Lessons From Clinical Trials of Targeted Therapies for Cancer

1
Lessons From Clinical Trials of Targeted
Therapies for Cancer

• George W. Sledge M.D.
• Indiana University
• Simon Cancer Center

2
What is Targeted Therapy?

• Well-defined molecular target
• Target is correlated with tumor biology
• Target is measurable in the clinic, or so common
  it doesnt need to be
• Target is correlated with therapeutic effect

3
The HER Family of Receptors
TGF-a EGF Epiregulin Betacellulin HB-EGF Amphiregu
lin
No ligand-binding activity
Ligands
Heregulin (neuregulin-1) Epiregulin HB-EGF Neuregu
lins-3, -4
Heregulin
Ligand- binding domain
Tyrosine kinase domain
Erb-B3 HER3
Erb-B1 HER1 EGFR
Erb-B2 HER2 neu
Erb-B4 HER4
HER2 dimerizes with other members of the HER
family. Roskoski. Biochem Biophys Res Commun.
20043191. Rowinsky. Annu Rev Med. 200455433.
4
Fluorescence In Situ Hybridization Test Measures
HER2 Gene Amplification
Chromosome 17 centromere
HER2 gene
HER2-normalRatio lt2.0
HER2-amplifiedRatio 2.0

• FISH tests are designed to detect amplification
  of the HER2 gene

PathVysion PI. Revised May 2004.
5
Disease-Free Survival
AC?TH
87
85
AC?T
75

67
N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
Years From Randomization
B31/N9831
6
Targets for which Targeted Therapies exist

• Steroid receptors for ER breast cancer,
  prostate cancer, and lymphoma
• HER2 for breast and gastric ca
• ALK for NSCLC
• CD20 for lymphoma
• bcr/Abl for CML
• c-Kit for GIST
• Hedgehog for basal cell and medulloblastoma
• RET for medullary thyoid ca
• b-RAF for melanoma

7
Sort-of Targeted Therapy

• VEGF-targeted therapies (except renal cell ca)
• rarely drives tumor hard to predict benefit
• EGFR (colon, lung, HN ca)
• ras, EGFR mutations
• CMF chemotherapy in high RS breast cancer
• redefining targted therapy?

8
EGF Receptor Role in CRC Therapy
Ligand
Antibodies to EGFRcetuximab, panitumumab
EGFR-TK
Gene transcription Cell-cycle progression
Proliferation
Survival (anti-apoptosis)
Invasion and metastasis
Chemotherapy /radiotherapy resistance
Angiogenesis

• Meyerhardt Mayer, N Engl J Med 2005
• Venook, Oncologist 2005

9
Mutant 7.4 vs 7.3 weeks
Wild type 12.3 vs. 7.3 weeks P lt0.0001
10
Oncotype DX 21 Gene Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2
ESTROGEN ER PR Bcl2 SCUBE2
BAG1
GSTM1
INVASION Stromolysin 3 Cathepsin L2
CD68
Category RS (0 100)
Low risk RS lt 18
Int risk RS 18 and lt 31
High risk RS 31
REFERENCE Beta-actin GAPDH RPLPO GUS TFRC
HER2 GRB7 HER2
11
Recurrence
Score and Distant Recurrence-Free Survival
Low RS lt 18 Rec. Rate 6.8 C.I. 4.0 - 9.6
Intermediate RS 18 - 31 Rec. Rate 14.3 C.I.
8.3 - 20.3
High RS ? 31 Rec. Rate 30.5 C.I. 23.6 -
37.4
Paik .S. et al. N Engl J Med 20043512817-26
12
B-20 Absolute Increase in DRFS at 10 Years

• Benefit of Chemo Depends on RS

n 353
Low RSlt18
n 134
Int RS18-30
n 164
High RS31
0 10 20 30
40
Increase in DRFS at 10 Yrs (mean SE)
13
Targeted Therapies Vary in Effectiveness

• Based on degree of pathway addiction
• Is there an ideal target?
• Based on drug-related issues

14
The Ideal Target?

• Driving mutation in a
• Dumb tumor that is
• Easily druggable
• and the mutation is really common

15
Dumb Tumors vs. Smart Tumors

• CML, MTC, GIST
• Non-Small Cell Lung Cancer
• Responses to EGFR and ALK-targeted therapy seen
  predominantly in non-smokers
• Bronchial epithelium of smokers are loaded with
  mutations (1 mutation/cell/3 cigarettes)
• Breast Cancer ER-neg vs. ER-pos
• BRCA and BRCA-ness of TNBC large mutational load
• ER-pos less LOH, more well-differentiated

16
Clinical Trial Implications of Biomarker-Driven
Therapy

• Number needed to study vs. Number needed to
  treat a source of tension
• Laboratory implications that follow from this

17
A Simulation of a Phase III Trial Assumptions T
wo subgroups (A and B) A is sensitive to targeted
therapy and will have a 25 improvement in
median survival from 22?27 mo. B is insensitive
to targeted therapy Three scenarios A
representing 100, 50, and 25 of the study
population.
18
The Crizotinib StoryHow Its Supposed to Work
19
Crizotinib Rationale for Development of a c-MET
inhibitor

• c-MET is potentially one of the most frequently
  genetically altered receptor tyrosine kinases in
  human cancers
• Activating mutations
• Hereditary papillary RCC 100, sporadic
  papillary RCC (13)
• HNSCC 10
• NSCLC (8) and SCLC (13)
• Gene amplification
• Gastric carcinoma 5-10
• Colorectal carcinoma 4 primary tumors, 20
  liver metastases
• Esophageal adenocarcinoma 5-10
• Anaplastic Lymphoma Kinase (ALK) (2? target for
  crizotinib)
• Anaplastic lymphoma is very sensitive to
  chemotherapy
• ALK point mutations and gene amplification are
  implicated in neuroblastoma a rare tumor
• ALK translocations in inflammatory
  myofibroblastic tumors a very rare tumor

20
Crizotinib Kinase Inhibition Profile
Cellular selectivity on 10 of 13 relevant hits
Upstate 102 kinase
Crizotinib (PF-02341066)
Kinase IC50 (nM) mean Selectivity ratio
c-MET 8
ALK 20 2X
RON 298 34X
RON 189 22X
Axl 294 34X
Axl 322 37X
Tie-2 448 52X
Trk A 580 67X
Trk B 399 46X
Abl 1,159 166X
IRK 2,887 334X
Lck 2,741 283X
Sky gt10,000 gt1,000X
VEGFR2 gt10,000 gt1,000X
PDGFR? gt10,000 gt1,000X
13 kinase hits lt100X selective for c-MET

• Selectivity findings
• ALK and c-MET inhibition at clinically relevant
  dose levels
• Low probability of pharmacologically relevant
  inhibition of any other kinase at clinically
  relevant dose levels

The cellular kinase activities were measured
using ELISA capture method
Pfizer Inc. Data on file
21
A8081001 Phase I Trial of Crizotinib
Cohort 5
300 mg BID
MDZ sub-study
Cohort 4
200 mg BID
Cohort 3
200 mg QD
Cohort 2
100 mg QD
MDZ sub-study
MTD Maximum tolerated dose RP2D Recommended
phase 2 doseMDZ Midazolam (in-vitro data
indicated that PF-02341066 is a major substrate
and inhibitor of CYP3A activity)
Kwak EL, et al. ESMO/ECCO 2009(Abstract G6 and
oral presentation)
22
Most Common Treatment-related Adverse Events
(10) Dose Escalation Cohorts (N37)
Adverse event 50 mg QD (n3) 100 mg QD (n4) 200 mg QD (n8) 200 mg QD (n8) 200 mg BID (n7) 300 mgBID (n6) 300 mgBID (n6) 250 mg BID (n9) 250 mg BID (n9)
Grade 12 12 12 3 12 12 3 12 3
Nausea 2 3 6 0 3 4 0 4 0
Vomiting 2 2 5 0 2 2 0 3 0
Diarrhea 3 0 1 0 2 0 0 2 0
Fatigue 2 2 0 0 0 0 2 1 1
Headache 0 2 1 0 1 0 0 0 0
Visual disturbance 0 0 0 0 1 1 0 0 0
ALT increased 0 0 0 1 1 0 0 0 0
AST increased 0 0 0 0 1 0 0 0 0
DLTs
3 objective responses observed in this part of
the Phase I trial
Kwak EL, et al. ASCO 2009 (Abstract 3509 and oral
presentation)
23
First Description of EML4-ALK Translocation in
NSCLC
24
Evidence for EML4-ALK as a Lung Cancer Oncogene

• Insertion of EML4-ALK into NIH 3T3 fibroblasts
  was tumorigenic when implanted subcutaneously
  into nude mice
• Engineered the specific expression of EML4-ALK
  fusion gene in lung progenitor cells using a
  surfactant protein C gene promoter
• 100 of EML4-ALK transgenic mice developed lung
  adenocarcinoma that were for ALK by IHC. No
  other primary cancers were observed.
• Following IV injection of EML4-ALK/3T3
• cells into nude mice, all developed lung
• cancer. Ten animals were treated with an
• ALK-specific TKI and 10 were observed

25
Key CollaborationPfizer and Massachusetts
General Hospital

• Of the 3 objective responders, all had ALK
  translocations
• Inflammatory myofibroblastic sarcoma NPM-ALK
  translocation
• NSCLC (2) EML4-ALK translocation

Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and
oral presentation)
26
Clinical and Demographic Features of Patients
with ALK-positive NSCLC
N82
Mean (range) age, years Mean (range) age, years Mean (range) age, years 51 (2578)
Gender, male/female Gender, male/female 43/39
Performance status, n () 0 0 24 (29)
Performance status, n () 1 1 44 (54)
Performance status, n () 2 2 13 (16)
Performance status, n () 3 3 1 (1)
Race, n () Caucasian Caucasian 46 (56)
Race, n () Asian Asian 29 (35)
Smoking history, n () Never smoker Never smoker 62 (76)
Smoking history, n () Former smoker Former smoker 19 (23)
Smoking history, n () Current smoker Current smoker 1 (1)
Histology, n () Adenocarcinoma Adenocarcinoma 79 (96)
Histology, n () Squamous Squamous 1 (1)
Histology, n () Other Other 2 (2)
Prior treatment regimens, n () 0 0 5 (6)
Prior treatment regimens, n () 1 1 27 (33)
Prior treatment regimens, n () 2 2 15 (18)
Prior treatment regimens, n () 3 3 34 (41)
Prior treatment regimens, n () Not reported Not reported 1 (1)
Y Bang et al ASCO 2010
27
Tumor Responses to Crizotinib for Patients with
ALK-positive NSCLC
Objective RR 57 (95 CI 46-68) DCR
(CRPRSD) 87 (95 CI 77-93)
60 40 20 0 20 40 60 80 100
Progressive disease Stable disease Confirmed
partial response Confirmed complete response
Maximum change in tumor size ()
30

Y Bang et al ASCO 2010
Partial response patients with 100 change have
non-target disease present
28
77 of Patients with ALK-positive NSCLC Remain on
Crizotinib Treatment
Individual patients

• Reasons for discontinuation
• Related AEs 1
• Non-related AEs 1
• Unrelated death 2
• Other 2
• Progression 13

0 3 6 9 12 15 18
21
Treatment duration (months)
N82 red bars represent discontinued patients
Y Bang et al ASCO 2010
29
Median PFS Has Not been Reached
1.00 0.75 0.50 0.25 0.00
PFS probability at 6 months 72 (95 CI 61,
83) 
Progression-free survival probability
Median follow-up for PFS 6.4 months (2575
percentile 3.510 months)
95 HallWellner confidence bands
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
Progression-free survival (months)
Y Bang et al ASCO 2010
30
Current Crizotinib Clinical Trials
PROFILE 1007
Crizotinib 250 mg BID (n159) administered on a
continuous dosing schedule
RANDOMIZE

• Key entry criteria
• Positive for ALK by central laboratory
• 1 prior chemotherapy (platinum-based)

Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2
(n159) infused on day 1 of a 21-day cycle
N318
PROFILE 1005

• Key entry criteria
• Positive for ALK by central laboratory
• Progressive disease in Arm B of study A8081007
• gt1 prior chemotherapy

Crizotinib 250 mg BID (N250) administered on a
continuous dosing schedule
N250
PROFILE 1007 NCT00932893 PROFILE 1005
NCT00932451
31
Crizotinib The Good News

• Important unmet medical need
• Straightforward, biology-based biomarker
  predicting response
• High response rate in heavily pre-treated
  patients (i.e., low NNT)
• Relatively non-toxic
• A triumph for targeted therapy

32
Crizotinib as an Example The Bad News

• 4-5 of Non Small Cell Lung Cancer, so
• 20-25 patients screened for every EML4-ALK
  patient
• Not all patients are trial eligible
• Not all patients give informed consent
• Best guess 50 patients screened for every
  patient entered on trial
• Screening FISH, which requires trained lab
  tech, time, and supply money
• Lab requires CLIA certification

33
A Thought ExperimentImagine ALK in Esophageal
Cancer

• Esophageal cancer 16,640 cases/year, with
  14,500 deaths
• Assume ALK-like rates of gene expression of 5
• .05 X 16,640 832 patients/year in the US
• Only 3 of patients with cancer go onto clinical
  trials
• .03 X 832 25 patients/year entering trial

34
Medullary Thyroid Cancer

• Thyroid cancer 2 of all cancers
• MTC 5 of all thyroid cancers
• RET proto-oncogene mutations drive
• all hereditary MTC and 50 of sporadic
• RTKis for RET exist

35
Vandetanib

• Inhibits VEGFR1,2, and RET
• A dud in lung cancer
• ASCO 2010 Phase III trial of 331 MTC patients
• 54 reduction in rate of progression, p 0.0001
• ORR 45 vs. 13
• International trial required accrued in 1 year
• NB the biomarker was the diagnosis of MTC

36
It Gets Worse
Multiple kinases are activated
Optimal cell kill requires inhibition
of multiple kinases
Stommel et al. SCIENCE VOL 318 287,2007
37
It Gets Worse

• Assume Cancers have multiple drivers
• Targeting multiple RTKs increases benefit
• So now imagine esophageal cancers with two
  drivers, requiring two different targeted
  therapies
• What is the number needed to screen to perform a
  trial of a combination of 2 RTKis?

38
Number Needed to StudyA New Concept for
Biomarker-Driven Clinical Research

• NNS ___________1________
• (fraction with biomarker X assay
  specificity X fraction trial-eligible X
  fraction giving informed consent X)
• Example HER2 1/(0.25 X 0.9 X 0.5 X 0.5)
• 17.8 patients screened/patient
  entered into trial

39
NNS Implications

• Fraction with biomarker is fixed by biology
• Maximize true positives (specificity) by
  optimized assay development
• Minimize number of exclusion criteria
• Make trial as user-friendly as possible for
  patients

40
Problems With Biomarker Studies

• Poor study design
• Lack of assay reproducibility
• Specimen availability issues
• Issues with quantity, quality preservation
• Variability in assay results
• Underpowered studies/overly optimistic reporting
  due to multiple testing, subset analyses cut
  point optimization

McShane, LM et al. J Clin Oncol 23 9067-72, 2005
41
Assay Marker Space
42
Clinical Assay Development Pipeline
Assess assay performance in context
reproducibility, sensitivity, specificity, etc.
Assess feasibility of detection/assay technology
and marker prevalence
Final late stage development, assay qualification
Test cut-points in new retrospective specimen set
Marker/technology discovery
Set preliminary cut-points
Test biomarker in retrospective set of
specimens
Trial activation
43
NCI Clinical Assay Development Program
Patient Characterization Center (PCC)
Clinical Assay Development Network (CADN)
Clinical Assay Development Center (CADC)
CADP overarching program to move assays from
research to the clinic CADN network of CLIA
certified labs providing services, including
assay optimization, assessment of analytical
performance, clinical validity in context of
clinical trials PCC internal lab performing gene
expression profiling and somatic mutation
detection using semi-quantitative NextGen
sequencing on newly diagnosed cancers CADC
internal lab, part of CADN, the assay development
arm of PCC develop high risk standardized
assays that can be disseminated
Specimen Retrieval System/caHUB
44
Why Drugs Fail
45
Failure Rates of Investigational Drugs in
Clinical Trials

• 9 of 10 drugs entering Phase 1 clinical trials
  will fail
• Historical timing of drug development failures
• 10 discontinuation in Phase 1
• 50-60 discontinuation in Phase 2
• 20-35 discontinuation in Phase 3

46
Why Targeted Agents Fail

• The drug isnt a drug
• The drug isnt used correctly
• The drug is used in the wrong disease
• Too much is asked of the drug
• The drug is too toxic

47
The Drug isnt a DrugSU5416
48
SU5416

• Potent, selective inhibitor of VEGFR2
• Preclinical activity in animal models
• Additivity/synergy with chemotherapeutics

49
SU5416 not a drug, a rock

• High lipophilicity (Log P 4.4), an extremely low
  aqueous solubility (lt 10 ng/ml at pH 2-13) and
  low solubility in common pharmaceutically
  acceptable organic solvents (i.e., ethanol, PEG
  400, propylene glycol, etc.)
• Rapid clearance (half-life lt 1 hour)
• Major metabolites are inactive

50
18FDG-PET of patient with GIST treated initially
with SU5416 and later with imatinib mesylate.
Pre- and post- treatment with SU5416
Pre- and post- treatment with imatinib
Heymach et al, CCR, 2004
51
The Drug Isnt Used RightPTK-787/ZK 225846
(Vatalanib)
52
PTK/ZK-787 - Oral VEGF Receptor Inhibitor

• Receptor PTK/ZK IC50, ?M
• VEGFR-2 (KDR) 0.037
• VEGFR-1 (Flt-1) 0.077
• PDGF-? 0.58
• VEGFR-3 (Flt-4) 0.66
• c-kit 0.73
• in vitro
• Potent inhibitor of VEGFR-1 and 2 tyrosine
  kinases
• Also inhibits VEGFR-3 and the PDGF-? and c-kit
  receptors

Wood JM, et al. Cancer Research,
2000602178-2189.
53
DCE-MRI of PTK-787
A B
Enhancement of a liver metastasis at baseline (A)
and 30 hours (B) after treatment with PTK/ZK
54
CONFIRM-1 Trial Design
R A N D O M I Z E D
1168 Patients Stratification Factors PS 0,
1-2 LDH , gt1.5 x ULN
FOLFOX 4 PTK/ZK 1250 mg po qd
FOLFOX 4 Placebo
Multinational randomized phase III trial in
previously untreated mCRC Negative!

55
Why Didnt it Work? One Possible Answer
The MTD of PTK/ZK administered is 750 mg bid.
The DCE-MRI suggests that the biologically active
dose of PTZ/ZK is at least 1000
mg/day. Pharamacokinetic data from this study
show that at equivalent daily doses, drug
exposure is comparable with the previous once
daily-dosing study however, the trough levels
are significantly higher with the bid dosing.
Whether this will translate into improved
efficacy is at this time unknown.
Thomas, AL et al. J Clin Oncol 23 4162-71, 2005.
56
The Drug is Used in the Wrong Disease

• Bevacizumab in pancreatic cancer

57
Locally advanced/metastatic pancreatic cancer
CALGB 80303
Gemcitabine 1000mg/m2 d1 8 15 q28d Placebo
Locally advanced or metastatic Pancreatic Ca N602
R
Gemcitabine 1000mg/m2 d1 8 15 q28d Bevacizumab
10mg/kg d1 d15 q28d

• Primary endpoint
• Overall survival
• Secondary endpoints
• objective response rate, duration of response,
  progression-free survival, toxicity

Trial closed by DSMB as crossed futility boundary
Kindler et al ASCO 2007
58
Locally advanced/metastatic pancreatic
cancerCALGB 80303
Gemcitabine Placebo Gemcitabine Bevacizumab
CR () 2 1
PR () 8 10
SD () 31 36
Disease control rate () 40 47
Median OS (months) 6.1 5.8 P0.78
PFS (months) 4.7 4.9 P0.99
1yr OS () 20 18
Kindler et al ASCO 2007
59
Is Pancreatic Cancer Inherently Resistant to
Anti-VEGF Therapy?

• Hypovascularized with dense stroma
• Pre-adapted to survive hypoxia
• Frequent TP53 inactivating mutations, which
  render tumors insensitive to hypoxia

60
The power of NORMAL
61
The tale of 3 therapies in TNBC
Treatment
Target
Rationale
Next
-
Gen
Next
-
Gen
Clinical
(prior data
)
Transcriptome
Fold
Change/
Trial
Tumor
vs
Tumor
Tumor
vs
Normal
P
-
value
Outcome
Cetuximab

EGFR
Overexpression
Not
-
1.61
NEGATIVE
Gefitinib
of EGFR
Overexpressed
(p 0.09)
Imatinib
c
-
KIT
Overexpression
Not
-
6.82
NEGATIVE
of c
-
KIT
Overexpressed
(p
1.8E
-
06)
BSI
-
201
PARP
Overexpression
Overexpressed
3.97
POSITIVE
of
PARP/Synthetic
(p
2.0E
-
05)
lethality in DNA
repair
62
ASCO-Plenary 2009PARP inhibitor Overall
Survival
BSI-201 Gem/Carbo (n 57) Median OS 9.2
months Gem/Carbo (n 59) Median OS 5.7
months P 0.0005 HR 0.348 (95 CI,
0.189-0.649)
While other reasons may explain these trial
results. Finding genes that are differentially
expressed maybe a good start.
OShaughnessy et al
63
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64
Too Much is Asked of the Drug

• Sunitinib in breast cancer

65
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66
Sunitinib and Capecitabine in Advanced Breast
Cancer

• Sunitinib
• All prior A and T
• RR 11 (4-21)
• Median TTP 10w (10-11)
• MDR 19 w (18-20)
• Burstein et al. J Clin Oncol 26 1810-16, 2008

• Capecitabine
• All prior A, and T-resistant
• RR 20 (14-28)
• Median TTP 3.1 mo
• MDR 8.1 mo
• Blum et al. J Clin Oncol 17 485-93, 1999

67
Results of SUN1107

• Sunitinib Capecitabine
• Median PFS 2.8 mo 4.2 mo
• Hazard Ratio 1.47
• p value 0.002
• Clinical Benefit () 19.3 27.0
• MDR (mo) 6.9 9.3
• Any SAE () 30 17

68
SUN1007 Shooting for the Fence?

• Capecitabine actually works in MBC
• it shrinks tumors
• it has easily manageable toxicity
• Sunitinib had a lower TTP, RR, and TTP in Phase
  II in a similar patient population
• Stats require huge sunitinib benefit 33
  increase in PFS
• Why would one expect this to work?

69
Conclusions

• Many of our trials fail for simple reasons
• the drug isnt a drug
• the drug isnt used right
• the drug is used in the wrong disease/setting
• too much is asked of the drug
• We owe it to our patients to avoid unforced errors

70
Avoiding Unforced Errors

• Get dose and schedule more or less right
• Spend on PK/PD (including combinations)
• Dont ignore Phase II data sets
• Respect the disease
• Its unique biology
• Its therapeutic context

71

• The race is not always to the swift, nor the
  battle to the strong, but thats the the way to
  bet.
• Damon Runyan
• 20th Century American Philosopher

72
Thank YouLaissez les bon temps rouler!