Top Five Asian Cancers – Trends in Clinical Development/media/In...incidence and mortality in...

Top Five Asian Cancers – Trends in Clinical Development

RACHEL MEIGHAN-MANTHA, PhDPrincipal Analyst, Oncology Citeline, Inc.

TrialtrovePharma intelligence |


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According to GLOBOCAN 2012, the top five cancers in all Asian countries for both genders in terms of age-standardized rates of incidence and mortality are: Lung, including both non-small cell and small cell, Stomach (Gastric), Breast, Colorectal and Liver.1 By 2035, the incidence and mortality in these cancers is expected to rise by rates of 51-97% and 63-101%, respectively.2 Therefore it is imperative that the current clinical landscape of these cancers be examined and thoroughly understood in order to aid in the strategic planning needed to facilitate development of effective therapies to combat these cancers in the future. Using data exported from Citeline’s competitive intelligence product suite in April 2014, an analysis of over 6500 trials from 1988 to 2014 in these five prevalent Asian cancers included locations, sponsorship, recent clinical activity, primary drugs and mechanisms of action, primary endpoints and incorporation of pharmacogenomic biomarkers. Supportive care trials in these five cancers were excluded from this analysis.


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locationsClinical trials of all statuses and phases for these five cancers have been or are being conducted primarily

in ten countries: China, Hong Kong, India, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan

and Thailand (Figure 1). By development status, trials conducted in Japan, China and South Korea comprise

77% of the total and 79% of ongoing trials (Figure 2). However, relative to the total number of trials conducted

in each of these ten countries, Japan, Malaysia and Singapore have the greatest proportion of ongoing

trials at 42%, 35% and 35%, respectively, while China, Taiwan and Japan have the greatest proportion of

planned trials at 4.5%, 2.7% and 2.6%, respectively. By phase, 86% of all phase I trials have been conducted

in just Japan, China and South Korea while 74% of all phase I/II trials have been conducted in these three

countries (Figure 3). For the early stage trials, Japanese sites participated in 61% of phase I and 52% of

phase I/II trials. In contrast, the locations of the later-stage trials, phases II, II/III and III, are more evenly

distributed among the top ten countries. Interestingly, while most completed and terminated trials were

conducted in China (26%), Japan (33%) and South Korea (16%), 49% of ongoing trials are being conducted

in Japan while only 19% and 11% of ongoing trials are being conducted in China and South Korea, respectively.

This difference between Japan and other Asian countries as a location for ongoing trials is most starkly

observed in phase II where 64% of ongoing trials are being conducted in Japan while only 36% are being

conducted in the remaining top 10 countries. In four countries — China, Japan, Singapore and South Korea

— phase II trials accounted for the majority of the country’s total regardless of trial status; however in Hong

Kong, Malaysia, the Philippines and Thailand, phase III trials accounted for their country’s majority.

Source: Citeline’s Trialtrove®, data accessed April 2014

0 500 1000 1500 2000 2500 3000 3500

Afghanistan Bangladesh

Brunei Cambodia

China Hong Kong

India Indonesia

Japan Kazakhstan Kyrgyzstan

Malaysia Mongolia Myanmar

Nepal North Korea (DPRK)

Pakistan Philippines Singapore

South Korea Sri Lanka

Taiwan Thailand

Turkmenistan Uzbekistan

Vietnam

Number of Trials

Figure 1. Cancer Types in Asia By Clinical Trial Location For All Trial Statuses

Lung

Gastric

Breast

Colorectal

Liver


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Figure 3. Trial Phase and Status By Clinical Trial Location(Ongoing trials include Open, Closed and Temporarily Closed.)

0 500 1000 1500 2000

China

Hong Kong

India

Japan

Malaysia

Philippines

Singapore

South Korea

Taiwan

Thailand

Completed and Terminated Trials

0 500 1000 1500

Ongoing Trials

I

I/II

II

II/III

III

III/IV

IV

Number of Trials Number of Trials

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0 500 1000 1500 2000 2500 3000

China

Hong Kong

India

Japan

Malaysia

Philippines

Singapore

South Korea

Taiwan

Thailand

Figure 2. Trial Status By Clinical Trial Location (Ongoing trials include Open, Closed and Temporarily Closed.)

Planned

Open

Temporarily Closed

Closed

Terminated

Completed

Number of Trials


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sponsor typesFor this analysis, the sponsorship of each trial was classified as Industry, Non-Industry or Joint, if both

industry and non-industry groups collaborated on conducting a trial. Trials in the top ten Asian countries

were predominantly industry sponsored except in Japan, China and South Korea, where non-industry trial

sponsorship predominates (Figure 4). This high level of non-industry sponsorship in these three countries

may reflect the heavy involvement in clinical development by government agencies such as the Japanese

Ministry of Health, Labour and Welfare; the Chinese Academy of Medical Sciences; and the National

Cancer Center in Goyang, South Korea. In addition, the trend in sponsorship by type over time for all five

cancers has changed at noticeably different rates when assessed by trial start year (Figure 5). Trial activity

by any of the sponsor types was quite low from the late 1980s, the earliest date of inclusion in Trialtrove,

until the late 1990s. During 1999-2011, non-industry sponsorship grew about 3.5 times as much as industry

sponsorship and almost 10 times as much as joint sponsorship. Start year data was not analyzed after 2011

since many trials are not disclosed in the public domain until years after they have been initiated or completed.

Thus the number of trials initiated within the last five years may be under-represented.3 Among ongoing

trials, non-industry sponsored the majority of the trials for every phase—with a surprising 85% of ongoing

phase II trials (Figure 6). In addition, joint sponsorship predominates in phase II and phase III ongoing trials.

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Figure 4. Sponsor Type By Clinical Trial Location

Industry

Joint

Non-Industry

0 1000 2000 3000

China

Hong Kong

India

Japan

Malaysia

Philippines

Singapore

South Korea

Taiwan

Thailand

Number of Trials



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Figure 5. Sponsor Type By Start Year

0

100

200

300

400

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Industry

Joint

Non-Industry

Num

ber

of

Tria

ls

Figure 6. Sponsor Type By Phase For Ongoing Trials

Industry

Joint

Non-Industry

0

500

1000

1500

I I/II II II/III III IV Other

Num

ber

of

Tria

ls


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Recent clinical activityThe initiation of clinical trials for all phases within the past five years was examined for the top ten industry

and non-industry sponsors. Even if the bias about the reporting of clinical trials in the public domain

is assumed, the number of trial starts each year provides a snapshot of recent clinical activity and by

extension, sponsor investment.

Most of the recent clinical development by the top ten industry sponsors has been in lung and breast

cancers with some clinical activity in gastric cancer and minimal clinical activity in colorectal and liver

cancers (Table 1). The recent clinical development sponsored by these multinational pharmaceutical

companies may reflect their interest in conducting global trials that will be used for approvals in multiple

countries. In both Europe and North America, breast, lung and colorectal cancers are among the top

five cancers for both genders in terms of age-standardized rates of incidence and mortality.1 A notable

exception is Bayer’s recent focus on liver cancer, which is 15th in terms of age-standardized rates of

incidence and mortality in North America and is ranked even lower in Europe.1

Recent clinical activity for non-industry sponsors is more evenly distributed among the top five Asian

cancers, but again, the least amount of recent clinical activity occurred in colorectal and liver cancers.

table 1. heatmap Of Recent clinical trial activity By the top ten sponsors (On a color intensity scale from white to dark red, white corresponds to zero

trials and dark red corresponds to the most trials of all sponsors shown.)

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4 1 2 1 3 2 4 4 1 0 0 1 0 3 0 2 0 1 2 0 9 5 1 3 0 4 2 1 1 0 6 2 0 2 1 1 0 4 0 0 5 7 6 2 5 0 1 3 0 0 3 2 2 2 0 0 2 1 0 0 8 5 7 3 6 1 0 0 2 1 4 5 4 0 2 0 0 2 0 0 4 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 3 0 0 0 0 0 0 0 0 0 0 2 3 2 2 2 3 3 1 1 0 1 1 0 1 0 3 2 0 0 1 0 4 4 0 4 4 5 1 1 0 0 1 1 1 1 2 3 1 0 2 0 1 1 0 3 4 2 2 0 2 0 0 0 0 0 2 2 0 0 1 0 3 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 6 1 3 2 2 2 2 0 1 2 6 1 1 0 0 1 2 6 0 0 8 4 3 1 0 5 0 0 0 1 8 1 0 1 0 1 1 5 0 0 6 12 4 1 0 2 0 0 0 0 5 1 0 1 0 4 4 1 0 0 7 8 1 2 0 0 0 0 0 0 0 0 3 1 0 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 1 0 1 2 0 1 2 2 1 4 2 0 1 2 1 1 2 0 1 1 5 0 1 1 1 0 0 1 1 5 1 1 0 0 0 0 2 1 2 2 2 0 1 0 0 2 0 1 0 3 1 2 0 2 0 0 2 3 0 2 0 0 1 0 0 1 0 3 0 0 1 0 0 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 2 1 1 0 0 1 3 0 2 3 0 1 0 2 0 1 0 0 1 4 0 1 0 1 0 0 0 0 3 5 4 0 0 0 0 0 0 0 1 0 0 1 0 0 0 2 2 0 2 3 1 0 0 0 0 0 0 0 1 1 2 1 0 1 0 0 7 1 1 0 3 1 2 0 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2010

LUN

G2011201220132014

4 1 2 1 3 2 4 4 1 0 0 1 0 3 0 2 0 1 2 0 9 5 1 3 0 4 2 1 1 0 6 2 0 2 1 1 0 4 0 0 5 7 6 2 5 0 1 3 0 0 3 2 2 2 0 0 2 1 0 0 8 5 7 3 6 1 0 0 2 1 4 5 4 0 2 0 0 2 0 0 4 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 3 0 0 0 0 0 0 0 0 0 0 2 3 2 2 2 3 3 1 1 0 1 1 0 1 0 3 2 0 0 1 0 4 4 0 4 4 5 1 1 0 0 1 1 1 1 2 3 1 0 2 0 1 1 0 3 4 2 2 0 2 0 0 0 0 0 2 2 0 0 1 0 3 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 6 1 3 2 2 2 2 0 1 2 6 1 1 0 0 1 2 6 0 0 8 4 3 1 0 5 0 0 0 1 8 1 0 1 0 1 1 5 0 0 6 12 4 1 0 2 0 0 0 0 5 1 0 1 0 4 4 1 0 0 7 8 1 2 0 0 0 0 0 0 0 0 3 1 0 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 1 0 1 2 0 1 2 2 1 4 2 0 1 2 1 1 2 0 1 1 5 0 1 1 1 0 0 1 1 5 1 1 0 0 0 0 2 1 2 2 2 0 1 0 0 2 0 1 0 3 1 2 0 2 0 0 2 3 0 2 0 0 1 0 0 1 0 3 0 0 1 0 0 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 2 1 1 0 0 1 3 0 2 3 0 1 0 2 0 1 0 0 1 4 0 1 0 1 0 0 0 0 3 5 4 0 0 0 0 0 0 0 1 0 0 1 0 0 0 2 2 0 2 3 1 0 0 0 0 0 0 0 1 1 2 1 0 1 0 0 7 1 1 0 3 1 2 0 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2010

GA

STr

iC2011201220132014

4 1 2 1 3 2 4 4 1 0 0 1 0 3 0 2 0 1 2 0 9 5 1 3 0 4 2 1 1 0 6 2 0 2 1 1 0 4 0 0 5 7 6 2 5 0 1 3 0 0 3 2 2 2 0 0 2 1 0 0 8 5 7 3 6 1 0 0 2 1 4 5 4 0 2 0 0 2 0 0 4 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 3 0 0 0 0 0 0 0 0 0 0 2 3 2 2 2 3 3 1 1 0 1 1 0 1 0 3 2 0 0 1 0 4 4 0 4 4 5 1 1 0 0 1 1 1 1 2 3 1 0 2 0 1 1 0 3 4 2 2 0 2 0 0 0 0 0 2 2 0 0 1 0 3 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 6 1 3 2 2 2 2 0 1 2 6 1 1 0 0 1 2 6 0 0 8 4 3 1 0 5 0 0 0 1 8 1 0 1 0 1 1 5 0 0 6 12 4 1 0 2 0 0 0 0 5 1 0 1 0 4 4 1 0 0 7 8 1 2 0 0 0 0 0 0 0 0 3 1 0 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 1 0 1 2 0 1 2 2 1 4 2 0 1 2 1 1 2 0 1 1 5 0 1 1 1 0 0 1 1 5 1 1 0 0 0 0 2 1 2 2 2 0 1 0 0 2 0 1 0 3 1 2 0 2 0 0 2 3 0 2 0 0 1 0 0 1 0 3 0 0 1 0 0 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 2 1 1 0 0 1 3 0 2 3 0 1 0 2 0 1 0 0 1 4 0 1 0 1 0 0 0 0 3 5 4 0 0 0 0 0 0 0 1 0 0 1 0 0 0 2 2 0 2 3 1 0 0 0 0 0 0 0 1 1 2 1 0 1 0 0 7 1 1 0 3 1 2 0 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2010

Br

eA

ST2011201220132014

4 1 2 1 3 2 4 4 1 0 0 1 0 3 0 2 0 1 2 0 9 5 1 3 0 4 2 1 1 0 6 2 0 2 1 1 0 4 0 0 5 7 6 2 5 0 1 3 0 0 3 2 2 2 0 0 2 1 0 0 8 5 7 3 6 1 0 0 2 1 4 5 4 0 2 0 0 2 0 0 4 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 3 0 0 0 0 0 0 0 0 0 0 2 3 2 2 2 3 3 1 1 0 1 1 0 1 0 3 2 0 0 1 0 4 4 0 4 4 5 1 1 0 0 1 1 1 1 2 3 1 0 2 0 1 1 0 3 4 2 2 0 2 0 0 0 0 0 2 2 0 0 1 0 3 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 6 1 3 2 2 2 2 0 1 2 6 1 1 0 0 1 2 6 0 0 8 4 3 1 0 5 0 0 0 1 8 1 0 1 0 1 1 5 0 0 6 12 4 1 0 2 0 0 0 0 5 1 0 1 0 4 4 1 0 0 7 8 1 2 0 0 0 0 0 0 0 0 3 1 0 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 1 0 1 2 0 1 2 2 1 4 2 0 1 2 1 1 2 0 1 1 5 0 1 1 1 0 0 1 1 5 1 1 0 0 0 0 2 1 2 2 2 0 1 0 0 2 0 1 0 3 1 2 0 2 0 0 2 3 0 2 0 0 1 0 0 1 0 3 0 0 1 0 0 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 2 1 1 0 0 1 3 0 2 3 0 1 0 2 0 1 0 0 1 4 0 1 0 1 0 0 0 0 3 5 4 0 0 0 0 0 0 0 1 0 0 1 0 0 0 2 2 0 2 3 1 0 0 0 0 0 0 0 1 1 2 1 0 1 0 0 7 1 1 0 3 1 2 0 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2010

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LOr

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2011201220132014

4 1 2 1 3 2 4 4 1 0 0 1 0 3 0 2 0 1 2 0 9 5 1 3 0 4 2 1 1 0 6 2 0 2 1 1 0 4 0 0 5 7 6 2 5 0 1 3 0 0 3 2 2 2 0 0 2 1 0 0 8 5 7 3 6 1 0 0 2 1 4 5 4 0 2 0 0 2 0 0 4 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 3 0 0 0 0 0 0 0 0 0 0 2 3 2 2 2 3 3 1 1 0 1 1 0 1 0 3 2 0 0 1 0 4 4 0 4 4 5 1 1 0 0 1 1 1 1 2 3 1 0 2 0 1 1 0 3 4 2 2 0 2 0 0 0 0 0 2 2 0 0 1 0 3 1 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 6 1 3 2 2 2 2 0 1 2 6 1 1 0 0 1 2 6 0 0 8 4 3 1 0 5 0 0 0 1 8 1 0 1 0 1 1 5 0 0 6 12 4 1 0 2 0 0 0 0 5 1 0 1 0 4 4 1 0 0 7 8 1 2 0 0 0 0 0 0 0 0 3 1 0 0 0 2 0 0 1 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 1 0 1 2 0 1 2 2 1 4 2 0 1 2 1 1 2 0 1 1 5 0 1 1 1 0 0 1 1 5 1 1 0 0 0 0 2 1 2 2 2 0 1 0 0 2 0 1 0 3 1 2 0 2 0 0 2 3 0 2 0 0 1 0 0 1 0 3 0 0 1 0 0 1 1 0 0 0 1 1 0 0 0 1 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 1 2 1 1 0 0 1 3 0 2 3 0 1 0 2 0 1 0 0 1 4 0 1 0 1 0 0 0 0 3 5 4 0 0 0 0 0 0 0 1 0 0 1 0 0 0 2 2 0 2 3 1 0 0 0 0 0 0 0 1 1 2 1 0 1 0 0 7 1 1 0 3 1 2 0 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2010

Liv

er2011

201220132014


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Primary drugs and mechanisms of actionThe majority of top ten unapproved, primary drugs for each type of cancer function by targeting specific

molecules as opposed to acting as broad, cytotoxic agents (Table 2). Subsequent to early April 2014

when the data was exported from Trialtrove for this analysis, three of these pipeline drugs were approved:

Novartis’ ceritinib in the USA for NSCLC, Ono’s nivolumab in Japan for melanoma and Eli Lilly’s ramucirumab

in the USA for gastric or gastroesophageal junction cancer. About 43% of the drugs were small molecule

receptor tyrosine kinase inhibitors or antagonists of VEGFR or ErbB family members (blue shaded cells),

and 61% of the drugs were small molecule kinase inhibitors (red bordered cells). Notably, liver contained

the most diversity in terms of drug mechanism of action.

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table 2. top ten current, Pipeline Primary Drugs and Mechanisms of action for each cancer4 (Fewer than ten drugs are shown in a column when a drug in last place resulted in a tie.)

lung gastRic BReast cOlORectal liveR

apatinib(RET/VEGFR-2 TKI)




orantinib (VEGFR2/PDGFR/FGFR TKI)

buparlisib(PI3 kinase inhibitor)

neratinib(Pan-EGFR/ErbB TKI)

buparlisib(PI3 kinase inhibitor)


pexastimogene devacirepvec(GM-CSF oncolytic virus)

dacomitinib(Pan-EGFR/ ErbB TKI)

ramucirumab(VEGFR-2 antagonist)



doxorubicin, Celsion(DNA topoisomerase II inhibitor)

ceritinib(ALK TKI)

dovitinib(Multi-kinase inhibitor)


dalotuzumab(IGF1R antagonist)

PEG-arginase, BioCancer(Arginase stimulant)

onartuzumab(MET/HGFR antagonist)

poziotinib(Pan-EGFR/ErbB TKI)

BYL-719(PI3 kinase inhibitor)

cediranib(Pan-VEGFR TKI)

peretinoin(Retinoid)

nintedanib(Multi-kinase inhibitor)

paclitaxel, NanoCap(Taxane)

dalotuzumab(IGF1R antagonist)

binimetinib(MEK inhibitor)

tyroserleutide(ICAM-1 inhibitor)

nivolumab(PD-1 antagonist)

rilotumumab(MET/HGFR antagonist)

olaparib(PARP inhibitor)

encorafenib(B-RAF kinase inhibitor)

refametinib(MEK inhibitor)

necitumumab(EGFR antagonist)

tesetaxel(Taxane)

LEE-011(CDK4/6 inhibitor)

fruquintinib(Pan-VEGFR TKI)

golvatinib(MET/VEGFR-2 TKI)

palbociclib(CDK4/6 inhibitor)

Novaferon(Immunostimulant)

LJM-716(HER3/ErbB3 antagonist)

ridaforolimus(mTOR kinase inhibitor)


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Primary endpoints In this analysis, all trials were categorized according to primary endpoint with an emphasis on primary

endpoints that most commonly occur in later-stage oncology trials. These endpoints included: Progression

Free Survival (PFS), Disease Free Survival (DFS), Time to Progression (TTP) and Overall Survival (OS).

Progression Free Survival included metastasis free survival; Disease Free Survival included relapse,

recurrence and event free survival; Time to Progression included time to recurrence; and Overall Survival

included trials with references to just “survival” when no other survival endpoint was specified. Common

early-stage primary endpoints were grouped as either Response/Efficacy or Safety/Toxicity. Response/

Efficacy included endpoints such as recurrence rate, clinical benefit, objective response (rate), overall

response (rate), disease control (rate) and tumor response. Safety/Toxicity included trials with vague

references to “safety” and trials with references to specific toxicities such as neutropenia or thrombocytopenia.

Other endpoints included in this analysis were Treatment Completion, which included completion rate or

compliance rate, Feasibility and Other, which included endpoints that did not belong to any other categories.

In order to easily observe the differences in the distribution of the primary endpoints in these cancers,

trials with the early-stage primary endpoints of Response/Efficacy and Safety/Toxicity were excluded from

the distribution comparison since they overwhelmingly contained the most trial counts among all the

primary endpoint categories (data not shown). The distribution of all other primary endpoints in these top

five cancers is shown in Figure 7 where the differences in distribution between the later-stage endpoints

are most notable. PFS and OS were the most common primary endpoints in both lung and gastric cancers.

PFS and DFS were the most common primary endpoints in both breast and colorectal cancers. OS was the

most common primary endpoint in liver cancer followed by almost a tie between PFS and DFS.

In addition, the distribution of all primary endpoints was examined as a percentage of all trials by each

sponsor type (Figure 8). Trials with PFS as the primary endpoint were conducted most by industry or jointly

with non-industry. Trials with DFS and OS as primary endpoints were conducted the most by a joint

collaboration between industry and non-industry sponsors. Trials with TTP, Response/Efficacy, Treatment

Completion or Feasibility as primary endpoints were conducted most by non-industry sponsors while

industry sponsors conducted most of the trials with Safety/Toxicity as the primary endpoint.

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Figure 7. Primary Endpoints By Cancer Type Inclusive Of All Sponsor Types

0

50

100

150

200

250

300

350

400

Lung Gastric Breast Colorectal Liver

Progression Free Survival

Disease Free Survival

Time to Progression

Overall Survival

Treatment Completion

Feasibility

Other

Num

ber

of

Tria

ls



Figure 8. Percentage Of Trials Conducted By Sponsor Type For Primary Endpoints

0

5

10

15

20

25

30

35

40

45

50

Progre

ssion F

ree S

urviv

al

Diseas

e Fre

e Sur

vival

Time t

o Pro

gress

ion

Overa

ll Sur

vival

Respons

e/Effi

cacy

Safe

ty/T

oxicity

Trea

tmen

t Complet

ion

Feas

ibility

Other

Industry

Joint

Non-Industry

Num

ber

of

Tria

ls


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Since there was a four-fold difference in the number of trial counts between the top ten industry and

non-industry sponsors (data not shown), primary endpoints for each individual sponsor were charted as

normalized trial counts instead of total trial counts to allow for easier comparisons (Figures 9 and 10). For

the later-stage primary endpoints, trials conducted by Roche, Novartis, AstraZeneca and Pfizer had the

highest relative percentages of trials with PFS as the primary endpoint (Figure 9). Among trials with OS

as the primary endpoint, the highest relative percentages were attributed to Eli Lilly, Bristol-Myers Squibb,

Bayer and Amgen. Of note, Eli Lilly and Bristol-Myers Squibb did not conduct any trials with DFS as the

primary endpoint; GlaxoSmithKline, Sanofi and Bristol-Myers Squibb conducted no trials with TTP; and

Sanofi conducted the most trials with DFS relative to the other later-stage endpoints.

In comparison, non-industry sponsors in general conducted fewer trials with PFS as the primary endpoint as

opposed to trials with DFS and OS (Figure 10). The Japanese sponsors, Japanese Ministry of Health and Japan

Clinical Oncology Group heavily favored OS for their trials relative to the other later-stage primary endpoints.

Figure 9. Primary Endpoints By Industry Sponsor

0% 20% 40% 60% 80% 100%

Roche

Novartis

AstraZeneca

Pfizer

Eli Lilly

GlaxoSmithKline

Sanofi

Bristol-Myers Squibb

Bayer AG

Amgen

Normalized Trial Counts

Progression Free Survival Treatment Compensation Safety/Toxicity Feasibility Other

Disease Free Survival Time to Progression Overall Survival Response/Efficacy



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The Japanese sponsors, Japanese Ministry of Health and Japan Clinical Oncology Group heavily favored OS for their trials relative to the other later-stage primary endpoints.

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Figure 10. Primary Endpoints By Non-Industry Sponsor

0% 20% 40% 60% 80% 100%

Fudan University - Shanghai

Japanese Ministry of Health

National Cancer Center Hospital - Tokyo

National Cancer Center - Goyang

Japan Clinical Oncology Group

NCI

Asan Medical Center

Chinese Academy of Medical Sciences

University of Tokyo School of Medicine

Osaka Gastrointestinal Cancer Chemotherapy Study Group

Progression Free Survival Treatment Compensation Safety/Toxicity Feasibility Other


Normalized Trial Counts

Progression Free Survival Treatment Completion Safety/Toxicity Feasibility Other




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incorporation of pharmacogenomic biomarkersTrials for these cancers were also analyzed for the incorporation of pharmacogenomic (PGX) biomarkers into

the study design. Trials were tagged with Biomarker/Efficacy if they included an objective of identifying/

evaluating any novel biomarkers as indicators/predictors of therapeutic efficacy. The Biomarker/Toxicity

trial tag included an objective of identifying/evaluating any novel biomarkers as indicators/predictors of

drug toxicity. The PGX-Biomarker Identification/Evaluation tag included an objective of identifying or

evaluating novel genomic biomarkers as indicators or predictors of response or toxicity to therapeutic

interventions. Finally, trials were tagged with PGX-Patient Preselection/Stratification if they incorporated

pharmacogenomic and/or pharmacogenetic analysis, including the use of genomic biomarkers for patient

selection or stratification.

For the later-stage endpoints, if all four categories of biomarkers were analyzed as a group, trials with PFS

as the primary endpoint were most likely to incorporate biomarkers into their study design, followed by trials

with OS, DFS and TTP, in decreasing order (Figure 11). When just pharmacogenomic patient preselection

or stratification was examined, then again trials with PFS as the primary endpoint were most likely to

incorporate this type of biomarker into their study design, followed in decreasing order by trials with

DFS, OS and TTP.

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Figure 11. Pharmacogenomic Biomarker Incorporation By Primary Endpoint

0 200 400 600 800 1000 1200 1400

Progression Free Survival

Disease Free Survival

Time to Progression

Overall Survival

Response/Efficacy

Safety/Toxicity

Treatment Completion

Feasibility

Other

Biomarker/Efficacy

Biomarker/Toxicity

PGX - Biomarker Identification/Evaluation

PGX - Patient Preselection/Stratification

Num

ber

of

Tria

ls



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trends and correlations Historically, clinical trials have been conducted almost exclusively in just ten Asian countries for lung,

gastric, breast, colorectal and liver cancers. Sponsorship by non-industry groups for these trials has risen

dramatically since the late 1990s while industry sponsorship and joint collaborations have lagged behind.

Trials started since 2010 by industry sponsors have been limited mainly to lung and breast cancers, cancers

that are also in the top five for North America and Europe, while non-industry sponsors have been more

equitable in starting clinical trials in all five cancers. These trends point to the opportunity for increased

clinical development in gastric, colorectal and liver cancers where less competition exists, the use of less

historically popular but ICH-regulated Asian countries as sites for conducting clinical trials to prevent

clinical trial patient saturation and the need for increased collaboration between industry and a variety

of non-industry sponsors including government agencies.

Trial success is due to multiple factors, but this analysis suggests that the shift in the mechanisms-of-action

in the primary drugs from broad-acting approved drugs to targeted pipeline drugs along with the increasing

incorporation of pharmacogenomic biomarkers especially to preselect or stratify patients in trials with the

later-stage primary endpoints of PFS, OS or DFS should result in Asian trials with a higher probability of

success in these five cancers.

15

References1 GLOBOCAN 2012 Population Fact Sheets (http://globocan.iarc.fr/Pages/fact_sheets_population.aspx)

2 Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed in April 2014.

3 What factors should I consider when determining trends in trials activity using Trialtrove? ( http://www.citeline.com/wp-content/uploads/Citeline-AnalystTip-9.pdf)

4 Drug Originators: apatinib, Advenchen; binimetinib, Array BioPharma; buparlisib, Novartis; BYL-719, Novartis; cediranib, AstraZeneca; ceritinib, Novartis; dacomitinib, Pfizer; dalotuzumab, Pierre Fabre; dovitinib, Novartis; doxorubicin, Celsion; encorafenib, Novartis; fruquintinib, Hutchison China MediTech; golvatinib, Eisai; LEE-011, Astex Pharmaceuticals; LJM-716, Novartis; necitumumab, Eli Lilly/ImClone; neratinib, Pfizer; nintedanib, Boehringer Ingelheim; nivolumab, Ono; Novaferon, Genova Biotech; olaparib, AstraZeneca; onartuzumab, Roche/Genentech; orantinib, Pfizer; paclitaxel, NanoCarrier; palbociclib, Pfizer; PEG-arginase, BioCancer Treatment; peretinoin, Kowa; pexastimogene devacirepvec, Jennerex Biotherapeutics; poziotinib, Hanmi; ramucirumab, Eli Lilly/ImClone; refametinib, AstraZeneca; ridaforolimus, Ariad; rilotumumab, Amgen; tesetaxel, Daiichi Sankyo; tyroserleutide, China Medical System

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