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![Page 1: Lessons From Clinical Trials of Targeted Therapies for Cancer George W. Sledge M.D. Indiana University Simon Cancer Center.](https://reader035.fdocuments.us/reader035/viewer/2022062409/56649e245503460f94b135ae/html5/thumbnails/1.jpg)
Lessons From Clinical Trials of Targeted
Therapies for Cancer
George W. Sledge M.D.Indiana University
Simon Cancer Center
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What is Targeted Therapy?
• Well-defined molecular target• Target is correlated with tumor
biology• Target is measurable in the clinic,
or so common it doesn’t need to be
• Target is correlated with therapeutic effect
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Erb-B1HER1EGFR
Erb-B2HER2neu
Erb-B3HER3
The HER Family of Receptors
Tyrosinekinase
domain
Ligand-bindingdomain
Erb-B4HER4
TGF-αEGFEpiregulinBetacellulinHB-EGFAmphiregulin Heregulin
Heregulin (neuregulin-1)EpiregulinHB-EGFNeuregulins-3, -4
No ligand-binding activity*
Ligands
*HER2 dimerizes with other members of the HER family. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433.
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Fluorescence In Situ Hybridization Test Measures HER2 Gene
Amplification
• FISH tests are designed to detect amplification of the HER2 gene
PathVysion® PI. Revised May 2004.
Chromosome 17centromere
HER2 gene
HER2-normalRatio <2.0
HER2-amplifiedRatio ≥2.0
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Disease-Free Survival
87%87%85%85%
67%
75%
N EventsACT 1679 261ACTH 1672 134
%
HR=0.48, 2P=3x10-12
ACACTHTH
ACT
Years From Randomization B31/N9831
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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
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Sort-of Targeted Therapy
• VEGF-targeted therapies (except renal cell ca)– rarely drives tumor; hard to predict
benefit
• EGFR (colon, lung, H&N ca)– ras, EGFR mutations
• CMF chemotherapy in high RS breast cancer– redefining targted therapy?
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Survival (anti-apoptosis)
Gene transcriptionGene transcriptionCell-cycle progressionCell-cycle progression
Angiogenesis
Invasion andmetastasis
Chemotherapy /radiotherapy resistance
Proliferation
pY
Ligand
Antibodies to EGFRcetuximab, panitumumab
EGFR-TKpY
EGF Receptor: Role in CRC Therapy
Meyerhardt & Mayer, N Engl J Med 2005Venook, Oncologist 2005
RAS RAF
MEK
MAPK
PI3K
AKTSTAT
PTEN
pY
pY
mTOR
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Copyright © American Society of Clinical Oncology
Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008
Progression-free survival by treatment within KRAS groups
Mutant – 7.4 vs 7.3 weeks
Wild type –12.3 vs. 7.3 weeksP= <0.0001
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RS = + 0.47 x HER2 Group Score
- 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1
Oncotype DX 21 Gene Recurrence Score (RS) Assay
PROLIFERATIONKi-67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromolysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBeta-actinGAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0 – 100)Low risk RS < 18
Int risk RS ≥ 18 and < 31
High risk RS ≥ 31
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Recurrence Score and Distant Recurrence-Free Survival
40
35
30
25
20
15
10
5
00 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Rat
e o
f D
ista
nt
Rec
urr
ence
at
10 y
ears
95% C.I.
Recurrence Rate
LowRS < 18Rec. Rate = 6.8%C.I. = 4.0% - 9.6%
IntermediateRS 18 - 31Rec. Rate = 14.3%C.I. = 8.3% - 20.3%
HighRS 31Rec. Rate = 30.5%C.I. = 23.6% - 37.4%
Paik .S. et al. N Engl J Med 2004;351:2817-26
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LowRS<18
IntRS18-30
HighRS≥31
0 10% 20% 30% 40%
B-20: Absolute % Increase in DRFS at 10 Years
• Benefit of Chemo Depends on RS
n = 353
n = 134
n = 164
% Increase in DRFS at 10 Yrs (mean ± SE)
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Targeted Therapies Vary in Effectiveness
• Based on degree of “pathway addiction”– Is there an ideal target?
• Based on drug-related issues
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The Ideal Target?
• Driving mutation in a• “Dumb tumor” that is• Easily druggable• and the mutation is really common
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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
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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
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A Simulation of a Phase III Trial:
Assumptions:Two subgroups (A and B)A is sensitive to targeted therapy and will have a 25% improvement in median survival from 2227 mo.B is insensitive to targeted therapy
Three scenarios: A representing 100, 50, and 25% of the study population.
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The Crizotinib Story:How It’s Supposed to Work
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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
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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
Cellular selectivity on 10 of 13 relevant hits
Upstate 102 kinase
13 kinase “hits” <100X selective for c-MET
Kinase % InhibitionMet(h) 94Tie2(h) 103
TrkA(h) 102ALK(h) 100
TrkB(h) 100Abl(T315I)(h) 98
Yes(h) 96
Lck(h) 95
Rse(h) [SKY] 94
Axl(h) 93
Fes(h) 93
Lyn(h) 93
Arg(m) 91
Ros(h) 90
CDK2/cyclinE(h) 87
Fms(h) 84EphB4(h) 80Bmx(h) 79
EphB2(h) 77Fgr(h) 73Fyn(h) 68IR(h) 64
CDK7/cyclinH/MAT1(h) 58cSRC(h) 58
IGF-1R(h) 56Aurora-A(h) 54
Syk(h) 52FGFR3(h) 50PKCµ(h) 50BTK(h) 35
CDK1/cyclinB(h) 25p70S6K(h) 24PRK2(h) 22
PAR-1Bα(h) 21PKBß(h) 21Ret(h) 21
GSK3ß(h) 18Flt3(h) 17
MAPK1(h) 17ZAP-70(h) 17
Abl(h) 16c-RAF(h) 16PKD2(h) 15
ROCK-II(h) 14Rsk3(h) 14
GSK3α(h) 11CDK5/p35(h) 10PDGFRα(h) 10
Rsk1(h) 7SGK(h) 6
CHK1(h) 5ErbB4(h) 5Rsk2(h) 5
JNK1α1(h) 4PKBα(h) 4Blk(m) 3
CDK3/cyclinE(h) 3PKCι(h) 3PKCθ(h) 3
CDK2/cyclinA(h) 2PAK2(h) 2PKCßI(h) 2Pim-1(h) 1PKCη(h) 1
SAPK4(h) 1CaMKII(r) 0MKK7ß(h) 0CaMKIV(h) -1CHK2(h) -1CK2(h) -1
JNK2α2(h) -1MKK6(h) -1CK1δ(h) -2PKCα(h) -2
MAPK2(h) -3MEK1(h) -3PKCδ(h) -3PKCε(h) -3Plk3(h) -3
PKCßII(h) -5MSK1(h) -6
PDGFRß(h) -6PKCζ(h) -6
SAPK3(h) -6MAPKAP-K2(h) -7
PKA(h) -7AMPK(r) -9
CDK6/cyclinD3(h) -9CSK(h) -9
SAPK2a(h) -9JNK3(h) -10PKBγ(h) -10IKKα(h) -11NEK2(h) -11 *The cellular kinase activities were
measured using ELISA capture method
KinaseIC50 (nM)mean*
Selectivity ratio
c-MET 8 –
ALK 20 2X
RON298 34X
189 22X
Axl294 34X
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 >10,000 >1,000X
VEGFR2 >10,000 >1,000X
PDGFR >10,000 >1,000X
Pfizer Inc. Data on file
Crizotinib (PF-02341066)
Crizotinib: Kinase Inhibition Profile
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A8081001: Phase I Trial of Crizotinib
Cohort 1
50 mg QD
Cohort 2100 mg QDMDZ 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)
Cohort 3
200 mg QD
Cohort 4
200 mg BID
Cohort 6250 mg BID
MTD/RP2D
Kwak EL, et al. ESMO/ECCO 2009(Abstract G6 and oral presentation)
Cohort 5300 mg BIDMDZ sub-study
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Most Common Treatment-related Adverse Events
(≥10%): Dose Escalation Cohorts (N=37)
Adverse event50 mg QD
(n=3)100 mg QD
(n=4)200 mg QD
(n=8)200 mg BID
(n=7)300 mgBID
(n=6)250 mg BID
(n=9)
Grade 1–2 1–2 1–2 3 1–2 1–2 3 1–2 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
Kwak EL, et al. ASCO 2009 (Abstract 3509 and oral presentation)
3 objective responses observed in this part of the Phase I trial
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First Description of EML4-ALK Translocation in NSCLC
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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:
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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)
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Clinical and Demographic Features of Patients with ALK-positive NSCLC
Clinical and Demographic Features of Patients with ALK-positive NSCLC
N=82Mean (range) age, years 51 (25–78)
Gender, male/female 43/39
Performance status,* n (%)
0 24 (29)
1 44 (54)2 13 (16)3 1 (1)
Race, n (%)Caucasian 46 (56)Asian 29 (35)
Smoking history, n (%)
Never smoker 62 (76)Former smoker 19 (23)Current smoker 1 (1)
Histology, n (%)Adenocarcinoma 79 (96)Squamous 1 (1) Other 2 (2)
Prior treatment regimens, n (%)
0 5 (6)
1 27 (33)
2 15 (18)≥3 34 (41)Not reported 1 (1)
Y Bang et al: ASCO 2010
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60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Max
imu
m c
han
ge
in t
um
or
size
(%
)
–30%
Tumor Responses to Crizotinib for Patients with
ALK-positive NSCLC
*Partial response patients with 100% change have non-target disease present
*
Objective RR = 57% (95% CI: 46-68%)DCR (CR+PR+SD): 87%(95% CI: 77-93%)
Y Bang et al: ASCO 2010
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77% of Patients with ALK-positive NSCLC Remain on Crizotinib
Treatment
0 3 6 9 12 15 18 21
Treatment duration (months)
N=82; red bars represent discontinued patients
Indi
vidu
al p
atie
nts
• Reasons for discontinuation– Related AEs 1– Non-related AEs 1– Unrelated death 2– Other 2– Progression 13
Y Bang et al: ASCO 2010
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Median PFS Has Not been Reached
1.00
0.75
0.50
0.25
0.00
Pro
gre
ssio
n-f
ree
surv
ival
pro
bab
ilit
y
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5Progression-free survival (months)
PFS probability at 6 months: 72% (95% CI: 61, 83%)
Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands
Y Bang et al: ASCO 2010
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Current Crizotinib Clinical Trials
PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451
Key entry criteria
● Positive for ALK by central laboratory
● 1 prior chemotherapy (platinum-based)
N=318
PROFILE 1007
Crizotinib 250 mg BID (N=250)
administered on a continuous dosing schedule
Key entry criteria
● Positive for ALK by central laboratory
● Progressive disease in Arm B of study A8081007
● >1 prior chemotherapy
PROFILE 1005
RANDOMIZE
N=250
Crizotinib 250 mg BID (n=159)
administered on a continuous dosing schedule
Pemetrexed 500 mg/m2 ordocetaxel 75 mg/m2 (n=159)
infused on day 1 of a 21-day cycle
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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
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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
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A Thought Experiment:Imagine 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
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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•RTKi’s for RET exist
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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
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It Gets Worse
Multiple kinases are activated
Optimal cell kill requiresinhibition ofmultiple kinases
Stommel et al. SCIENCE VOL 318: 287,2007
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It Gets Worse
• Assume: Cancers have multiple drivers• Targeting multiple RTK’s 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 RTKi’s?
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Number Needed to Study:A 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
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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
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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
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If Assay Used For Individual Patient Decision Making
Discovery Clinical Practice
PharmacokineticPharmacokinetic
PharmacodynamicPharmacodynamic
PrognosticPrognostic
PredictivePredictive
PharmacogenomicPharmacogenomic
CLIA
Research Lab Clinical Lab
Phase of Trial: Preclinical 0 I II III IV
Assay & Marker Space
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Marker/technology discovery
Assess feasibility of detection/assay technology and
marker prevalence
Test biomarker in retrospective set of specimens
Assess assay performance in
context: reproducibility,
sensitivity, specificity, etc.
Set preliminary cut-points
Final late stage development, assay
qualification
Trial activation
Test cut-points in new retrospective specimen set
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NCI Clinical Assay Development Program
Patient Characterization Center (PCC)
Clinical Assay Development
Center (CADC)
Clinical Assay Development
Network(CADN)
Specimen Retrieval System/caHUB
CADP: overarching program to move assays from research to the clinicCADN: network of CLIA certified labs providing services, including assay optimization, assessment of analytical performance, clinical validity in context of clinical trialsPCC: 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
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Why Drugs Fail
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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
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Why “Targeted” Agents Fail
• The drug isn’t a drug• The drug isn’t used correctly• The drug is used in the wrong
disease• Too much is asked of the drug• The drug is too toxic
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The Drug isn’t a Drug:SU5416
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SU5416
• Potent, selective inhibitor of VEGFR2• Preclinical activity in animal models• Additivity/synergy with
chemotherapeutics
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SU5416: not a drug, a rock
• High lipophilicity (Log P= 4.4), an extremely low aqueous solubility (< 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 < 1 hour)• Major metabolites are inactive
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18FDG-PET of patient with GIST treated initially with SU5416 and later with
imatinib mesylate.
Heymach et al, CCR, 2004
Pre- and post- treatment with SU5416
Pre- and post- treatment with imatinib
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The Drug Isn’t Used Right:
PTK-787/ZK 225846 (Vatalanib)
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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, 2000;60:2178-2189.
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DCE-MRI of PTK-787
Enhancement of a liver metastasis at baseline (A) and 30 hours (B) after treatment with PTK/ZK
A
B
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1168 Patients
Stratification Factors:PS: 0, 1-2
LDH: ≤, >1.5 x ULN
FOLFOX 4 +PTK/ZK 1250 mg po qd
CONFIRM-1 Trial Design
FOLFOX 4 +Placebo
Multinational randomized phase III trial in
previously untreated mCRC:
Negative!
RANDOMIZED
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“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.
Why Didn’t it Work? One Possible Answer
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The Drug is Used in the Wrong Disease
• Bevacizumab in pancreatic cancer
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Locally advanced/metastatic pancreatic cancer: CALGB
80303
Locally advanced or metastatic Pancreatic Ca
N=602
R
Gemcitabine 1000mg/m2 d1 8 15 q28d Placebo
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
Kindler et al ASCO 2007
Trial closed by DSMB as crossed futility boundary
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Locally advanced/metastatic pancreatic cancer
CALGB 80303Gemcitabine
PlaceboGemcitabine Bevacizumab
CR (%) 2 1
PR (%) 8 10
SD (%) 31 36
Disease control rate (%)
40 47
Median OS (months)
6.1 5.8 P=0.78
PFS (months) 4.7 4.9 P=0.99
1yr OS (%) 20 18
Kindler et al ASCO 2007
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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
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The power of NORMAL
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The tale of 3 therapies in TNBC…
Treatment Target Rationale(prior data)
Tumor vs Tumor
Next-GenTranscriptome
Tumor vs Normal
Next-GenFold Change/
P-value
ClinicalTrial
Outcome
Cetuximab& Gefitinib
EGFR Overexpressionof EGFR
NotOverexpressed
-1.61(p= 0.09)
NEGATIVE
Imatinib c-KIT Overexpressionof c-KIT
Not Overexpressed
-6.82(p= 1.8E-06)
NEGATIVE
BSI-201 PARP Overexpressionof PARP/Synthetic
lethality in DNA repair
Overexpressed 3.97(p = 2.0E-05)
POSITIVE
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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)
O’Shaughnessy et al
While other reasons may explain these trial results…. Finding genes that are differentially expressed maybe a good start….
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Too Much is Asked of the Drug
• Sunitinib in breast cancer
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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
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Results of SUN1107
SunitinibCapecitabine
Median PFS 2.8 mo 4.2 moHazard Ratio 1.47p value 0.002
Clinical Benefit (%) 19.3 27.0MDR (mo) 6.9 9.3Any SAE (%) 30 17
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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?
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Conclusions
• Many of our trials fail for simple reasons:– the drug isn’t a drug– the drug isn’t 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
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Avoiding Unforced Errors
• Get dose and schedule more or less right
• Spend $$ on PK/PD (including combinations)
• Don’t ignore Phase II data sets• Respect the disease
– Its unique biology– Its therapeutic context
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“The race is not always to the swift, nor the battle to the strong, but that’s the the way to bet.”
Damon Runyan20th Century American Philosopher
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Thank You
Laissez les bon temps rouler!