The document discusses the evolution and challenges of developing targeted cancer therapies, highlighting the roles of various agents such as kinase inhibitors and the emergence of immunotherapies. It addresses issues like tumor heterogeneity, resistance to treatments, and the need for personalized medicine through molecular profiling. Additionally, it emphasizes the importance of clinical trials in refining treatment approaches and the complexities of drug approval processes.

1. Development of Novel Targeted Drugs:
Which Target ?
Prof. Eric RAYMOND MD, PhD
Chair of Medical Oncology @ Groupe Hospitalier Paris Saint-Joseph – France
(eraymond@hpsj.fr)

3. Disclosures
• Pfizer
• Novartis
• Eli Lilly
• Ipsen
• Celgen
• AFR-Oncology
• Genoscience Pharma
• SCOR

4. The Emeritus Legend
From 1984 till 15 June 2009: PAM then PAMM member
• From 15 June 2009 till 1st July 2015 (Toulouse 2010, Gdansk, Tenerife 2012, Cardiff 2013, Muenster 2014, Marseille 2015): chairman PAMM
• From June 2015 till February 2018 (Antwerp 2016, Split 2017, Rome 2018): secretary PAMM
Joint PAM-BACR: Aston 1984
• PAM as part of the Early Drug Development meeting: Lugano 1985, Edinburgh 1986, Lyon 1987,Aviano 1988, Glasgow 1990, Vienna 1991, Rotterdam 1993, Corfu 1995, Lugano 1997,
Vienna 1999.
• EORTC Preclinical Therapeutic Models Group: associated member ended in Nov 2012 (end of PTMG)
• PAMM meetings: Leicester 2000, Verona 2001, Copenhagen 2002, Florence 2003, Bradford 2004, Arcachon 2005, Edinburgh 2006, then
• Berlin 2007: Iduna Fichtner passed on to Frits as chairman of the NCI cpds committee and to Angela Burger as chair of the DDC
• Palermo 2008, Brussels 2009, Toulouse 2010, Tenerife 2012: chairman of the joint EORTC Committee on European NCI compounds and DDC for the NCI cpds part
• Cardiff 2013, Marseille 2015, Antwerp 2016, Split 2017, Rome 2018: chairman of the joint EORTC Committee on European NCI compounds with Andy Westwell as secretary (resigned in
2015 from then Frits acted as chairman and secretary)
Other EORCc activities
• EORTC imaging group: Associated Member 27 Oct 2009 - 25 Apr 2012
• EORTC Cancer in Elderly Task Force: Associated Member 15 Jul 2010 -
• EORTC Translational Research Advisory Committee: member from 11 Aug 2009 -
• EORTC New Drug Advisory Committee: member from 18 June 2012

5. The armamentarium in medical oncology
Chemotherapy (direct/indirect DNA- & -tubulin targeting drugs)
Hormonotherapy (hormone receptor targeting agents)
Targeted agents (kinase inhibitors and various other allosteric inhibitors
Antiangiogenic agents (agents that interfere with vascular cell signaling)
Immunotherapy (antibodies that restore the intra-tumor immunity)

6. Historical evolution of drug development
Palliative
Phase II/Advanced disease
Institution/Academic
Adjuvant trials
Institution/Academic
Industry sponsored
Meta-analysis
Prevention trials
Translational
Biomarkers
Phase I->III
$5 K/pt
$15 K/pt (1-2K)
$35 K/pt (3-5K)
$60 K/pt (8-10K)
>$100 K/pt (25-40K)
NDAoriented
RegulatorycomplexityCRORole
Infrastructure
Medical
Investigator
Role
Cost/Pt
(Investigator
fees)
Few Institutions,
90% Academic, oligo-institutional
Anticancer Center Board,
Disease Subtype
(grant funded)
Isolated Research Groups,
Retrospective Analyses
Industry 1/4
Industry 2/3
International
Collaborations
(NCI funded)
Industry 1/2
Industry 3/4
Industry 4/5
Biotech à Big Pharma
1950
1960
1970
1980
2005
1975
2000
1990
2017
RegulatoryReimbursement
Corporateinterest
“Consensus”
Marketing
Medical
Decisio
n
Role
$600 – 1K USD
$1-3 K USD
≥ $12K USD
≥ $5K USD
Price per cycle
Esteban Cvitkovic PAMM2017 - Croatia

7. The ideal development path for drug approval
Various preclinical and clinical methods have been developed
aiming to shorten the drug development duration

8. In real, for many biotech companies that now handle with
limited resources the maturation of the drug to the clinic

9. Attrition rate in drug development

10. The conjunction of disruptive technology & drug discovery
recall the old ‘myth of antibiogram’ for cancer therapy during
the kinase inhibitor era
Full capacity of deep nucleic
acid sequencing
Identification of several
oncogenic mutation and
activating translocations
Drug screening for kinase
inhibition on the various
oncogene drivers
Development of facilities for
live access to nucleic acid
evaluation in samples from
patients
“The right drug for the
right patient”
Activity without toxicity
A straight forward drug development
path
Less patients in clinical trials (quicker
breakthrough) before approval (reduced
cost)
The chase for biomarkers

11. Selected
treatment
Molecular analysis
§ Molecular biology
§ RT-PCR
§ Immunohistochemistry
Identification of
TARGETS
Biopsy
Surgical specimen
Courtesy of Pr Valérie Paradis, BJN
Molecular biology requires access to tumor biopsy

12. Identification of molecular alterations
Andrew V. Biankin, et al. NATURE | VOL 526 | 15 OCTOBER 2015

13. The kinase inhibitor era shaded the era of chemotherapy
• Because it works in few diseases (or subtypes of diseases) that are:
• Homogeneous in the target distribution within the primary and the metastases
• Highly dependent of few oncogene for cell survival
• Do not develop rapid resistance
• For some very oncogenic kinase results have been astonishing
• Bcr-Abl / KIT
• ALK
• HER1-2
• VEGFR, …
• This reinforced the idea that there shall be for all tumors at least one
major oncogenic driver to be found and targeted by one promising drug

14. Molecular Driven Clinical Trial Designs
Araujo et al. Expert Rev Prec Med &Drug Dev. 2016; 1:3, 255-65
14

15. Numerous academic trials have been launched
aiming for precision medicine
Andrew V. Biankin, et al. NATURE | VOL 526 | 15 OCTOBER 2015
Currently published results: - High attrition rate (thousands of patients to offer access to few)
- Short duration benefits for the happy few selected for therapy
- Costly nucleic acid testing vacuuming other resources
- Distracting attention on targeted agents while immunotherapy disrupted the filed

16. Limitations of targeted therapies
• Cell signaling is plastic by essence allowing bypasses for survival in case of
inhibition
• Targeted agents are cytostatic and, while active, don’t cure patients
• Targeted agents often significantly delay tumor progression but with
inconstant and limited survival benefits
• Tumor progression is a mainstay of targeted therapies suggesting that
tumors may adapt and develop acquired resistance
• Multiple targets (either using multi-targeted agents or combinations)
should be hit simultaneously to derive significant clinical benefits
• Suggesting signaling redundancies in cancer cells
• Or the presence of cellular clones with distinct signaling pathways

17. Why were those
approaches not
more successful ?

18. Targetable cellular & molecular components of tumors are
many (too many) for a single drug therapeutic approach
Endothelial cells
Pericytes
VEGFR-PDGFR
T cells (CD4-Treg)
CD4:PD1-CTLA4-CD28
Treg: CD73-CD39
Dendritic cells
PDL1-PD1-MSH II-CD80/86
Tumor associated macrophages
CXCR4-TGFβR
Tumor cells
TGFβR-MET-PDL1
Fibroblasts
FGFR
TGFβ HGF
FGF19 IL8 IL10
SDF1/CXCL12

19. Marusyk A et al. Narure Review Cancer 2012
Tumor heterogeneity:
Evaluation of inter- &
intra-tumoral clonal
variations
Access to tumor biopsy only partly address the question
of tumor heterogeneity

21. Yates et al, Nat Rev Genet 2012
Temporal drift
Clonal variations over
time (spontaneous &
treatment induced)
The tumor biology may change over time: requiring
access to tissue samples immediately prior to therapy

22. Treatment-induced
heterogeneity
Clonal variations over time may be
affected by therapeutic interventions
Eric RAYMOND – Kinases oncogéniques et thérapies ciblées – Académie des sciences – 23 avril 2013
Unselected population
One major oncogenic disfunction
Inter-patient heterogeneity
Progression
Intra-tumor heterogeneity
Multiple oncogenic abnormalities
Relapse
Sub-clone selection
Oncogenic resistance
Traitement 1 Traitement 2
Cellules cancéreuses
Microenvironnement
tumorale
Rechute: Clones avec
mutations minoritaires
Stratégies de thérapies ciblées anticipatoires
Traitement 1 Traitement 2

23. Inter- and intra-patient heterogeneity of resistance
mechanisms to rociletinib in lung cancer
NATURE COMMUNICATIONS | 7:11815 | DOI: 10.1038/ncomms11815 |www.nature.com/naturecommunications
Liquid biopsy may help
for real time appraisal of
oncogenic changes under
therapy (at least if
mutations associated
with resistance are
already known

24. Multiple cellular systems and interactions have been identified in tumors
Adapted from Hida K. et al, Pathology International 2011; 61: 630–637

25. Adaptive stroma results from tumor heterogeneity
Marusyk A et al. Narure Review Cancer 2012

26. Effects of Sunitinib on tumor vessels result in cellular hypoxia and necrosis
Faivre et al. Nat Rev Drug Disc, 2007

27. Acquired resistance to sunitinib in renal cell carcinoma
Faivre et al. Nat Rev Drug Disc, 2007
Poorly vacularized
Fibrosis/necrosis
Skin and muscle invasion
Resection
Gross macroscopical examination at progression

28. Vascular mimicry may occur in renal carcinomas from patients who
progress under sunitinib therapy
Responder
Progressive
CD10hs+FvWhs CD10hs+FvWhs

29. EMT associated with sunitinib resistance

30. Resistance to sunitinib in PNET is associated with increased
invasiveness and MET expression
Sennino B et al. Drug Discovery, 2012
Lynn KD et al. Drug Discovery, 2012

31. HGF/MET Cooperates with HER1-3 to Develop Aggressive Phenotypes
Adapted from Petr Szturz et al, in press 2016

32. Current MET/HGF Inhibitors
Tepotinib
DARPin
MP0250
Adapted from S Peters & A.A. Adjei Nature Reviews Clinical Oncology 9, 314-326 (2012)

33. Response to MET inhibitors in lung cancer harboring
Exon 14 skipping mutations

34. S49076 (MET/AXLi) delays tumor progression and angiogenesis in a transgenic HCC mouse model
Liver volume Blood flow velocity
S 49076 delays tumor progression S 49076 inhibits proliferation and nodule size
CD31 staining and quantification at 12W and 16W
12 16
weeks
Placebo
S 49076
***
***
8 12 16
0
2
4
6
8
weeks
Livervolume(mm3)
Placebo
S 49076
***
***
8 12 16
0
10
20
30
40
weeks
BoodflowinCT(m/s)
Placebo
S 49076
***
***
12 16
0
50
100
150
weeks
Vesselnumberperfield
***
***
12 16
0
10
20
30
40
50
weeks
Nodulespersection
Placebo
S49076
**
**
12 16
0
50
100
150
200
weeks
Macronodulesnumber
Placebo
S49076
***
***
12 16
0
10
20
30
40
50
weeks
Nodulespersection Placebo
S49076
**
**
12 16
0
10
20
30
40
50
weeks
Nodulespersection
Placebo
S49076
**
**
12 16
0.0
0.5
1.0
1.5
2.0
weeks
Meannodulesize(mm2)
*
*
12 16
0.0
0.5
1.0
1.5
2.0
weeks
Meannodulesize(mm2)
Placebo
S49076
*
*
Courtesy Annemilaï Tijeras-Raballand – AFR Oncology

35. Inhibition of FGF19/FGFR4 Activation with BLU-554

37. Baseline Week 16
0 8 16 24 32
-26% SD -44% PR -45% PR PD
Week
Baseline
IHC+
FISH-
Radiographic response in post-sorafenib, non-viral HCC
Kim R et al. ILCA 2017

38. *4 confirmed responses
IHC-positivity enriches for radiographic tumor reduction and response
Kim R et al. ILCA 2017

39. Galunisertib: TGF-βRI Inhibitor
Neuzillet C., Pharmacol. Ther. (2015)
Wakefield LM., Nat. Rev. Cancer (2013)

40. TGFbRI Inhibition Induced by Galunisertib in Human Hepatocellular Carcinoma Explants
Ex vivo Proliferation
Control TGFb inh.
Apoptosis
P-SMAD2/3 (PD biomarker)
(13pts)
(13pts)
(11pts)
By Serova et al, Oncotarget 2015

41. Galunisertib (TGFbRI Inhibitor) in Patients With Hepatocellular Carcinoma
n/N (%) Median
AFP responders 25/103 (24%) 21.4 mo
AFP non-responders 78/103 (76%) 6.8 mo
Overall survival
AFP responders = patients who
decreased circulating AFP levels by
>20%
AFP non responders
AFP responders
Courtesy of Faivre S. et al.
Pres. ASCO GI 2014 and ASCO 2016
Part A
AFP ≥1.5 ULN
Part B
AFP <1.5 ULN
AFP>200
at Baseline

42. The future

43. Engineering of CAR-T cell receptor
CAR, chimeric antigen receptor; mAb,
monoclonal antibody; TAA, tumor-associated
antibody; TCR, T-cell receptor.
Sadelain M, et al. Nat Rev Cancer. 2003;3:35-45.

44. Main companies involved in CAR-T cell therapy
• JONO Therapeutics (Celgene)
• KITE pharma (Gilead)
• Novartis
• Cellectis (Pfizer – Servier)

45. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL
• Patient characteristics:
• 51 pts evaluable for toxicity assessment
• 50 pts evaluable for response assessment with ≥ 1 mos of follow-up
• Activity results:
• Morphologic disease: 31/51 (61%) pts
• Minimal disease: 20/51 (39%) pts
• Follow-up:
• Median: 8.5 mos (range: 1-54), data cutoff date of 5/2/16
• 29/50 (58%) pts with ≥ 6 mos of follow-up
• 17/50 (34%) pts with ≥ 1 yr of follow-up
Park JH, et al. ASCO 2016. Abstract 7003.

46. Scans from Dr. Rosenberg NCI
Ongoing Complete Response
15+ months in a patient with
chemo-refractory PMBCL
A patient with recurrent DLBCL
post-SCT treated with anti-
CD19 CAR T cells
Example of response under CAR-T cell therapy
Before Treatment Post Treatment
Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014

47. Phase I Trial of CD19-Targeted T-Cell Therapy in Adults With R/R B-Cell ALL
•Post–CAR T-Cell Infusion Clinical Courses
• 16 of 41 CR (39%) pts proceeded to allogeneic HSCT after
achieving CR to CAR T-cells
• By disease burden cohort:
• 9/23 (39%) pts in morphologic disease cohort
• 7/18 (39%) pts in minimal disease cohort
• 15/33 MRD-CR (45%) pts relapsed
• 4/15 (27%) relapses were CD19 negative/undetectable
• 9/33 (27%) pts remain disease free for > 1 yr
Park JH, et al. ASCO 2016. Abstract 7003.

48. Overview of activity of CAR-T cell therapy
Jessica Hartmann et al. EMBO Mol Med. 2017

49. Adverse events in CAR T-Cell Therapy
• Often severe and require specific/hematologic resuscitation units
• Cytokine release syndrome (CRS) G3/4 in 42% of patients
• Fever
• Hypotension
• Respiratory insufficiency
• Neurologic toxicity in G3/4 in 35% of patients
• Delirium
• Global encephalopathy
• Aphasia
• Seizure-like symptom/seizure
• Neurologic symptoms are reversible and can occur independent of CRS
• Treatment related death in about 10% of patients
Park JH, et al. ASCO 2016. Abstract 7003.

50. Conclusions
• Over the last 20 years we observed waves of novel anticancer agents that demonstrate
significant antitumor activities in some tumor types that were highly dependent of one
oncogene (or a specific oncogenic pathway)
• Targeted therapies led to the concept of personalized medicine with unconfirmed
expectation that all tumor would always show dependency to oncogenes
• Tumor heterogeneity and epigenetic changes (either spontaneous or induce by therapies)
may profoundly modify the tumor biology over type being a driving force for drug
resistance
• Immunotherapy as a generic concept is providing high level of interest, although based on
prior experience with other therapies we may already anticipate that targeting one single
antigen and cell type may lead to resistance in a fair number of tumor types

51. Thanks for your attention