jean marc nabholtz : médicaments biologiques : critères d’enregistrement et de developpement

Médicaments biologiques: Critères d’enregistrement et de developpement

Prof. Jean Marc NABHOLTZ

Director ,Division of Clinical Research,

Jean Perrin Comprehensive Cancer Center of Auvergne, Clermont-Ferrand, FRANCE

Professor and Former Director, Cancer Therapy Development Program

University of California at Los Angeles (UCLA), CA, USA

Founder and Past Chairman, Breast Cancer International Research Group (BCIRG)

Jean Perrin Comprehensive Cancer Center of Auvergne

Clermont-Ferrand - France .

Breast Cancer Drug Development

NEW SINGLE AGENT

2nd LINE M+

1st LINE M+

ADJUVANT

NEW COMBINATIONS M

+

Nabholtz et al. SABCS 1994.

Trial design •  The quality of a clinical trial

depends upon its design •  A good quality trial should

–  ask a good question –  Define the proper patient population

Analysis of trial findings •  Main analysis specified by the Statistical

Plan (SAP) – Scientific Hypothesis –  Sample size – Patient population à Nb of Events

•  Intent to Treat+++ •  Evaluable

•  Use hazard ratio/confidence intervals in preference to p-values

SAP, statistical analysis plan

•  Use appropriate key endpoint(s) to determine the answer: –  PFS –  TTF –  Response –  Clinical benefit (Hormonotherapy/

targeted therapies…) –  Overall survival

•  Concept of Therapeutic Index •  Quality of life

Analysis of trial findings

6 « Document réservé à l’usage exclusif des médecins régionaux/centres investigateurs »

Scénarios critère principal

X Pivot et al, ESMO 2012, LBA5_PR

Équivalent

Supérieur

Non Inférieur

Inférieur

A

B

C

D

E 0,85 1 1,15 1,3 1,45 1,6

HR Pivot X. et al. SABCS 2012


Equivalence

7

Traitement Expérimental (CT-‐P6) Absence d’effet

ORR

Equivalence Non

équivalence

Traitement de Référence (T)

-‐15 15 Non équivalence

On accepte que C fasse un peu moins bien ou un peu mieux que T de 15% en ORR

H0 : |T – C| ≥ M vs. H1 : |T – C| < M

0


Non Inferiority

8

Experimental Therapy No effect

Non Inferiority

Reference rherapy)

Inferiority

0

Unilateral SituaJon

13 December 2012 EMA/CHMP/205/95/Rev.4/ Guidelines on the evaluaEon

of anEcancer medicinal products in man

1.   Significant clinical benefit based on improved efficacy Efficacy greater than that of an authorised medicinal product should be assessed using clinically meaningful endpoint(s) in adequate and well-‐controlled clinical trials.

2.   Significant clinical benefit based on improved safety Non inferiority on efficacy and robust improved safety.

3.   Significant clinical benefit based on major contribuJon to paJent care A new mode of administraEon could be considered a clinical benefit.

13 December 2012 EMA/CHMP/205/95/Rev.4 Oncology Guidelines on the evaluaEon


•  Acceptable primary endpoints include cure rate, OS and PFS/DFS.

•  If PFS/DFS is the selected primary endpoint, OS should be reported as a secondary and vice versa.

FDA Approvals of Oncology Drugs: 1990–2002

�  A review of FDA approvals has shown that during the period 1990–2002

�  only 32% of the regular marketing authorizations used OS as the basis for approval

�  progression-based and ORR endpoints were the dominant clinical endpoints used to support marketing authorizations

�  In first-line mBC, 100% of all regular marketing authorizations were based on progression-based or ORR endpoints

Johnson, et al. JCO 2003

Recommended Clinical Endpoints Vary Between Regulatory Bodies: FDA

• United States Food and Drug Administration (FDA)

– recommends OS as the primary trial endpoint in oncology

FDA guidance for industry 2009

“The analysis of overall survival may be confounded by cross-over and/or subsequent therapies. PFS, measured prior to the introduction of other therapies, may more accurately depict a treatment’s therapeutic effect.”

FDA Oncology Head Richard Pazdur “PFS can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy.”

FDA guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics

Primary Endpoint of MBC Trials (by time)

Verma et al Oncologist 2011

Only 12% of all MBC trials have shown an improvement in OS

Verma et al Oncologist 2011 PFS, progression-free survival; OS, overall survival; TTP, time-to-progression NR – Not Reported

Median TTP, mo 7.4 4.6 .0001

Response Rate, % 50 32 .0001

Median duration 9.1 6.1 .0001 of response, mo

Median TTF, mo 6.6 4.5 .0001

Chemotherapy ± Herceptin as First-Line Therapy (H0648g): Summary of Benefits

H + CT (n = 235)

CT (n = 234)

Slamon et al. N Eng J Med, 2001.

P value

5 15 25 35 45 Months

0.2

0

0.4

0.6

0.8

1.0

Herceptin + CT CT

Prob

abili

ty A

live

Overall Survival

RR = .80 p = .046

20.3 mo 25.1 mo

65 % of CT group crossed over to Herceptin

Comparative Study H0648g

Slamon et al. N Eng J Med, 2001.

0 10 20 30 40 50 Months

0.0

0.2

0.4

0.6

0.8

1.0 Herceptin +Chemo (n = 169) Chemo Alone (n = 176)

Risk ratio = 0.70 p=0.007 95% Cl = 0.54, 0.91

Survival Chemotherapy +/- Herceptin, 1st line MBC

Clinical Outcomes Analysis

FISH - FISH+

Pro

babi

lity

0 10 20 30 40 50 Months

0.0

0.2

0.4

0.6

0.8

1.0 Herceptin + Chemo (n = 50)

Chemo Alone (n = 56)

Risk ratio = 1.13 p=ns 95% Cl = 0.72, 1.79

Nabholtz et al. Semin Oncol, 2000.

Breast Cancer Drug Development

NEW SINGLE AGENT

2nd LINE M+

1st LINE M+

ADJUVANT

NEW COMBINATIONS M

+

Updated Nabholtz et al. SABCS 1994. NEOADJUVANT

pCR CORRELATES WITH BETTER EFS IN SUBSETS OF BC INCLUDING HER2+ BC

A FDA led Meta-‐analysis (N=11,955 paJents / 1,989 HER2+)

Cortazar; Lancet 2014 (in press)

San Antonio Breast Cancer Symposium -‐ Cancer Therapy and Research Center at UT Health Science Center – December 10-‐14, 2013

This presentaEon is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute

Trastuzumab

No Trastuzumab pCR rates (%)

Lum A Lum B/HER2- Lum B/HER2+

non lum/ HER2+ TN all pCR

pCR to predict breast cancer outcome?

von Minckwitz et al. JCO 2012

SUBPOPULATION DEFINITION REGIMEN N MEDIAN FU

(MONTHS)

DFS p-‐value pCR vs non-‐

pCR

OS p-‐value pCR vs non-‐pCR HR 95% CI HR 95% CI

HER2 SUBGROUP

HER2+ -‐ CT with Trastuzumab -‐ CT without Trastuzumab

665 662 46.3 2.85

2.10 [1.69-‐4.83] [1.27-‐3.48]

<0 .001 0.04

14.11 2.05

[1.93-‐103.03] [1.03-‐4.10]

0.009** 0.04*

Luminal HER2+ Pure HER2+

-‐ CT with Trastuzumab -‐ CT without Trastuzumab -‐ CT with Trastuzumab -‐ CT without Trastuzumab

356 395 298 239

46.3

1.227 1.180 8.738 3.953

[0.63-‐2.37] [0.59-‐2.36] [3.17-‐24.12] [1.89-‐8.28]

n.s. n.s.

< 0.001** < 0.001**

29.72 0.94 13.80 4.91

[0.63-‐>1.000] [0.37-‐2.41] [1.87-‐102] [1.75-‐13.77]

n.s. n.s.

0.01** 0.002**

TRIPLE NEGATIVE SUBGROUP

HR-‐/HER2-‐

-‐ Anthracyclines/Taxanes or, -‐ Taxanes/AnJmetabolites or, -‐Anthracylines/Taxanes/AlkylaJng agents

911 46.3 6.020 [3.92-‐9.25] <0.001** 12.41 [5.82-‐26.49] <0.001**

von Minckwitz G, et al, J Clin Oncol 2012

pCR to predict breast cancer outcome?

Generated 27NOV13 17:07 by F_EFS4LandmarkHR_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)

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Generated 27NOV13 17:07 by F_EFS4Landmark_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)

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LANDMARK ANALYSIS: EFS BY PCR

All paJents



Tests for interacJon: pCR x HR p=0.34

Generated 27NOV13 17:07 by F_EFS4LandmarkHR_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)

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Tests for interacJon: Lap + Tras vs. Tras x pCR, p=0.42 Lap vs. Tras x pCR, p=0.94

LANDMARK POPULATION BY ARM: EFS BY PCR



Generated 27NOV13 17:08 by F_EFS4LandmarkTrt_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)

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Generated 27NOV13 17:08 by F_OS4Landmark_slide.sas (r3893) from data as of 13-NOV-2013 11:21 (UTC)

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Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-NOV-2013 11:21 (UTC)

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Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-NOV-2013 11:21 (UTC)

Generated 27NOV13 17:08 by F_OS4Landmark_slide.sas (r3893) from data as of 13-NOV-2013 11:21 (UTC)

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LANDMARK ANALYSIS: OS BY PCR

All paJents



Tests for interacJon: pCR x HR p=0.36

pCR en Europe The note for guidance does not address the possible use of pathological complete remission (pCR) as primary endpoint in neoadjuvant trials for high-‐risk early-‐stage breast cancer Currently, there is liqle regulatory experience with this endpoint and the published data are limited. Further experience and robust prospecJve clinical data are warranted before firm recommendaJons can be made.

27 November 2012 EMA/768937/2012 Answers from the CHMP ScienEfic Advisory Group (SAG) for Oncology for Revision of the anEcancer guideline hep://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformaEon/Guidances/UCM30550 1.pdf)

13 December 2012 EMA/CHMP/205/95/Rev.4/ Guidelines on the evaluaEon


1.   Significant clinical benefit based on improved efficacy Efficacy greater than that of an authorised medicinal product should be assessed using clinically meaningful endpoint(s) in adequate and well-‐controlled clinical trials.

2.   Significant clinical benefit based on improved safety Non inferiority on efficacy and robust improved safety.

3.   Significant clinical benefit based on major contribuJon to paJent care A new mode of administraEon could be considered a clinical benefit.

Phase III, non-inferiority trial

Stratification factors

Breast cancer type (operable vs. locally advanced vs. inflammatory)

Oestrogen receptor status (positive vs. negative vs. unknown)

Secondary endpoints

PK: Observed Ctrough at pre-dose cycle 13; predicted Ctrough for pre-dose Cycle 8 and 13

Efficacy: tpCR (pCR in breast and axilla); overall response rate and time to response; event-free and overall survival

Safety (including immunogenicity)

HER2+ EBC (N=596)

A trastuzumab

B trastuzumab

surgery

Follo

w-‐up: 24 mo

pCR

18 cycles/ 1year

Docetaxel 75 mg/m2

FEC 500/75/500

Neo-‐adjuvant Adjuvant

R

1 :1

HannaH: Both co-‐primary endpoints met

PK Efficacy

Difference in pCR rate: 4.7%† (95% CI: –4.0, 13.4)

Geometric mean ratio: 1.33* (90% CI: 1.24, 1.44)

Seru

m C

trou

gh le

vels

pCR

in th

e br

east

Trastuzumab SC (n = 234)

Trastuzumab IV (n = 235)

Trastuzumab SC (n = 260)

Trastuzumab IV (n = 263)

51.8 µg/mL

69.0 µg/mL

45.4% 40.7%

100

75

50

25

0

100

75

50

25

0

Trastuzumab SC demonstrated a comparable efficacy and PK profile to the IV formulation

* Non-inferiority margin for the ratio between groups of 0.80 † Non-inferiority margin for the difference between groups of –12.5% CI, confidence interval Ismael G, et al. Lancet Oncol 2012; 13:869–878.

PrefHer: PaEents overwhelmingly preferred trastuzumab SC over IV

SC preferred (exact binomial): Overall = 91.5% (95% CI 87.2% to 94.7%) Pivot X, et al. Lancet Oncol 2013; 14:962–970.

IV No pref

6.8% n = 16

n = 4 1.7%

3.5% n = 11

94.7% n = 54

1.8% n = 1

7.8% n = 14

1.7% n = 3

90.5% n = 162

91.5% n = 216

SC

CONCLUSION

•  Analysis of the compound – Define the appropriate quesEon

•  Define the type of trial –  Superiority, Equivalence, Non-‐inferiority… – Non-‐inferiority trials become more and more common

•  Define the endpoints –  Primary endpoint –  Secondary endpoints

CONCLUSION

•  Follow the guidelines of regulatory agencies •  Learn to interpret the results within the defined quesEon

•  Define the impacy for clinical pracEce

jean marc nabholtz : médicaments biologiques : critères d’enregistrement et de developpement

Health & Medicine

anecancer medicinal products

regular marketing authorizations

1st line

adjuvant

mbc trials

fda approvals

pcr

survival