臨床薬理学的立場から見た outlines 抗悪性腫瘍薬使用の...

1

第３回日本ファーマコメトリクス研究会

臨床薬理学的立場から見た抗悪性腫瘍薬使用の適正化

埼玉医科大学大学院・腫瘍内科学講座国際医療センター腫瘍内科

佐々木康綱

[email protected]年9月4日昭和大学

2

Outlines Basic concept of cancer therapeutics PK based treatment optimization PD based treatment optimization Clinical evaluation of biomarkers Endpoint of phase III studies

3

Death Rates for Cancers in Japan

M F

4

Advances in M-CRC TreatmentImproved Median Overall Survival

5

Concept of “All-3-Drugs”11 Phase III Trials, 5768 Patients

(Grothey & Sargent, JCO 2005)

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

LV5FU2

0 10 20 30 40 50 60 70 80

222120191817161

Med

ian

OS

(mo)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

Multivariate analysis:Effect on OS PFirst-line doublet 0.69All 3 drugs 0.005

6

Final Endpoints for Cancer Therapeutics Cure Prolongation of survival Symptom relief

Standard Treatment

7

Anti-Cancer Treatment by Drugs Chemotherapy Endocrine therapy

Molecularly targeting therapy

8

Concept of Chemotherapy“Recommended Dose”

= “Maximum Tolerated Dose”

9

Concept of Chemotherapy“Biomarker for Efficacy”

= “Tumor Shrinkage”

10

Signal-Transduction Pathways The Emergent Integrated Circuit of the Cell

(Hanahan D and Weinberg RA, Cell 2000)

11

Molecularly Targeting Agents Cancer cell selective effect? Recommended dose based on biology? Non-lethal myelosuppression? More profound non-hematological

toxicities? Dramatic effect in some cases?

Patient enrichment strategy

12

Concept of Targeting Drugs“Recommended Dose” below “MTD”

13

Concept of Targeting DrugsVarious “Biomarker for Efficacy”

14

Biomarker Definition A characteristic that is objectively

measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

(Janet Woodcock M.D. November 4, 2004 www/fda.org)

15

What Biomarkers are Needed…? PK-PD markers For dose selection

Predictive markers For patients selection

Surrogate markers For early Go/No Go

Synergy markers For combination selection

(Edwin Clark, AACR 2008) 16

Intrinsic and Extrinsic Factors Responsible for Drug Reaction

(ICH Harmonized Tripartite Guideline: ETHNIC FACTORS IN THE ACCEPTABILITY OFFOREIN CLINICAL DATA E5)

17

Same Drug with Same Dosage?

18

Clinical Practice in Oncology

Doseand

DosageRegimen

Responseor

Adverse Events

Black Box

19

DPD DefficiencyPharmacogenetic Syndrome

T1/2(min.)

CL(ml/min/m2)

Unchanged FU in 24 hrs urine

% of Dose“Normal” control(Cancer Res 1987)

13±7 594±198 9.8±1.6

DPD def. Pt-1(JCI 1988)

159 70 89.7

(Diasio RB., AACR 2008) 20

Pharmacological Approach in Oncology

Doseand

DosageRegimen

Responseor

Adverse Events

PlasmaExposure

Siteof

action

Pharmacokinetics Pharmacodynamics

ADMEGenetic polymorphism ofthe drug metabolizing enzyme

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Therapeutically Relevant Genetic Variation in Oncology

Genomic Aberration Agents ConsequenceTPMT 6-MP NeutropeniaDPD 5-FU Neutoropenia, Neurotox.CYP2D6 Tamoxifen Lower active metaboliteCYP2A6 Tegafur ?

Letrozol ?UGT1A1 Irinotecan Neutropenia

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PMS of All Patients Treated with Irinotecan in JapanEvents # of Patients Monotherapy Combination Total ADR All events 12,336 13,935Grade 3/4 Leukopenia 23.8% 38.3%

Thrombocytopenia 6.5% 14.3%Diarrhea 10.2% 10.0%Intestinal paralysis

0.5%

Interstitial pneumonia

0.3%

(Tadokoro, et al. ASCO 2002)

23

IrinotecanPK Variability

AUC CPT-11(mg/ml h)

SN-38(ng/ml h)

Mean 6.41 236.14Max. 12.06 348.27Mini. 4.14 97.00CV 25.97 38.91

(Sasaki et.al. Jpn J Cancer Res 86, 101, 1995) 24

Irinotecan Metabolic Pathway

Transporter(MRP2)

UGT

IrinotecanIrinotecanCarboxylesterase

SN-38G

SN-38

LiverIntestine

SN-38G

SN-38

glucuronidase

+ glucuronic acid

APC NPCCYP3A

Enterohepatic circulation

UGT, UDP-glucuronosyltransferase

25

IrinotecanUGT1A1*28 and Severe Adverse Events

Term χ２ P OR (95%CI)UGT1A1*28 12.95 .0003 7.23 (2.52-22.3)Regimen 7.36 .0067 4.52 (1.53-13.9)Female 3.10 .0782 2.45 (0.90-6.75)

(Ando Y, Cancer Res 60: 6921-6926, 2000) 26

Drug-Metabolizing EnzymesPolymorphism

Time

Conc

entr

atio

n

Time

Conc

entr

atio

n

Time

Conc

entr

atio

n

wild/wild wild/variant variant/variant

Therapeutic

Toxic

27

Recommended Nomenclature UGT Gene

A(TA)8TAAUGT1A1*37A(TA)7TAAUGT1A1*28A(TA)5TAAUGT1A1*36-3263T>AUGT1A1*60

NucleotideAmino AcidAllele

1456T>GY486DUGT1A1*7 Exon 5

686C>AP229QUGT1A1*27 Exon 1211G>AG71RUGT1A1*6 Exon 1

1099C>GR367GUGT1A1*29 Exon 4

TATA

I II III IV VPromoter5’ 3’

TATATATATATA TA7 repeatsUGT1A1*28

TATATATATATA6 repeatsWild-type

Physiological hyperbilirubinemiaGilbert syndrome

Promoter

(http://som.flinders.edu.au/FUSA/ClinPharm/UGT/currnom.htm) 28

Camptosar® Labeling Revision

Patients with Reduced UGT1A1 Activity

Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele.

Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.

(http://www.fda.gov/cder/foi/label/2005/020571s026lbl.pdf)

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UGT1A1 Genotypes and SN-38/SN-38G Metabolic RatioGenotype N SN-38 metabolic ratio

AUC [SN-38/SN-38G] (0-25.5 h)

wild 11 0.39 ± 0.27* (0.06 – 1.00)

*6 heterozygote 1 0.44, 0.20*6 homozygote 1 1.40*28 and *6 heterozygote

2 1.56(1.13), 2.16

(Araki and Sasaki, Cancer Science 2006) 30

Genotype Frequencies of UGT1A1*28 and *6

Genotype Number (%)Japanese Korean Caucasian

Ando Minami Han Innocenti ToffoliUGT1A1*28 Wild 93 (78.8) 131 (74.4) 69 (85.2) 30 (46.2) 109 (45.7)

Hetero 18 (15.3) 41 (23.3) 12(14.8) 25 (38.5) 108 (45.3)

Homo 7 (5.9) 4 (2.3) 0 (0) 6 (9.2) 21 (8.8)UGT1A1*6 Wild 91 (77.1) 123 (69.9) 49 (60.5)

Hetero 25 (21.2) 48 (27.3) 26 (32.1)

Homo 2 (1.7) 5 (2.8) 6 (7.4)

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Genotype Frequencies of UGT1A1*28 and *6 in Japanese

Genotype N (%) 95% CI (%)Total # of patients 300

UGT1A1*1/*1 135 (45.0) 39.3-50.8

UGT1A1*1/*28 47 (15.7) 11.7-20.3

UGT1A1*1/*6 88 (29.3) 24.1-34.8

UGT1A1*28/*28 2 (0.7) 0.1-2.4

UGT1A1*6/*6 17 (5.7) 3.3-8.9

UGT1A1*6/*28 11 (3.7) 1.8-6.5

(Akiyama and Sasaki, Ann. Oncol. 2008) 32

UGT1A1 Polymorphisms Focused Phase I Trial

UGT1A1Genotype

*28

- / - - /*28 *28/*28

*6

- /- Wild Hetero Homo

- /*6 Hetero Homo

*6/*6 Homo

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Study Design and Objectives

ChemoTx resistant unresectableStomach/Colorectal Cancer（PS 0,1）

ChemoTx resistant unresectableStomach/Colorectal Cancer（PS 0,1）

Gen

otyp

ing

Gen

otyp

ing

*1/*1：Fixed Dosing

*1/*28 or *1/*6：CRM

*28/*28, *6/*6or *1/*28 & *1/*6： CRM

Stratification

CRM=Continual Reassessment Method

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Probability of DLTsDose Level（mg/m2）

Heterozygotesn=20

Homozygotesn=19

1 （50） 0.8% 2.0%2 （75） 1.5% 3.0% （0/2)3 （100） 1.9% （0/2) 8.0% （0/1)4 （125） 4.0% （0/2) 13.2% （0/1)

5 （150） 5.9% （0/16)80%CI：2.2%-11.2%

37.4% （6/15)80%CI：22.8%‐52.7%

(Probability of DLTs were estimated by CRM)

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Components of S1

S136

S1 Based Clinical Trials for M-GCJCOG9912 SPIRITS

(Boku ASCO 2007, Narahara ASCO 2007)

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S1Drug Design

5-FU5FUH2DPD

FdUrd FdUMP FdUDP FdUTP

FUrd FUMP FUDP FUTP

DNA

RNA

UrineFBAL

Elimination Activation in Tumor Cell

Tegafur

CDHP

CYP2A6

38

Difference in S1 related PKsBetween Japanese and US and European Patients

Dose of S1 (mg/m2)

AUC/FT(ngxh/mL)

AUC/CDHP

AUC/Oxonic Acid

Japan 32-40 28,217* 1,372 365

US 30 13,653 1,583 232US 35 18,863 1,784 206Europe 35 18,427 1,562 347

(* mean value)

(Ajani JA. J Clin. Oncol.23:6957-6963, 2005)

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Difference in S1 related PKs Between Japanese and US and European Patients

Area Author n Dose of S1

(mg/m2)

Cmax/5-FU(ng/mL)

AUC/5-FU

(ngxh/mL)

Japan Hirata 12 32-40 128.5* 723.9*US Van Hoff 26 30 144 782

35 176 1,00440 319 1,528

Europe Van Groeningen

28 25 118.4 588.6

35 179.5 1,133.040 226.3 1,493.0

(* mean value)

(Ajani JA. J Clin. Oncol.23:6957-6963, 2005) 40

CYP2A6 PolymorphismEthnic Difference

Allele White Black Korean Japanese*1A 84.5 74.4 53.3 45.1*4A 0 0.6 10.8 10.0*4D 0 0.3 0 0*7 0 0 9.8 9.8*9 8.0 8.5 19.6 19.0*10 0 0 1.0 2.2*11 0 0 0.7 0.5

(Nakajima M., Clin. Pharmacol. Ther. 80:282-297, 2006)

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S1Drug Design

5-FU5FUH2DPD

FdUrd FdUMP FdUDP FdUTP

FUrd FUMP FUDP FUTP

DNA

RNA

UrineFBAL

Elimination Activation in Tumor Cell

Tegafur

CDHP

CYP2A6

42

CYP2A6 PolymorphismEthnic Difference

Is poor tolerability of S1 in Caucasian patients due to CYP2A6 polymorphism?

43

Study Objectives This prospective study was designed to

examine the contributions of CYP2A6genotype, plasma CDHP levels, and patient’s characteristics on the PK of FT and 5-FU.

44

0

1

2

3

4

5

6

7

CYP2A6 genotypeC

L/F

for F

T (l/

h)

Wild One-variant allele Two-variant alleles

Genotypes of CYP2A6 and Tegafur Clearance

(Fujita and Sasaki, Cancer Science 2008)

45

Clearance of FTMultivariate Analysis

R2 PAUC for CDHP 0.20 0.787BSA 0.010 0.537Age 0.010 0.539Total bilirubin 0.019 0.404CYP2A6 genotype 0.57 0.0000136Gender 0.023 0.351

(Fujita K Cancer Science 2008) 46

AUC of 5-FUMultivariate Analysis

R2 PAUC for CDHP 0.29 0.000380BSA 0.061 0.631Age 0.00083 0.860Total bilirubin 0.033 0.260CYP2A6 genotype 0.080 0.212Gender 0.020 0.384

(Fujita K Cancer Science 2008)

47

5FU Exposure and Renal Function

(Fujita and Sasaki, Cancer Science 2008) 48

Discussing Points Contribution of CYP2A6 polymorphism

for tolerability of S1 is minimal. Unanswered questions Susceptibility against 5-Fluorouracil

between Japanese and Caucasian patients

Non linear pharmacokinetics of 5-Fluorouracil treated by S1

49

Dosing of S1 BSA based dosing?

50

“Targets” for Targeting Agents EGFR family VEGF/VEGFR Others RAS/MEK/ERK pathway PI3K/AKT/mTOR pathway Insulin-like growth factor Poly (ADP-Ribose) polymerase 1

51

Epidermal growth factor Receptor (EGFR) Family

Copyright © American Society of Clinical Oncology

(Alvarez, R. H. et al. J Clin Oncol; 28:3366-3379 2010) 52

EGFR/HER2 Targeting Drugs

53

TrastuzumabHumanized Anti-her2 Monoclonal Antibody

• High affinity (Kd=0.1nM) and specificity• 95% human, 5% murine

–decrease potential for immunogenicity54

Pharmacological Approach in Oncology

Doseand

DosageRegimen

Responseor

Adverse Events

PlasmaExposure

Siteof

action

Pharmacodynamics

Receptor sensitivity

Pharmacokinetics

55

TrastuzumabFor ＨＥＲ２ Overexpressing Breast Cancer

Protein 3+ >10 gene copies

56

TrastuzumabHumanized Anti-her2 Monoclonal Antibody

Trastuzumab(Herceptin） HercepTestTM

Biomarker

57

Docetaxel/Trastuzumab in MBCPhase III Trial

Outcome T/Doc Doc alone pORR (%) 61 34 .0002CR (%) 7 2PR (%) 54 32SD (%) 27 44TTP (mo) 11.7 6.1 .0001OS (mo) 31.2 22.7 .0325

(Marty M J Clin Oncol 23: 1-10, 2005) 58

Algorithm for Treatment of M-BC

59

Inhibiting PARP-1 Increases Double-strand DNA Damage

PARPInhibition of PARP-1 prevents recruitment of repair factors to repair SSB

XRCC1LigIII

PNK 1pol β

Replication (S-phase)

DNA DSB

DNA SSB

(AstraZeneca slide kit) 60

BSI-201Phase II Trial Design

Endpoints Clinical benefit rate PFS and OS

Patients with M-TNBC

<2 prior cytotoxic regimens

(N=86/120)

Gemcitabine(1000mg/m2 on D1,8)

+Carboplatin(AUC=2 on D1,8)

+BSI-201 (5.6mg/kgIV biweekly)

G/C

(J. O'Shaughnessy J Clin Oncol 27:18s, 2009 suppl; abstr 3)

61

BSI-201Phase II in Pts with m-TNBC

(J. O'Shaughnessy J Clin Oncol 27:18s, 2009 suppl; abstr 3) 62

ToGA Trial Study Design

Primary: PFS Secondary: PFS, TTP, ORR, Clinical Benefit

Rate, Duration of Response, QoL

HER2-positive

advanced GC

(n=584)

5-FU or capecitabinea

+ cisplatin(n=290)

5-FU or capecitabinea

+ cisplatin+ trastuzumab

(n=294)

63

ToGAPrimary Endpoint: OS

64

EGFR/HER2 Targeting Drugs

65(Van Cutsem E et al. N Engl J Med 2009;360:1408-1417)

Cetuximab for m-CRC1st Line: CRYSTAL (FOLFIRI±Cmab)

66Copyright © American Society of Clinical Oncology

（Chung, K. Y. et al. J Clin Oncol; 23:1803-1810 2005）

Representative EGFRImmunohistochemistry Scoring

67

CRYSTAL Recent Efficacy Update in KRAS WT

FOLFIRI(N=350)

FOLFIRI+C(N=316)

P value

RR (%) 39.5 57.3 <0.0001mPFS (mo) 8.4 9.9 0.0012mOS (mo) 20 23.5 0.0094

(Van Cutsem ASCO2010) 68Copyright © American Society of Clinical Oncology

(Bokemeyer, C. et al. J Clin Oncol; 27:663-671 2009)

Cetuximab for m-CRC1st Line: OPUS (FOLFOX±Cmab)

69

Cetuximab for m-CRC1st Line: OPUS (FOLFOX±Cmab)


(Bokemeyer, C. et al. J Clin Oncol; 27:663-671 2009) 70

Cetuximab for m-CRC3rd Line: CO17

OS

PFS

Jonker D et al. N Engl J Med 2007;357:2040-2048


(Lievre, A. et al. J Clin Oncol; 26:374-379 2008)

Progression-free Survival

Overall Survival

? KRAS Mutation as a Prognostic Factor Treated with Cetuximab

72(Ciardiello F and Tortora G. N Engl J Med 2008;358:1160-1174)

Signal Transduction Pathways Controlled by EGFR Activation

KRASMutation

73

KRAS Mutation for CmabRetrospective but Consistent Results

Study Wild KRAS Mutant KRASPFS without

CmabPFS with

CmabPFS without

CmabPFS with

Cmab

CRYSTAL1st line FOLFIRI±C-mab

7.6 m 9.9 m 8.1 m 8.7 m

OPUS1st line FOLFOX±C-mab

7.2 m 7.7 m 8.6 m 5.5 m

EPIC2nd line IRI±C-mab

2.79 m 3.98 m 2.59 m 2.60 m

CO.173rd line Placebo±C-mab

1.9 m 3.8 m 1.9m 1.8 m

74

Pitfalls of Biomarker Validation True biomarker has not been identified

even after completion of positive phase III trial.

Evidence level of biomarker is not identical with positive clinical result in phase III trial.

Prospective validation of biomarker is sometimes difficult to conduct in post marketing study because of ethical problems.

75

KRAS Mutation Analysis Methods

Method Sensitivity (MT/WT; %)

Disadvantages

Direct sequencing 20-50 Poorly quantitative, insensitive, prolonged turnaround

RFLP 0.10 Complicated; requires sequencing confirmation

Allele specific probe 10 Relatively low sensitivityHigh resolution melting analysis

5 Complicated; requires sequencing confirmation

Amplification refractory mutation system

1 Detects only single specific mutation per reaction

(Jimeno A J Clin Oncol, 27:2009: pp. 1130-1136) 76

Gefitinib Orally available Selective EGFR-TK (epidermal growth factor

receptor-tyrosine kinase) inhibitor

77

Gefitinib Phase III for NSCLCCDDP/GEM ±Gefitinib (INTACT 1)

(Giuseppe G J Clin Oncol Mar 1 2004: 777-784) 78Published by AAAS

J. G. Paez et al., Science 304, 1497 -1500 (2004)

Missense mutations G719S and L858R and the Del-1 deletion

79

A LC Cell Line with EGFR Mutation is Sensitive to Gefitinib

Published by AAASJ. G. Paez et al., Science 304, 1497 -1500 (2004) 80

IPASSPhase III Study Design

The primary end point was PFS.

1st linePatients with

Adeno-CaNon/light smoker

Stage IIIB/IV

Carboplatin(AUC 5 or 6, day 1)

Paclitsaxel(200 mg/m2, daqy1)

Gefitinib(250 mg/body oral 1xdaily)

(Mok T et al. N Engl J Med 2009;10.1056/NEJMoa081069)

81

IPASSKaplan-Meier Curves for PFS

(Mok T et al. N Engl J Med 2009;10.1056/NEJMoa081069)

OverallOverall EGFR Mutation (+)EGFR Mutation (+)

EGFR Mutation (-)EGFR Mutation (-) Unknown EGFR MutationUnknown EGFR Mutation

82

NSCLC with sensitive EGFR mutationsStage IIIb/ IVNo prior

chemo.PS 0-1age of 20-75

y.o

NSCLC with sensitive EGFR mutationsStage IIIb/ IVNo prior

chemo.PS 0-1age of 20-75

y.o

Gefitinibn=160Gefitinibn=160

CBDCA+TXLn=160

CBDCA+TXLn=160

Primary endpoint

PFS2ndary

endpointsOSResponseSide-effectsQOL

Primary endpoint

PFS2ndary

endpointsOSResponseSide-effectsQOL

Rbalanced :Institution sex stage

Prospective RCT of Gefitinib based on EGFR Mutation

( Kobayashi K ASCO 2009)

83


（Maemondo M, et al. N Engl J Med 2010;362:25） 84


（Maemondo M, et al. N Engl J Med 2010;362:25）

85

Incidence of EGFR Mutations in Surgically Resected Specimens

(Sekine I BJC 99, 1757-1762, 2008) 86

Vascular Endothelial Growth Factor (VEGF) Family


Alvarez, R. H. et al. J Clin Oncol; 28:3366-3379 2010

87

VEGF Inhibitors Agents that block the VEGF pathway have

been shown to effectively inhibit tumor angiogenesis and growth in preclinical tumor models.

Studies in early-stage breast cancer show that elevated VEGF expression is associated with decreased RFS and OS in patients with breast cancer Bevacizumab Aflibercept

88

BevacizumabRecombinant Humanized Monoclonal Antibody to VEGF-A

89

Bevacizumab Phase III for 1st Line CRC (AVF2107g)

(Hurwitz H et al. N Engl J Med 2004;350:2335-2342) 90Sandler A et al. N Engl J Med 2006;355:2542-2550

Bevacizumab in M-NSCLCPhase III

OS

PFS

91Miller K et al. N Engl J Med 2007;357:2666-2676

Bevacizumab in M-BCPhase III: E2100

PFS OS

92

Phase III TrialsE2100 and AVADO

Endpoint E2100 AVADOTaxane T+bev. Taxane T+bev.

Low/High doasRR overall (%) 21.2 36.9 NA NARR measurable (%) 25.2 48.5 49 55/83PFS (mo) 5.9 11.8 8.0 8.7/8.8Hazard ratio, p 0.60, p<0.0001 Vs. low: 0.79, p=0.0319

Vs. high: 0.72, p=0.0099OS (mo) 25.2 26.7 NR NRHazard ratio, p 0.88, p=0.16 Vs. low: 0.92(0.62-1.37)

Vs. high: 0.68, p=(0.45-1.04)

93

FDA Approval of Bevacizumab Was this the right decision (no OS benefit)?

Albain KS, ASCO 2008 94

Meta-analysis of B-mab for MBC Comparison of Studies

E2100 AVADO RIBBON-1# of pts 722 488 1237Geography US Ex-US USRandomization ratio (BV:PL)

1:1 1:1 2:1

ChemoTx Paclitaxel weekly

Docetaxel CapecitabineDoce/PacliDOX/EPI

Primary endpoint PFS PFS PFSSecondary endpoints OS, ORR OS, ORR, 1YS OS, ORR, 1YS

O’Shaughnessy, ASCO 2010

95

Meta-analysis of B-mab for MBC Overview of Efficacy Results


E2100 AVADO RIBBON-1(Cape)

RIBBON-1(Tax/Anthra)

PL BV PL BV PL BV PL BVPFS (m)

5.8 11.3 7.9 8.8 5.7 8.6 8.0 9.2

HR(95%CI)

0.48(0.39-0.61)

0.62(0.48-0.79)

0.69(0.56-0.84)

0.64(0.52-0.80)

p <0.0001 0.0003 0.0002 0.0001

96

Meta-analysis of B-mab for MBC Overview of PFS and OS, Pooled Population


PLN=1008

BVN=1439

M-PFS (mon.) 6.7 9.2HR (95%CI) 0.64 (0.57-0.71)

M-OS (mon.) 26.4 26.7HR (95%CI) 0.97 (0.86-1.08)1YS rate (%) 77 82


Buyse, M. et al. J Clin Oncol; 25:5218-5224 2007

Correlation between Treatment Effects on PFS and on OS in CRC

98

ODAC: Voting ResultQ1: Does the addition of bevacizumab to

docetaxel represent a favorable risk/benefit analysis for the initial treatment of patients with metastatic breast cancer? For : Against＝0 : 13

Q2: Does the addition of bevacizumab to taxenes, anthracyclines or capecitabine represent a favorable risk/benefit analysis for the initial treatment of patients with metastatic breast cancer? For : Against＝1 : 12

99

ODAC: Voting ResultQ3: Taking into consideration the totality of

findings, and the responses to Questions 1 and 2 above, do the AVADO and RIBBON1 results provide confirmatory evidence of clinical benefit of bevacizumab in combination with paclitaxel for the initial treatment of MBC? For : Against＝0 : 13

100

ODAC: Voting ResultQ4: If the Committee's answer to question 3 is

No: Should the indication for treatment of metastatic breast cancer be removed from the Avastin label? For : Against＝12 : 1

Q5: If the Committee's answer to question 4 is No, please discuss what additional trials should be performed to verify the clinical benefit of Avastin in the treatment of HER2-negative, metastatic breast cancer.

101

Progression Free Survivalin First Line Ovarian Cancer Is PFS gain meaningful to patients? Is PFS a surrogate for overall survival? Is PFS an indicator of time without disease

/treatment symptom?

No data yet to show PFS gain in indicator of improved QOL or symptom benefit!

No data yet to show PFS gain in indicator of improved QOL or symptom benefit!

Eisenhauer E, ASCO 2010 as discussant 102

Ovarian Cancer 2006 FDA/ASCO/AACR Workshop on

Endpoints for Regulatory Approval 1st line trials The strength of PFS as a surrogate for OS is

essentially clear in first line therapy……. Increased FPS is a valid endpoint but studies still need to be powered to measure OS

Maintenance studies OS is the most significant endpoint. Improvement

in PFS might be acceptable

Eisenhauer E, ASCO 2010 as discussant

103

Analytical Approach We address these questions by use of a

simple device. We partition OS into two parts by

expressing it as the sum of PFS and survival postprogression (SPP) [ie, OS = PFS + (OS-PFS)].

SPPSPP

Copyright restrictions may apply.

Broglio, K. R. et al. J. Natl. Cancer Inst. 2009 101:1642-1649; doi:10.1093/jnci/djp369 104

# of Pts. Detecting Significant Difference in OS by M-SPP

Copyright restrictions may apply.

Broglio, K. R. et al. J. Natl. Cancer Inst. 2009 101:1642-1649; doi:10.1093/jnci/djp369

105

Saitama International Medical Ctr.-Comprehensive Cancer Center

106

CollaboratorsDepartment of Medical OncologySaitama Medical School

臨床薬理学的立場から見た outlines 抗悪性腫瘍薬使用の...

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