Pharma Disease Insight: Gastric Cancer

DISEASE INSIGHT
GASTRIC CANCER
BIG PHARMA

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Key Findings
The entry of three PD-1/PD-L1 inhibitors
into the gastric and GEJ adenocarcinoma
market (Merck & Co.’s Keytruda
[pembrolizumab], Bristol Myers-
Squibb/Ono Pharmaceutical’s Opdivo
[nivolumab], and Merck KGaA/Pfizer’s
avelumab) will significantly drive growth
during the forecast period. We also
forecast the approval of Yervoy (Bristol
Myers-Squibb/Ono Pharmaceutical’s
ipilimumumab) to be used in conjunction
with Opdivo.
In addition, we anticipate the launch of a
next generation HER2-targeting therapy
(Roche/Genentech/Chugai’s Perjeta
[pertuzumab]), a cancer 'stemness'
inhibitor (Boston Biomedical’s
napabucasin), and a MMP-9 inhibitor
(Gilead Sciences’ GS-5745). Collectively,
these agents will contribute 80% of total
sales in the gastric and GEJ
adenocarcinoma in 2025.
In 2015, major-market sales totaled $1.2
billion for gastric and gastroesophageal
junction (GEJ) adenocarcinoma. We expect
that major-market sales will rapidly
increase over the forecast period, totaling
almost $9.5 billion in 2025. This growth
will be predominantly fuelled by the
approval of seven agents in the indication,
and also by Cyramza (Eli Lilly’s
ramucirumab).
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+ Anti-PD-1 immunotherapies are promising in other
indications, and experts interviewed are keen to see
further data for these agents now that they are being
evaluated in gastric and CEJ adenocarcinoma
+ The gastric and CEJ adenocarcinoma market is
relatively untapped with only two approved biological
targeted therapies. The developer of an efficacious drug
could reap high commercial rewards
+ There are currently no targeted therapies approved for
resectable disease of specifically as 1st line treatment for
HER2-negative unresectable of metastatic disease
+ As the population ages across the major markets, the
total number of incident cases is expected to increase,
especially in US
+ Segmentation of gastric and
CEJ adenocarcinoma
populations by biomarkers
limits the eligible populations
and sales potential for some
targeted therapies
+ Given the aggressive nature
of gastric and CEJ
adenocarcinoma, patients
quickly progress or
succumb to their disease,
resulting in short treatment
duration
+ There are few late-phase
therapies being assessed as
adjuvant treatment for
resectable gastric cancer
+ Identifying and validating drug
targets in gastric cancer and
translating promising preclinical
compounds into clinical
successes remains challenging
+ New approvals could make the
comparator arm of ongoing
clinical trial obsolete, potentially
negatively impacting
recruitment, interpretation of
the trial, and ultimately
regulatory approval
+ Reimbursement authorities will
seek to restrict pricing and use
of expensive new brands that
are not meaningfully
differentiated from current
therapies
Gastric Cancer Market
SWOTAnalysis
+ Despite repeated clinical trial failures, the
gastric and GEJ adenocarcinoma pipeline
comprises a relatively large number of late-
phase drugs and diverse group of drug
classes
+ Drug development of some drugs is focused on
the Japanese market, where disease incidence
is highest and thus potential for greatest
commercial reward
Strength Market
Opportunities
Weaknesses Threats
01 02 03 04

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Unlikecolorectalcancerorbreastcancer,gastriccanceris
heterogeneousinhistologicalappearance.Duetodifferentiated
tissues,itisveryhardtoidentifyappropriatebiomarkers.Ithas
beencontroversialwhetherbiopsysamplesclarifytheoverall
pictureofgastriccancer.Therefore,correlationbetween
histologicalfeaturesandbiomarkersshouldbeelucidatedinorder
todevelopeffectivetargetedtherapies.
Oncologist
“
”
Expert Insight

13|
Disease
Pathophysiology
Gastric cancer arises from the epithelium of the mucosal layer of the stomach and has two distinct histological types: intestinal and diffuse. These
tumor types are distinguishable by their pathogenesis, epidemiology, and clinical outcome and are based on the Lauren classification (Lauren P,
1965). Intestinal-type tumors are well differentiated and form gland-like structures, whereas the rarer diffuse-type tumors are poorly differentiated,
lack cohesion, cause the loss of gastric function, and often affect large portions of the stomach. Prognosis and treatment can be more easily
determined by distinguishing between these subtypes, although histological classification is usually ambiguous because tumors are frequently
composed of both types.
The sporadic development of both intestinal and diffuse types of gastric cancers is linked to chronic infection with Helicobacter pylori. Infection with
H. pylori induces a cascade of premalignant stages, from chronic gastritis and atrophy to intestinal metaplasia and dysplasia, which are precursory
steps in the development of gastric cancer (Egi Y, 2007). In the case of intestinal-type gastric cancer, a clear line of progression occurs from precursor
lesions to gastric cancer tumors. Initially, gastritis progresses to chronic inflammation of the stomach mucosa, known as mucosal atrophy (atrophic
gastritis). In the next step, intestinal metaplasia, the gastric epithelium is replaced by intestinal-type epithelium, and abnormalities in cell maturation
then follow, forming dysplasia and then progressing to carcinoma, with subsequent metastasis (Smith MG, 2006). Intestinal metaplasia is split into
simple intestinal metaplasia and atypical intestinal metaplasia. Simple intestinal metaplasia occurs as a result of an environmental change, whereas
atypical intestinal metaplasia is a malignant transformation and is regarded as a precancerous lesion (Zheng Y, 2010). Patients with atypical intestinal
metaplasia are at higher risk of developing gastric cancer than patients with simple intestinal metaplasia. No such predisposing pathogenesis has
been described for diffuse-type gastric cancer, other than chronic gastritis due to H. pylori infection. See the "Key Stages in the Development of
Intestinal and Diffuse Types of Gastric and Gastroesophageal Junction Cancer" figure for more information.
Subtypes

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Key Pathways and
Drug Targets
Given the success of
Herceptin in gastric and GEJ
adenocarcinoma, late-phase
efforts in developing a next-
generation HER2-targeting
agent are ongoing
Gastric and GEJ adenocarcinomas can
accumulate many genetic abnormalities
that lead to the activation of oncogenes
and/or inactivation of tumor suppressor
genes and have a downstream effect on
signaling of regulatory mechanisms (e.g.,
angiogenesis, apoptosis, cell-cycle
regulation), aiding carcinogenesis and
tumorigenesis. A variety of genes and
proteins have been implicated in the
development of gastric and GEJ
adenocarcinoma. These genetic
abnormalities are a potential means of
revealing new molecular targets for
therapy or predictive markers of therapy,
prognosis, and survival, though currently
HER2 is the only biomarker available for
this indication.
The most active areas of research are those drug pathways and targets
that have proven successful in other solid tumor indications. However,
drug targets that have led to effective therapies in other indications
have had mixed success in gastric and GEJ adenocarcinoma to date. This
result highlights gastric and GEJ adenocarcinoma as being a difficult-to-
treat indication and that geography/ethnicity appears to be crucially
important in target selection and trial design. There is much excitement
around targeting pathways that stimulate and block immune
checkpoints, and in particular PD-1 (including a combination with a
CTLA-4 targeting agent) and PD-L1 inhibitors are being evaluated in a
plethora of solid tumor indications, with gastric and GEJ
adenocarcinoma being no exception. Given the success of Herceptin in
gastric and GEJ adenocarcinoma, late-phase efforts in developing a
next-generation HER2-targeting agent are ongoing. Phase III studies are
also evaluating cancer stem cell 'stemness' inhibitors, cytotoxic agents,
and EGFR and MMP-9 inhibitors. See the "Drug Targets for Gastric and
GEJ Adenocarcinoma" and "Biology of Negative Immune Regulators"
figures for more information.
Overview Cell-Surface Antigens

19|
Key Pathways and
Drug Targets
DrugTarget Function/Role Potential Drug Class
VEGF/VEGFR The VEGF ligand and its cognate receptor,VEGFR, are primarily
responsible for regulating angiogenesis in both normal physiological
processes and in tumorigenesis.
VEGF MAb inhibitors. VEGFR MAb inhibitors, targeting the extracellular
domain and small-molecule VEGFR tyrosine kinase inhibitors,
targeting the intracellular domain.
c-Met A proto-oncogene that binds HGF. c-Met activation drives tumor
growth,angiogenesis, and metastasis. Amplification and
overexpression of c-Met are associatedwith poorer survival in
gastric and GEJ adenocarcinoma patients.
c-Met and HGF-targeted small molecule
tyrosine kinase inhibitors and MAb inhibitors.
EGFR EGFR is important in cell proliferation, adhesion, and invasion in
cancers. It is upregulated in gastric and GEJ adenocarcinoma and is
associatedwith lowersurvival rates.
EGFR MAb inhibitors, targeting the extracellular domain.

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Historytellsusthatthefirst-in-classdrugtoaparticularmarket
normallyhasabigadvantage.Ican'tseeanylogicalreasonwhy
therewouldbemajordifferencesinefficacyoutcomebetweenthe
PD-1/PD-L1inhibitors,andsoIthinkthefirstofthesedrugstothe
gastriccancermarketwillhavealargeadvantageintermsof
usage.
Hematological oncologist
“
”
Expert Insight

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What FactorsAre Driving the Market
for Gastric Cancer?
The approval of two PD-1 inhibitors Approval of a first-line maintenance treatment The growing number of incident cases of gastric and
GEJ adenocarcinoma
The emergence of immune checkpoint inhibitors, in particularly PD-1
inhibitors (i.e.,nivolumab and pembrolizumab) during the first half of our
forecast period, will drive considerable growth in sales through 2025.
Nivolumab and pembrolizumabwill be the top-selling drugs in the gastric
and GEJ adenocarcinoma market in 2025(combined sales of over $6
billion; 65% market share). The high sales of these agents will in part be
driven by their approval early in the forecast period (2018) in Japan and
the broad labels that they are expected to secure in Japan (almost three-
quarters of PD-1 drug sales for gastric and GEJ adenocarcinoma will be
capturedin Japan in 2025).
The PD-L1 inhibitor, avelumab,is expected to be the first therapy for
unresectable locally advancedor metastatic gastric and GEJ
adenocarcinoma to be granted regulatory approval as a maintenance
treatment. As a maintenance treatment, avelumab will be usedfollowing a
first-line of chemotherapy and will therefore add to sales. Avelumabsales
resulting from first maintenance will account for 88% of total avelumab
sales ($700 million).
Major-market incident cases of gastric and GEJ adenocarcinoma are
expected to increase from 179,170 in 2015 to 195,030 in 2025,
correspondingto an annual growth rate of 0.9%.The annual growth rate is
most pronouncedin the United States (2.3%), France (0.8%),Japan
(0.8%),and Spain (1.0%). The rise in diagnosed incidence is most likely
because of an aging population.

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Pharma Disease Insight: Gastric Cancer

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Pharma Disease Insight: Gastric Cancer