希少フラクションの臨床開発
Clinical development forrare frac1on cancer
ファイザー株式会社 クリニカルリサーチ統括部 オンコロジー領域部
廣橋 朋子
Tomoko Hirohashi, PhD
Director, Clinical research, Oncology, Pfizer Japan
杉田 潤子（薬事部門）

Pfizer Confidential

1Agenda• Background• Successful factors to enhance drug
development for a rare frac1on cancer• Drug development plan in Japan for rarefrac1on of cancer• SummaryPfizer Confidential2Precision medicine for rare frac1on cancer
Driver geneに対する分子標的治療薬の高い有効性

Driver gene

Takeda M. et al., Ann Oncol. 2015 Dec;26(12):2477-82

Difficult to initiate clinical study for rare fraction cancer
Pfizer Confidential3Points to be considered to pursue clinical development forrare frac1on cancer

NegaBve
CoDxDevelopment

PosiBve

Unclearregulatory
path

High medicalneeds
For thepa1ents

Limitedindica1on(LCP)

Expectedlarge eﬀect
size

Large scale
screening,long term
enrollment

Transla1onis good fromanimal tohumanStudy Cost

(inc.Human
EAP
resources) Pfizer Confidential

Cost4

Rare frac1on cancer

1~2%
5%
2~3%

Pfizer Confidential

5General Basket Trial (In case of G-FIH study)
Dose escalation

Expansion A
Mutation A (ALK)US NDAAA

Expansion B
Mutation B (ROS1)

US NDA
FULL

Expansion C
Mutation C (MET)

Expansion D
Mutation D

Pfizer Confidential

6Rare Frac1on Cancer
The 3rd Party
Sponsored（Asia only）

1~2%
5%
The 3rd PartySponsored:
InvesBgator iniBated clinical trial(IICT) or External funding

2~3%

Pfizer Confidential

FULL PFE
Sponsored(in the world)

Under discussion
Mixed Model?

7

Successful factors• Focused on of a par1cular compound(anchor drug) or in a par1cular area (homeground)• Eﬃcient drug development strategy wasavailable• Flexible concept drug approval is existed(Pink sheet)

Pfizer Confidential

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Eﬃcient drug development strategy
The same compound
NSCLC
ALK～5％

NSCLC
ROS1
～1~2%

NSCLC
MET
～2~3%

ORR

ORR

ORR

CoDx for ALK

CoDx for ROS1

CoDx for MET• Large eﬀect size is expected from preclinical data (alltargets are “driver gene” , KEY factor)• ORR can be a primary endpoint• Basket trial is easily available• NGS will resolve the issue of mul1ple CoDx
Pfizer Confidential

9Eﬃcient drug development strategy
The same compound
NSCLC
ALK～5％NSCLC
ROS1～1~2%

NSCLC
MET～2~3%

ORR

ORRORR• No randomized trials for each indica1on are required
BEFORE approval
For while 20% if a popula1on of the pa1ents with a commontumor types may con1nue to represent a rela1vely large pa1ent
group such that it is realis1cally possible to conduct “ transi1onal”
regulatory agency-mandated randomized trial (M. Maurie et.al.
Oncology 2016;91:299-301)
Pfizer Confidential

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Eﬃcient drug development strategy
The same compound
NSCLC
ALK～5％NSCLC
ROS1～1~2%

NSCLC
MET～2~3%

ORR（AA）

ORR（FULL）

ORR（FULL？）

Randomized trial G-P3 was required
for full approval• No randomized trials for each indica1on are required
from 2nd indica1on
Pfizer Confidential

11Flexible drug approval concept in the US“The Pink Sheet”
The Next Phase In Oncology: FDA’s
Pazdur Has New Vision For DrugDevelopment- November 11 2013 12:00 AM
Execu1ve Summary
FDA’s top cancer drug reviewer has taken to the podium topaint a picture of the next phase in cancer drug development,
which includes new business models, a return to single-arm trials and a new emphasis on safety.

Pfizer Confidential
Richard Pazdur: FDA Oﬃce of Hematology
and Oncology Products Director

12Flexible drug approval concept in the US…So profound that FDA’s primary advocate for randomized trials in

oncology now acknowledges that randomized trials may

be unnecessary, if not impossible, given the drama1cresponse rates shown by some of these targeted agents.

前例のない効果が示された場合は、必ずしもP3が必要であるとは限らない。
(特に希少の場合)
Pfizer Confidential

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Flexible drug approval concept in the US• Pazdur explained that many cancer pa1ents enroll in
randomized trials to cross over to the experimental drug at the1me of disease progression. That suggests a “loss of equipoiseand clearly the trial should not have been done.”• “Single-arm trials do not give us compara1ve safety data. They
give us a snapshot in 1me of the safety of a par1cular popula1onor adverse events that occur. But one doesn’t know whetherthese are associated with the drug, one doesn’t know whether
they are associated with the underlying disease,” he explained.

比較試験はむしろSafety評価として重要となる
à 最初のIndication（肺がん）でP3が実施され安全性が確認されていていれば，同一癌腫のMutation違いの場合はP3の比較試験は必要がない

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Flexible drug approval concept in the US…FDA could approve a drug indicated not for a

par1cular type of cancer but for inhibi1ng a
par1cular molecular pathway. “There is nothing in thelegisla1on that would prohibit us from approving a drug forinhibi1ng pathway X or inhibi1ng pathway Y without any reference
to a known established disease here. So that is open, we do havethat degree of ﬂexibility.”

臓器ごとの承認ではなく標的分子別の適応で承認する可能性もある。
ALCOMAでの適応取得を支持する考え方？
Pfizer Confidential15• If successful factors are exited, drug
development for rare frac1on cancer can beenhanced and ac1vated

How about Japan?
How to establish drug development planin Japan for rare frac1on cancer
Pfizer Confidential

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Conduct/Par1cipate into basket trial(G-FIH)vsConduct local/regional phase 2 study

Pfizer Confidential

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Japan par1cipa1on into basket Trial (G-FIH study)
Doseescala1onFood EﬀectCohort
DDI Cohort

Expansion A
Muta1on A
Japan join

USNDA
J-NDA

Expansion B
Muta1on B
Japan join

USNDA
J-NDA

Expansion C
Muta1on C
Japan join

USNDA
J-NDA

Expansion D
Muta1on D
Japan join

USNDA
J-NDA

Pfizer Confidential

18Points to be considered• How to set enough sample size of J-pts for eachcohort for JNDA ?
– Need to show consistency between non-Japanese andJapanese on the primary endpoint?
– Addi1onal clinical study is required?

• From Japan regulatory perspec1ve, Phase 1 isconsidered as “for safety”– Endpoint can be acceptable from Japan regulatory
authority?

• Can we meet CoDx development (approval andlaunch)?
Pfizer Confidential

19Flexible ac1on in the US for CoDx approval

hXp://www.accessdata.fda.gov/drugsa\da_docs/appleXer/2016/202570Orig1s016ltr.pdf

Pfizer Confidential

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Conduct local/regional phase 2 study(Concept)
In case of rare frac1on cancer, “N-of-1 Trial” forrare disease can be applicable if;• a primary endpoint can be ORR• indica1on will be obtained regardless of line
ABDCPDPD PDPD

If same approach is used in single arm study,
robust data packaged (compared with standard ofcare) can be obtained
Pfizer Confidential

21Single arm study having a SOC data at maximum
1

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

2

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

3

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

4

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

5

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

6

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

7

1st Regimen

2nd Regimen

3rd Regimen

4th Regimen

1st regimen

2nd regimen

3rd regimen

4th regimen

50%

40%

30%

20%

70%

60%

70%

60%

SOC
治験薬

Pfizer Confidential

22Points to be considered• The regulatory success rate might be higher than joining
basket trial– Robust data packages can be obtained such, including
a certain level of SOC data
• Drug lag must be existed• Diﬃcult to get endorsement for an addi1onal regional
study(Mi1ga1on plan)– Then the 3rd party collabora1on (IICT or externalfunding) will be eﬀec1vely used
– If SOC data can be obtained from real world data
(both safety and eﬃcacy), the sample size can beminimized
Pfizer Confidential23

Summary• In global perspec1ve, drug development for rare frac1on cancer
can be enhanced and ac1vated, if successful factors are exited– Eﬃcient drug development strategy is available– Flexible concept drug approval is existed (Pink sheet)• On the other hand, s1ll some diﬃcul1es are existed in Japan– Less experiences of the 3rd party collabora1on– Regulatory path for clinical development of rare frac1on cancer
has not been established yet• Japan requires a regulatory scheme for drug development/approval
for rare frac1on cancer– Flexibility for both drug and CoDx approvals– Addi1onal regulatory value• NOTE: Current SAKIGAKE is not applicable for LCM (Expansion ofindica1on).

– Eﬀec1ve use of real world data (using pa1ent registry ini1a1ve)
Pfizer Confidential

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