 months for patients
receiving cabozantinib versus 21.2 months for those receiving sunitinib
(HR= 0.80, 95% CI 0.53-1.21, two-sided P=0.29).

"We are very encouraged by the clinically meaningful and
statistically significant efficacy results on the primary endpoint of
progression-free survival, which formed the basis of the recent
supplemental New Drug Application submitted to the U.S. Food and Drug
Administration for cabozantinib in first-line advanced renal cell
said Michael M. Morrissey, Ph.D., President and Chief
Executive Officer of Exelixis
. "The latest CABOSUN data continue
to underscore the value that cabozantinib may offer patients with
previously untreated renal cell carcinoma, and we are working tirelessly
in our efforts to bring this option to patients and their physicians as
quickly as possible."

David Meek, Chief Executive Officer of Ipsen stated "Following
the recent European approval of cabozantinib for second-line treatment
of patients with advanced renal cell carcinoma following prior
VEGF-targeted therapy, the latest data from the CABOSUN study being
presented this year at ESMO extends the clinical benefit of cabozantinib
in first-line therapy setting of patients with advanced RCC. With our
partner Exelixis, we are committed to strengthening the medical value of
cabozantinib and to continuing to bring innovative therapeutic solutions
for the treatment of patients with RCC. "

The most common all-causality grade 3 or 4 adverse events in more than 5
percent of patients for cabozantinib (N=78) and sunitinib (N=72),
respectively, were diarrhea (10 vs. 11 percent), hypertension (28 vs. 21
percent), fatigue (6 vs. 17 percent), increased alanine aminotransferase
(ALT; 5 vs. 0 percent), decreased appetite (5 vs. 1 percent),
palmar-plantar erythrodysesthesia syndrome (PPES; 8 vs. 4 percent),
decreased platelet count (1 vs. 11 percent) and stomatitis (5 vs. 6
percent). Twenty-one percent of patients in the cabozantinib arm and 22
percent of patients in the sunitinib arm discontinued treatment due to
adverse events.

Exelixis filed a supplemental New Drug Application based on the CABOSUN
data with the FDA for cabozantinib as a treatment for previously
untreated advanced RCC on August 16, 2017. Ipsen also submitted to EMA
the regulatory dossier for cabozantinib as a treatment for first-line
advanced RCC in the European Union on August 28, 2017; on September 8,
2017, Ipsen announced that the EMA validated the application.

About the CABOSUN Study

On May 23, 2016, Exelixis announced that CABOSUN met its primary
endpoint, demonstrating a statistically significant and clinically
meaningful improvement in PFS compared with sunitinib in patients with
advanced intermediate- or poor-risk RCC as determined by investigator
assessment. The CABOSUN trial is being conducted by The Alliance for
Clinical Trials in Oncology as part of Exelixis' collaboration with the
NCI-CTEP. These results were first presented in a plenary session by Dr.
Toni Choueiri at the ESMO 2016 Congress, and published in the JCO.2
In June 2017, a blinded IRC confirmed that cabozantinib provided a
clinically meaningful and statistically significant improvement in the
primary efficacy endpoint of investigator-assessed PFS.

CABOSUN is a randomized, open-label, active-controlled phase 2 trial
that enrolled 157 patients with advanced RCC determined to be
intermediate- or poor-risk by the IMDC criteria. Patients were
randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib
(50 mg once daily, 4 weeks on followed by 2 weeks off). The primary
endpoint was PFS. Secondary endpoints included OS and objective response

Eligible patients were required to have locally advanced or metastatic
clear-cell RCC, ECOG performance status 0-2 and had to be intermediate
or poor risk per the IMDC criteria (Heng, JCO, 2009).3
Prior systemic treatment for RCC was not permitted. Baseline
characteristics included:

Characteristic   Cabozantinib
ECOG performance status, %


  46   46
1   42   41
2   13   13
IMDC risk group, %
Intermediate   81   81
Poor   19   19
Bone metastasis per IxRS,a %
Yes   37   36
No   63   64
Prior nephrectomy, %        
Yes   72   77
No   28   23
Number of metastatic sites per investigator, %
1   22   33
2   47   26
≥3   32   41

a interactive voice/web response system

CABOMETYX is approved in the EU for the treatment of advanced renal cell
carcinoma in adults following prior vascular endothelial growth factor
(VEGF)-targeted therapy. Please see full EU prescribing information at:

Webcast for the Financial Community and Media

Exelixis and its partner Ipsen will jointly host a live webcast later
today, Sunday, September 10. The webcast will begin at 18:45 CEST (local
Madrid time) / 12:45 p.m. EDT / 9:45 a.m. PDT. During the webcast,
Exelixis and Ipsen management and invited guest speakers will review
results from the CABOSUN trial, along with the other relevant data sets
presented at the conference.

To access the webcast link, log onto
and proceed to the News & Event Calendar page under the Investors &
Media heading. Please connect to the company's website at least 15
minutes prior to the webcast to ensure adequate time for any software
download that may be required to view the program. To listen to an
audio-only version of the program by phone, please dial (855) 793-2457
(domestic) or (631) 485-4921 (international/toll dial) and use passcode
68961937. A telephone replay will be available until 11:59 p.m. EDT on
September 17, 2017. Access numbers for the telephone replay are:
855-859-2056 (domestic) and 404-537-3406 (international); the passcode
is 68961937. A webcast replay will also be available archived on
for one year.

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.4 Clear cell RCC is the most common type
of kidney cancer in adults.5 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.6
Approximately 30,000 patients in the U.S. and 68,000 globally require
treatment, and an estimated 14,000 patients in the U.S. each year are in
need of a first-line treatment for advanced kidney cancer.7

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.8,9 These proteins promote tumor angiogenesis
(blood vessel growth), growth, invasiveness and metastasis.10-13
MET and AXL may provide escape pathways that drive resistance to VEGF
receptor inhibitors.8,9


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 RCC who have received prior anti-angiogenic
therapy. In February of 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. This agreement was amended in December of 2016 to
include commercialization rights for Ipsen in Canada. On September 9,
2016, the European Commission approved CABOMETYX tablets for the
treatment of advanced RCC in adults who have received prior vascular
endothelial growth factor (VEGF)-targeted therapy in the European Union,
Norway and Iceland.

On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited
announced an exclusive licensing agreement for the commercialization and
further clinical development of cabozantinib for all future indications
in Japan, including RCC.

CABOMETYX is not indicated for the treatment of previously untreated
advanced RCC.

Indications: CABOMETYX® is indicated for the treatment of
advanced renal cell carcinoma (RCC) in adults following prior vascular
endothelial growth factor (VEGF)-targeted therapy.

Dosage and Administration: The recommended dose of CABOMETYX® is
60 mg once daily. Treatment should continue until the patient is no
longer clinically benefiting from therapy or until unacceptable toxicity
occurs. Management of suspected adverse drug reactions may require
temporary interruption and/or dose reduction of CABOMETYX® therapy. For
dose modification, please refer to full SmPC. CABOMETYX® is for oral
use. The tablets should be swallowed whole and not crushed. Patients
should be instructed to not eat anything for at least 2 hours before
through 1 hour after taking CABOMETYX®.

Contraindications: Hypersensitivity to the active substance or to
any of the excipients listed in the SmPC.

Special warnings and precautions for use: As most events can
occur early in the course of treatment, the physician should evaluate
the patient closely during the first eight weeks of treatment to
determine if dose modifications are warranted. Events that generally
have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia,
hypertension, palmarplantar erythrodysaesthesia syndrome (PPES),
proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal
inflammation, constipation, diarrhoea, vomiting). Dose reductions and
dose interruptions due to an AE occurred in 59.8% and 70%, respectively,
of cabozantinib-treated patients in the pivotal clinical trial. Two dose
reductions were required in 19.3% of patients. The median time to first
dose reduction was 55 days, and to first dose interruption was 38 days.Perforations
and fistulas
: Serious gastrointestinal perforations and fistulas,
sometimes fatal, have been observed with cabozantinib. Patients who have
inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis,
peritonitis, diverticulitis, or appendicitis), have tumour infiltration
in the GI tract, or have complications from prior GI surgery
(particularly when associated with delayed or incomplete healing) should
be carefully evaluated before initiating cabozantinib therapy and
subsequently they should be monitored closely for symptoms of
perforations and fistulas including abscesses. Persistent or recurring
diarrhoea while on treatment may be a risk factor for the development of
anal fistula. Cabozantinib should be discontinued in patients who
experience a GI perforation or a fistula that cannot be adequately

Thromboembolic events: Events of venous
thromboembolism, including pulmonary embolism, and events of arterial
thromboembolism have been observed with cabozantinib. Cabozantinib
should be used with caution in patients who are at risk for, or who have
a history of, these events. Cabozantinib should be discontinued in
patients who develop an acute myocardial infarction or any other
clinically significant arterial thromboembolic complication.

Haemorrhage: Severe haemorrhage has been
observed with cabozantinib. Patients who have a history of severe
bleeding prior to treatment initiation should be carefully evaluated
before initiating cabozantinib therapy. Cabozantinib should not be
administered to patients that have or are at risk for severe haemorrhage.

Wound complications: Wound complications
have been observed with cabozantinib. Cabozantinib treatment should be
stopped at least 28 days prior to scheduled surgery, including dental
surgery, if possible. The decision to resume cabozantinib therapy after
surgery should be based on clinical judgment of adequate wound healing.
Cabozantinib should be discontinued in patients with wound healing
complications requiring medical intervention.

Hypertension: Hypertension has been
observed with cabozantinib. Blood pressure should be well-controlled
prior to initiating cabozantinib. During treatment with cabozantinib,
all patients should be monitored for hypertension and treated as needed
with standard anti-hypertensive therapy. In the case of persistent
hypertension despite use of anti-hypertensives, the cabozantinib dose
should be reduced. Cabozantinib should be discontinued if hypertension
is severe and persistent despite anti-hypertensive therapy and dose
reduction of cabozantinib. In case of hypertensive crisis, cabozantinib
should be discontinued.

Palmar-plantar erythrodysaesthesia syndrome:
Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed
with cabozantinib. When PPES is severe, interruption of treatment with
cabozantinib should be considered. Cabozantinib should be restarted with
a lower dose when PPES has been resolved to grade 1.

Proteinuria: Proteinuria has been observed
with cabozantinib. Urine protein should be monitored regularly during
cabozantinib treatment. Cabozantinib should be discontinued in patients
who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome:
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as
Posterior Reversible Encephalopathy Syndrome (PRES), has been observed
with cabozantinib. This syndrome should be considered in any patient
presenting with multiple symptoms, including seizures, headache, visual
disturbances, confusion or altered mental function. Cabozantinib
treatment should be discontinued in patients with RPLS.

Prolongation of QT interval

Cabozantinib should be used with caution in patients with a history of
QT interval prolongation, patients who are taking antiarrhythmics, or
patients with relevant pre-existing cardiac disease, bradycardia, or
electrolyte disturbances. When using cabozantinib, periodic monitoring
with on-treatment ECGs and electrolytes (serum calcium, potassium, and
magnesium) should be considered.

Interactions: CYP3A4 inducers and inhibitors: cabozantinib is a
CYP3A4 substrate. Concurrent administration of cabozantinib with the
strong CYP3A4 inhibitor ketoconazole resulted in an increase in
cabozantinib plasma exposure. Caution is required when administering
cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent
administration of cabozantinib with the strong CYP3A4 inducer rifampicin
resulted in a decrease in cabozantinib plasma exposure. Therefore,
chronic administration of agents that are strong CYP3A4 inducers with
cabozantinib should be avoided. P-glycoprotein substrates: Cabozantinib
was an inhibitor but not a substrate, of P-glycoprotein (P-gp) transport
activities in a bi-directional assay system using MDCK-MDR1 cells.
Therefore, cabozantinib may have the potential to increase plasma
concentrations of co-administered substrates of P-gp. Subjects should be
cautioned regarding taking a P-gp substrate while receiving
cabozantinib. MRP2 inhibitors: Administration of MRP2 inhibitors may
result in increases in cabozantinib plasma concentrations. Therefore,
concomitant use of MRP2 inhibitors should be approached with caution.
Bile salt-sequestering agents: Bile salt-sequestering agents may
interact with cabozantinib and may impact absorption (or reabsorption)
resulting in potentially decreased exposure. The clinical significance
of these potential interactions is unknown. Excipient related warnings:
Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not
take this medicine.

Pregnancy and lactation: Avoid pregnancy, use effective methods
of contraception and discontinue breast-feeding during treatment with
cabozantinib, and for at least 4 months after completing therapy.

Drive and use machines: Caution is recommended

Undesirable effects:

The most common serious adverse reactions associated with cabozantinib
are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%), and
nausea (2%). The most frequent adverse reactions of any grade
(experienced by at least 25% of patients) included diarrhoea (74%),
fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar
erythrodysaesthesia syndrome (PPES) (42%), hypertension (37%), vomiting
(32%), weight decreased (31%), and constipation (25%). Other very common
adverse reactions: anemia, hypophosphataemia, hypoalbuminaemia,
hypomagnesaemia, hyponatraemia, hypokalaemia,hyperkalaemia,
hypocalcaemia, hyperbilirubinemia, dysgeusia, headache, dizziness,
dysphonia, dyspnea, cough, stomatitis, abdominal pain, dyspepsia, rash,
dry skin, muscle spasms, arthralgia, proteinuria, mucosal inflammation,
serum ALT, AST, and ALP increased, creatinine increased, triglycerides
increased, hyperglycaemia, hypoglycaemia, lymphopenia, neutropenia,
thrombocytopenia, GGT increased, amylase increased, blood cholesterol
increased, lipase increased

For all common and uncommon adverse reactions, please refer to full
SmPC. For more information, see the regularly updated registered product
information on the European Medicine Agency

About Exelixis

Founded in 1994, Exelixis, Inc. (NASDAQ:EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in model
genetic systems, we established a broad drug discovery and development
platform that has served as the foundation for our continued efforts to
bring new cancer therapies to patients in need. We discovered our lead
compounds, cabozantinib and cobimetinib, and advanced them into clinical
development before entering into partnerships with leading
biopharmaceutical companies in our efforts to bring them to patients
globally. With growing revenues from the three resulting commercialized
products – CABOMETYX®, COMETRIQ®, and COTELLIC® – we are reinvesting in
our business to maximize the potential of our pipeline, which we intend
to supplement with targeted business development activities and internal
drug discovery, all to deliver the next generation of Exelixis medicines
and help patients recover stronger and live longer. For more information
about Exelixis, please visit
or follow @ExelixisInc on Twitter.

About Ipsen

Ipsen is a global specialty-driven biopharmaceutical group focused on
innovation and specialty care. The group develops and commercializes
innovative medicines in three key therapeutic areas - Oncology,
Neurosciences and Rare Diseases. Its commitment to oncology is
exemplified through its growing portfolio of key therapies for prostate
cancer, neuroendocrine tumors, renal cell carcinoma and pancreatic
cancer. Ipsen also has a well-established Consumer Healthcare business.
With total sales close to €1.6 billion in 2016, Ipsen sells more than 20
drugs in over 115 countries, with a direct commercial presence in more
than 30 countries. Ipsen's R&D is focused on its innovative and
differentiated technological platforms located in the heart of the
leading biotechnological and life sciences hubs (Paris-Saclay, France;
Oxford, UK; Cambridge, US). The Group has about 5,100 employees
worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the United
States through a Sponsored Level I American Depositary Receipt program
(OTCMKTS:IPSEY). For more information on Ipsen, visit

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are based on the Group's management strategy, current views and
assumptions. Such statements involve known and unknown risks and
uncertainties that may cause actual results, performance or events to
differ materially from those anticipated herein. All of the above risks
could affect the Group's future ability to achieve its financial
targets, which were set assuming reasonable macroeconomic conditions
based on the information available today. Use of the words "believes,"
"anticipates" and "expects" and similar expressions are intended to
identify forward-looking statements, including the Group's expectations
regarding future events, including regulatory filings and
determinations. Moreover, the targets described in this document were
prepared without taking into account external growth assumptions and
potential future acquisitions, which may alter these parameters. These
objectives are based on data and assumptions regarded as reasonable by
the Group. These targets depend on conditions or facts likely to happen
in the future, and not exclusively on historical data. Actual results
may depart significantly from these targets given the occurrence of
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