Dr. Hager Presentation 2016

1. 1
The challenges of achieving early efficacy
in clinical development
Dr. Martin H. Hager, MBA
Cambridge Science Park
August 19, 2016

2. 2
Daiichi-Sankyo Co. Ltd. at ASCO 2016
R&D Pipeline as of May 2016
Introduction of Daiichi-Sankyo Co. Ltd.

3. 3
AstraZeneca Investor Day 2013
AstraZeneca Investor Relations General Presentation March 2015
AstraZeneca Official Presentation Material 2013 & 2015

4. 4
Daiichi-Sankyo Co. Ltd.’s new Executive VP
& Global Head of R&D Oncology
Dr. Antoine Yver

5. 5
 DS-1205: RTK inhibitor → erlotinib-resistant, T790M-negative NSCLC
 DS-6051: ROS1/NTRK dual kinase inhibitor → NSCLC
 DS-4950: Reptin/Pontin (AAA+ superfamily) inhibitor → CRC
 LDC GmbH CDK7 inhibitor → T-ALL, NMC
 ArQule Inc. BTK inhibitor → NHL
Overview of Projects

6. 6
• Soaring costs, long timelines, and high failure rates result in relatively few
investigational drugs progressing all the way to marketing approval
 Are initial candidate selection processes not optimal?
 Or is it the way we select treatment dose?
Breitfeld, Groves & Learn: White paper, Quintiles 2014
The reality of drug development
Attrition rate seems to be particularly
high for phase II
Why are so many phase II trials
unsuccessful?

7. 7
Why are we so poor at predicting Phase II success?
• For decades, the recommended phase II dose (RP2D) has typically been
determined using the maximum tolerated dose (MTD), a toxicity-based endpoint
• RP2D has been derived independent of efficacy and independent of a significant
safety signal
Dose Escalation
1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)
Dose escalation to MTD
All attention focuses on finding the MTD
CRM, mCRM, TITE-CRM, accelerated titration…

8. 8
Why are we so poor at predicting Phase II success?
 Historical solution: Expansion phase Ib at MTD
• Good approach to reveal additional safety concerns, demonstrating that MTD is not
the appropriate dose. => Efficacy without AEs may have been possible at a lower dose
• Bad approach to assess efficacy, easily confounded by AEs
• Tolerable AEs persist just short of DLT range and limit compliance, => ultimately limit
efficacy
Inherently poor assessment of efficacy and safety in
phase I is contributing to risk
Part A: Dose Escalation
1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)
Dose escalation to MTD
Part B: Dose Expansion
20 pt cohort at MTD level
Patient population: unselected Patient population: selected
RP2D

9. 9
How can we fix this?
First-in-human clinical trials must have 3 objectives:
1. Establish Proof-of-Concept
• Establish a relationship between efficacy and mechanism, i.e. evidence
of target engagement via assessment of PK/PD
2. Recommend a phase II dose
• Establish optimal relationship between efficacy and safety
3. Recommend design for registration studies
• Establish sufficient information regarding indication, patient population,
line of treatment
“Efficacy” is linking all 3 tasks
Efficacy must be a function of dose escalation

10. 10
What is needed to obtain early efficacy data?
• Biomarker
• Clearly defined patient population
• Cost-effective and time-efficient approach to screening
How do I use early efficacy data to obtain the right dose?
• Innovative and adaptive trial design
• Early incorporation of intermediate cohorts covering dose range
• Dosing beyond 1st cycle (long term)
• Dose/exposure-response data & models
• Early incorporation of food-effect studies
We need stratified clinical studies!

11. 11
DS-6051
ROS1/NTRK dual kinase inhibitor

12. 12Saito et al. Cancer Sci 107 (2016) 713–720
 Genomic instability is a hallmark of cancer and can result in chromosomal
rearrangements
 The resulting gene fusions can lead to the constitutive activation of
oncogenes
 Fusions of the tyrosine kinase genes
• ALK (anaplastic lymphoma kinase)
• ROS1 (c-ros oncogene 1)
• RET (rearranged during transfection)
occur in 1%–6% of lung adenocarcinomas and their products constitute
therapeutic targets for kinase inhibitors
Oncogenic gene fusions in lung cancer

13. 13
2011
Saito et al. Cancer Sci 107 (2016) 713–720
United States Patent Guo et al. US 8,383,799 B2
Date: Nov. 5, 2010
2016
ROS1 fusion genes
NTRK fusion genes
FGFR, NRG1 etc.
fusion genes
Beyond ALK: Oncogenic gene fusions now and then

14. 14
crizotinib (Xalkori®)
Pfizer
ALK inhibitor
(ROS1 inhibitory activity)
ceritinib (Zykadia®)
Novartis
ALK inhibitor
(crizotinib-resistance)
DS-6051
Daiichi-Sankyo Co. Ltd.
ROS1/NTRK inhibitor
PF-06463922 lorlatinib
Pfizer
ROS1/ALK inhibitor
The competitive landscape in 2012

15. 15
Comparison of inhibitor performance

16. 16
Types of Lung Cancer by Histology
Molecular Profile of
Squamous Cell Carcinoma
Molecular Profile of
Adenocarcinoma
Including large-cell neuroendocrine
carcinoma (LCNEC)
modified from LUNGevity Foundation 2016
Lung Cancer: Histologies and Molecular Profiles (2016)

17. 17
A Genomics-Based Classification of Lung and Colorectal Cancer
The Clinical Lung Cancer Genome Project
(CLCGP) and Network Genomic Medicine (NGM)
Thomas R. et al. Science Translational Medicine 30 Oct 2013: Vol. 5, Issue 209, pp. 209
Seshagiri et al. Nature 30 Aug 2012: Vol 488 Issue 7413 pp 660

18. 18
DS-6051 points of differentiation
Differentiation from the competition based on:
1. Dual inhibition of ROS1 and NTRK1/2/3 kinases
2. Able to overcome resistance by inhibition of
 ROS1 kinase gatekeeper mutation L2026M
 ROS1 kinase with crizotinib-resistance mutation G2032R
3. Targeting of
 Oncogenic ROS1 / NTRK gene fusions in lung adenocarcinoma
 Oncogenic NTRK gene fusions in pulmonary large cell
neuroendocrine carcinoma (LCNEC)
 and wild-type KRAS colorectal cancer (CRC) with NTRK gene
fusions (R-spondin dataset)

19. 19
Screening is cost-intensive
Assumption:
1. Traditional phase I dose-expansion with molecular subgroup
2. Detection of a chromosomal translocation with 2% incidence
3. Screening cost per patient $1500 (FISH) (kit plus pathology service)
4. Screening failure rate (SFR) 15%
5. Patient drop-out rate 15%
For every single recruited patient
 70 patients need to be screened
 at $105,000 screening cost
For a 20-patient dose expansion study
 1400 patients need to be screened
 at $2.1MM screening cost for the sponsor

20. 20
Foundation Medicine Investor Relations General Presentation 2014
ROS1NTRK1 NTRK2
FoundationOne screening at clinical sites as part of standard-of-care
An approach to cost-effective screening

21. 21
Inclusion Criteria:
• Histologically or cytologically confirmed advanced solid tumors, recurrent or refractory to
standard therapy
• Solid tumors with documented ROS1 or NTRK1/2/3 gene rearrangements
• Neuroendocrine tumors (LCNEC)
50 mg
QD
400 mg
QD
200 mg
QD
100 mg
QD
800 mg
QD
1200 mg
QD
Phase I Study Design
Accelerated Titration Design
Traditional 3+3 Design
Doseescalation
DS-6051b is orally administered
once daily in 21-day cycles
NCT02279433

22. 22
2xSD
SD
4xSD
6xSD
8xSD
10xSD
6mo
12xSD
14xSD
16xSD
18xSD
20xSD
22xSD
24xSD
Predicted Efficacy Threshold
Phase I Dose Escalation
NCT02279433

23. 23
• Primary Objective: Determination of MTD and/or RP2D for expansion
• Secondary Objective: Safety, PK/PD and early efficacy
50 mg
QD
400 mg
QD
200 mg
QD
100 mg
QD
800 mg
QD
1200 mg
QD
Doseescalation
NCT02279433
n=1
n=1
n=3
n=3
n=11
n=3
DLT
MTD
Phase I Dose Escalation

24. 24
DS-6051: Treatment-related Adverse Events (≥ 10% )
All Grades
Papadopoulos et al. AACR 2016
Adverse events (AE) were collected throughout the treatment and were graded according to NCI-CTCAE v4 criteria
DS-6051 was tolerated at dose of up to 800 mg QD with mostly
Grade 1 or 2 adverse events
No signs of neuropathy or visual disturbances

25. 25
Pharmacokinetics of DS-6051
• Peak exposure occurred between 2 and 5 h post-dose
• Preliminary PK analysis showed that the exposure increased with dose in a
dose proportional manner between 100 mg QD and 1200 mg QD
• Target concentration for ROS1 mutant (G2032R) which was estimated from
non-clinical studies was achieved at 400 mg QD
Papadopoulos et al. AACR 2016
Steady State Kinetics at C1D15

26. 26
Efficacy of DS-6051
64-year old male, never smoker with ROS1 gene fusion-positive NSCLC
Extensive liver metastases
1200 mg QD
Partial Response
(PR) on DS-6051
max. 58% decrease
in tumor size
Subject had progressed on crizotinib (BOR:SD) and ceritinib (BOR: PD)
Papadopoulos et al. AACR 2016
Tumor assessments were performed
at baseline and every 3 cycles
thereafter using RECIST 1.1 criteria

27. 27
Efficacy of DS-6051
Patient with LCNEC and extensive liver metastases
800 mg QD
Partial Response
(PR) on DS-6051
max. 41% decrease
in tumor size
Papadopoulos et al. AACR 2016

28. 28
Results
Enrolled Subjects and Dose
• As of the data cut-off date (March 23, 2016), 23 subjects were enrolled in the
dose escalation portion at 50–1200 mg dose levels
• Enrolled population included 19 subjects with advanced solid tumors, 1 large
cell neuroendocrine carcinoma, 2 subjects with ROS1 fusion-positive
NSCLC, and 1 subject with leiomyosarcoma with a ROS1 point mutation in
the extracellular domain
Safety
• Nineteen (86.4%) subjects experienced treatment-related AE, mostly Grade 1
or 2
• Most frequent treatment-related AEs (≥20%) were nausea, diarrhea, vomiting,
and dehydration
• 2 DLT cases (Grade 3 transaminase increase) occurred in 2 subjects at 1200
mg, which resulted in incomplete dosing for Cycle 1 (<16 of planned 21
doses)
• The MTD was 800 mg QD

29. 29
• Primary Objective: Determination of MTD and/or RP2D for expansion
• Secondary Objective: Safety, PK/PD and early efficacy
Dose escalation (solid tumors)
NCT02279433
Dose expansion (ROS1+ or NTRK+)
800 mg
Phase I Dose Expansion

30. 30
New Screening Approaches
Umbrella Trial
Multiple drugs targeting multiple mutations
in a single tumor type
Basket Trial
Single drug targeting a single mutation
in a variety of tumor types
Same tumor type Different tumor types
Modified from Kummar S. et al. J Natl Cancer Inst (2015) 107 (4)

31. 31
LC-SCRUM Japan
Lung Cancer Genomic Screening Project for Individualized Medicine
• 186 institutions participating
in 46 prefectures (Sep 2015)
• > 2000 patients enrolled
New Screening Approaches: LC-SCRUM Japan

32. 32
New Screening Approaches: LC-SCRUM Japan

33. 33
New Screening Approaches: LC-SCRUM Japan

34. 34
DS-1205
Combating erlotinib-resistance

35. 35
Pre-clinical xenograft model
Camidge R. et al. Nature Reviews Clinical Oncology 11, 473–481 (2014)
DS-1205 is able to re-sensitize a subset of erlotinib-
resistant tumors

36. 36
Part A: Dose Escalation
1 pt cohorts → 3 pt cohorts (with 3 pt expansion if DLT)
Dose escalation to MTD
Dose Confirmation
12-15 pt cohorts to explore MED, BED, MTD
dose range / regimen
Patient population: selected
MTD
MED
BED
Phase I/II design to support better assessment of
efficacy and safety
Exposure-Response relationship for efficacy Exposure-Response relationship for safety

37. 37
1. The traditional MTD approach is not suitable for oncology drug dose selection
2. Demonstration of efficacy is crucial
3. Use biomarker-defined target population during dose escalation
4. Test more than one dose
5. Use dose/exposure-response models to integrate all available data
6. Integrate target inhibition data if MOA is well understood
7. Establish long-term safety/tolerability for chronic use
8. Integrate food-effect studies early in development
Lessons Learned