Lenvatinib Phase II Results Published in The Lancet Oncology Show Significant Improvement in Progression-Free Survival When Used With Everolimus in Metastatic Renal Cell Carcinoma

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Potential future role of lenvatinib in combination with everolimus
to meet unmet need

of people with difficult-to-treat renal cancer

Phase II results show lenvatinib, when used in combination with
everolimus, demonstrates significantly improved progression-free
survival (PFS) versus everolimus alone in people with metastatic
renal cell carcinoma (mRCC) following prior VEGF-targeted therapy
(14.6 months versus 5.5 months respectively (HR=0.40; 95%
CI,0.24-0.68; p<0.001)). Further results from the study, published
today in The Lancet Oncology, show significant improvements in
objective response rates (ORR) for the lenvatinib plus everolimus
combination compared to everolimus alone (43% vs. 6%, p<0.0001) and
for lenvatinib compared to everolimus alone (27% vs. 6%, p=0.0067).
ORR is defined as the proportion of patients to see a tumour size
reduction of a predefined amount for a minimum time period. [1]

"Metastatic renal cell carcinoma remains a difficult-to-treat
cancer and people with this tumour type are in desperate need for new
treatment options. The publication of these important Phase II
results in The Lancet Oncology indicates lenvatinib's potential in
treating patients with metastatic renal cell carcinoma," comments Dr
James Larkin, Consultant Medical Oncologist at The Royal Marsden,
London.

One of the study's secondary endpoints shows that, in an updated
analysis, lenvatinib plus everolimus extends overall survival,
compared to everolimus alone (median OS 25.5, 95% CI 16.4 to NE and
15.4, 95% CI 11.8 to 19.6 months, respectively; HR 0.51, 95% CI 0.30
to 0.88; P=0.024). For lenvatinib in combination with everolimus, the
most common treatment-emergent adverse events (TEAE) reported were
diarrhoea, fatigue and decreased appetite. The most common TEAEs of
Grade 3 or higher (Common Terminology Criteria for Adverse Events)
included diarrhoea, fatigue and hypertension.[1]

Patients in the study were previously treated with a VEGF-targeted
therapy and randomized 1:1:1 to receive lenvatinib (18 mg once a day)
and everolimus (5 mg once a day), lenvatinib (24 mg once a day) or
everolimus (10 mg once a day). Nearly all patients (99%) had received
one prior VEGF-targeted therapy, 1% had received two prior
VEGF-targeted therapies, and 18% had received prior immunotherapy
treatment.

"Eisai are proud to have these data presented. We look forward to
further developing lenvatinib in this indication to help patients
with metastatic renal cell cancer that has relapsed after a
VEGF-targeted therapy," comments Dr. Alton Kremer, Deputy President,
Oncology PCU and Chief Medical Officer, Global Oncology Business
Unit, Eisai Inc.

Lenvatinib is currently indicated for the treatment of adult
patients with progressive locally advanced or metastatic,
differentiated (papillary, follicular, Hürthle cell) thyroid
carcinoma (DTC) refractory to radioactive iodine (RAI).

Renal cell carcinoma is the most common form of kidney cancer. The
standard treatment for metastatic or advanced renal cell carcinoma is
molecular targeted drug therapy, which is designed to interfere with
the specific molecules necessary for tumour growth and progression.
Despite this, it remains a disease for which patients have very few
treatment options.[2] Progression-free survival is important as it
extends the period of time before which a tumour progresses and
improves the overall prognosis for the patient.

Everolimus is a treatment recommended by the National
Comprehensive Cancer Network guidelines as a 2nd-line therapy for
unresectable advanced or metastatic renal cell carcinoma.[3]
Currently, no combination therapy for this indication has been
approved anywhere in the world.

Lenvatinib, discovered and developed by Eisai, is an oral
molecular tri-specific targeted therapy that possesses a potent
selectivity and a binding mode different to other tyrosine kinase
inhibitors (TKI). Lenvatinib simultaneously inhibits the activities
of several different molecules including vascular endothelial growth
factor receptors (VEGFR), fibroblast growth factor receptors (FGFR),
RET, KIT and platelet-derived growth factor receptors (PDGFR).[4],[5]
This potentially makes lenvatinib the first TKI that simultaneously
inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3. In
addition, lenvatinib was found to have a new Type V binding mode of
kinase inhibition that is distinct from existing compounds.[6],[7]

Lenvatinib received Marketing Authorisation from the European
Commission in May 2015 for the treatment of adult patients with
progressive locally advanced or metastatic, differentiated
(papillary, follicular, Hürthle cell) thyroid carcinoma (DTC)
refractory to radioactive iodine (RAI).

Eisai is dedicated to discovering, developing and producing
innovative oncology therapies that can make a difference and impact
the lives of patients and their families. This passion for people is
part of Eisai's human health care (hhc) mission, which strives for
better understanding of the needs of patients and their families to
increase the benefits health care provides.

Notes to Editors

About Lenvatinib

Lenvatinib, discovered and developed by Eisai, is an oral
molecular tri-specific targeted therapy that possesses a potent
selectivity and a binding mode of action different to other tyrosine
kinase inhibitors (TKI). Lenvatinib simultaneously inhibits the
activities of several different receptors including vascular
endothelial growth factor receptors (VEGFR), fibroblast growth factor
receptors (FGFR), RET, KIT and platelet-derived growth factor
receptors (PDGFR). This potentially makes lenvatinib the first TKI
that simultaneously inhibits the kinase activities of FGFR 1-4 as
well as VEGFR 1-3. In addition, lenvatinib was found to have a new
Type V binding mode of kinase inhibition that is distinct from
existing compounds.

About Lenvatinib's Novel Binding Mode (Type V)[6],[7]

Kinase inhibitors are categorized into several types (Type I to
Type V) depending on the binding site and the conformation of the
targeted kinase in complex with them. Most of the currently approved
tyrosine kinase inhibitors are either Type I or Type II, however
according to X-ray crystal structural analysis, lenvatinib was found
to possess a new Type V binding mode of kinase inhibition that is
distinct from existing compounds. In addition, lenvatinib was
confirmed via kinetic analysis to exhibit rapid, durable and potent
inhibition of kinase activity, and it is suggested that this may be
attributed to its novel binding mode.

Eisai in Oncology

Our commitment to meaningful progress in oncology research, built
on scientific expertise, is supported by a global capability to
conduct discovery and preclinical research, and develop small
molecules, therapeutic vaccines, and biologic and supportive care
agents for cancer across multiple indications.

About Eisai Co., Ltd.

Eisai Co., Ltd. is a leading global research and development-based
pharmaceutical company headquartered in Japan. We define our
corporate mission as "giving first thought to patients and their
families and to increasing the benefits health care provides," which
we call our human health care (hhc) philosophy. With over 10,000
employees working across our global network of R&D facilities,
manufacturing sites and marketing subsidiaries, we strive to realise
our hhc philosophy by delivering innovative products in multiple
therapeutic areas with high unmet medical needs, including Oncology
and Neurology.

As a global pharmaceutical company, our mission extends to
patients around the world through our investment and participation in
partnership-based initiatives to improve access to medicines in
developing and emerging countries.

For more information about Eisai Co., Ltd., please visit
http://www.eisai.com.

References

1. Motzer R, et al. Randomized phase 2 three-arm trial of
lenvatinib, everolimus, and the combination in patients with
metastatic renal cell carcinoma. The Lancet Oncology. 2015. Available
at http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)
00290-9/abstract

2. National Cancer Institue at the National Institute of Health.
Available at:
http://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq.
Accessed: October 2015

3. Cancer Network. NCCN Updates Kidney Cancer Guidelines to
Incorporate FDA Approval of Everolimus. Available at:http://www.cance
rnetwork.com/kidney-cancer/nccn-updates-kidney-cancer-guidelines-inco
rp orate-fda-approval-everolimus. Assessed: October 2015

4. Matsui J et al. Multi-kinase inhibitor E7080 suppresses lymph
node and lung metastases of human mammary breast tumor MDA-MB-231 via
inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2
and VEGF-R3 kinase. Clin Cancer Res 2008 Sep 1;14(17) :5459-65.

5. Matsui J et al. E7080, a novel inhibitor that targets multiple
kinases, has potent antitumor activities against stem cell factor
producing human small cell lung cancer H146, based on angiogenesis
inhibition. Int J Cancer. 2008;122(3):664-71.

6. Okamoto K, et al. Distinct Binding Mode of Multikinase
Inhibitor Lenvatinib Revealed by Biochemical Characterization. ACS
Med. Chem. Lett 2015;6:89-94

7. Wu P et al. Small-molecule kinase inhibitors: an analysis of
FDA-approved drugs. Drug Discovery Today 2015; 1-6

ots Originaltext: Eisai
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