Lessons From Clinical Trials of Targeted

Therapies for Cancer

George W. Sledge M.D.Indiana University

Simon Cancer Center

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

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.

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

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

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

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?

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

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

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

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

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)

Targeted Therapies Vary in Effectiveness

• Based on degree of “pathway addiction”– Is there an ideal target?

• Based on drug-related issues

The Ideal Target?

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

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

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

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.

The Crizotinib Story:How It’s Supposed to Work

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

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

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

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

First Description of EML4-ALK Translocation in NSCLC

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:

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)

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

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

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

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

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

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

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

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

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

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

It Gets Worse

Multiple kinases are activated

Optimal cell kill requiresinhibition ofmultiple kinases

Stommel et al. SCIENCE VOL 318: 287,2007

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?

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

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

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

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

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

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

Why Drugs Fail

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

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

The Drug isn’t a Drug:SU5416

SU5416

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

chemotherapeutics

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

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

The Drug Isn’t Used Right:

PTK-787/ZK 225846 (Vatalanib)

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.

DCE-MRI of PTK-787

Enhancement of a liver metastasis at baseline (A) and 30 hours (B) after treatment with PTK/ZK

A

B

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

“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

The Drug is Used in the Wrong Disease

• Bevacizumab in pancreatic cancer

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

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

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

The power of NORMAL

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

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….

Too Much is Asked of the Drug

• Sunitinib in breast cancer

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

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

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?

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

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

“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

Thank You

Laissez les bon temps rouler!