RAGMA - GEICAM Madrid, Spain

Clinical Research: A critical appraisal

Eitan Amir MD PhD Princess Margaret Cancer Centre

20 June 2015

Overview

• Early breast cancer:

– Neoadjuvant endpoint selection – the utility of pCR

– Meta-analyses to identify efficacy and toxicity

• Metastatic breast cancer:

– Optimal endpoint selection

– Toxicity of new cancer drugs

– Statistical methods and bias –informative censoring

• Efficacy-effectiveness gap

Early Breast Cancer

0

20%

40%

60%

80%

100%

2 4 6 8 Year

P<0.001 cPR

cNR

pCR

2 4 6 8

cPR

cNR

pCR P<0.001

Wolmark N: CDC, 2000

Pathologic response predicts overall survival

pCR and prognosis

B-18 DFS by response B-18 OS by response

Figure 6 Trial-level correlation between treatment effect on pathological complete response and event-free survival or overall

survival Each circle corresponds to one randomised comparison and the size of the circle represents the sample size.

A=GeparQuat...

Patricia Cortazar , Lijun Zhang , Michael Untch , Keyur Mehta , Joseph P Costantino , Norman Wolmark , Hervé Bonn...

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis

The Lancet, Volume 384, Issue 9938, 2014, 164 - 172

http://dx.doi.org/10.1016/S0140-6736(13)62422-8

Treatment effect on pathologic complete response (pCR) versus (A) disease-

free survival (DFS) and (B) overall survival (OS).

Berruti A et al. JCO 2014;32:3883-3891

©2014 by American Society of Clinical Oncology

Winer EP, SABCS 2010

When would differences in pCR lead to improvement in long-term outcome?

Likelihood of distant relapse in patients with residual cancer burden (RCB) -0

(pathologic complete response), RCB-I, RCB-II, or RCB-III

Symmans W F et al. JCO 2007;25:4414-4422

Summary

• pCR should be used for hypothesis generation, not hypothesis testing.

• Should very seldom be the basis for drug registration except in exceptional situations:

– Large magnitude benefit in metastatic trials

– Require confirmation in adequately powered adjuvant trials with definitive endpoints.

Meta-analysis

• Method for pooling “similar” data from different sources.

• Primary advantage is to provide increased power and regression of results to the mean. – Valuable in the assessment of rare events (e.g. certain

toxicities)

– Can allow for more formal assessment of effect in subgroups which are underpowered in individual trials

• Main negative consequence is an increase in the alpha error (higher risk of false positive results).

Adjuvant Endocrine Therapy for Breast Cancer

Cardiovascular Events

ITA 1.22 [0.59-2.54]

ABCSG8/ARNO 1.51 [0.25-9.02] IES 1.15 [0.92-1.43]

N-SAS BC03 0.67 [0.11-4.03]

ATAC 1.24 [0.95-1.61]

Subtotal 1.15 [0.93-1.41]

BIG 1-98 1.43 [1.01-2.03]

Upfront AI versus tamoxifen

Subtotal 1.30 [1.06-1.61]

Subtotal 1.37 [1.05-1.79]

Switch versus tamoxifen

0.5 0.7 1 1.5 2

Study or Group OR [95% CI]

P for overall effect = 0.01

P for overall effect = 0.20

TEAM 1.37 [1.05-1.79]

P for overall effect = 0.02

Switch versus AI

TOTAL 1.26 [1.10-1.43] P for overall effect < 0.001

Increased with tamoxifen Increased with AI

Amir E et al. J Natl Cancer Instit 2011

0 5 10

Yrs

Breast Cancer Recurrence: All Women

Bone Recurrence

888 events

Nonbone Recurrence

18% Relative Reduction <1% Relative Reduction

Coleman R, et al. SABCS 2013. Abstract S4-07.

1947 events

50

40

30

20

10

0 0 5 10

Yrs

Bo

ne

Re

cu

rre

nc

e, %

17709 women

5.2%

4.0%

8.4%

10-yr gain 1.5% (SE: 0.6)

Log-rank 2P = .0009

17709 women

50

40

30

20

10

0

10.2%

10.0%

15.1%

10-yr gain 0.1% (SE: 0.8)

Log-rank 2P = .71

Dis

tan

t R

ec

urr

en

ce

Ou

tsid

e B

on

e, %

Bisphosphonates No Bisphosphonates

6.9%

15.0%

0 5 10

Yrs

Breast Cancer Recurrence:

Postmenopausal Women

508 events 1056 events

Coleman R, et al. SABCS 2013. Abstract S4-07.

11036 women 11036 women

34% Relative Reduction

10-yr gain 2.9% (SE: 0.8)

Log-rank 2P < .00001

8.8%

5.9% 5.1%

3.2%

8% Relative Reduction

9.2%

8.4%

14.3%

13.3%

10-yr gain 0.9% (SE: 1.0)

Log-rank 2P = .24

Bone Recurrence Nonbone Recurrence

Bisphosphonates No Bisphosphonates

50

40

30

20

10

0

50

40

30

20

10

0

Bo

ne R

ecu

rren

ce, %

Dis

tan

t R

ecu

rren

ce

Ou

tsid

e B

on

e, %

0 5 10

Yrs

General Assumptions in Clinical Trials

• Hypotheses tested usually address an overall or ‘average’ treatment effect in the study population.

• No assumption of homogeneity of effect across (unstratified) subgroups.

• Direction, not magnitude, of the treatment effect is expected be the same in subgroups.

Summary

• Meta-analysis can be an effective tool to determine effects among trials where there is insufficient power among individual studies.

• Results based on full datasets are more robust than pooling of data from subgroups.

– Results of pooled subgroup analyses have more validity if similar outcomes observed in other settings (metastatic vs. early-stage) and when a robust biological rationale is present.

Metastatic Breast Cancer

Endpoint Selection

• It is expensive and time consuming to conduct trials with overall survival as the primary endpoint

• Use of surrogate endpoints is reasonable if “surrogacy” has been established

• For surrogacy to be established: – There should be strong and consistent correlation

between the surrogate and definitive endpoints.

– A surrogate endpoint should also predict the net effect of treatment on the clinical outcome

Ann Intern Med. 1996;125(7):605-613. doi:10.7326/0003-4819-125-7-199610010-00011

Intra-tumoral heterogeneity

Treatment-related toxicity

Safety and Tolerability of New Cancer Drugs

• New anti-cancer drugs are associated with an increase in all safety and tolerability endpoints:

– Death (OR = 1.40; P < 0.001)

– Discontinuation (OR = 1.33; P < 0.001)

– Grade 3 & 4 AEs (OR = 1.52; P < 0.001)

Niraula S et al. J Clin Oncol 2012

Problems with BOLERO-2 Trial

• Everolimus is toxic:

– SAEs due to treatment: 11% vs. 1%

– Early discontinuation due to SAE or withdrawn consent: 24% vs. 6%

– Both worse than for many palliative chemotherapy regimens

• Analysis was biased by informative censoring leading to over-estimation of benefit of everolimus.

Arnoud J. Templeton , Olga Ace , Eitan Amir , Francisco Vera-Badillo , Alberto Ocana , Gregory R. Pond , Ian F. T...

Influence of censoring on conclusions of trials for women with metastatic breast cancer

European Journal of Cancer, 2015

http://dx.doi.org/10.1016/j.ejca.2014.12.016

Endpoints

• Overall survival need to remain a prominent endpoint in trials of metastatic breast cancer.

• Improvements in progression-free survival without clear improvement in overall survival especially if there is increased toxicity likely do not reflect benefit to patients.

• Care needs to be applied to the interpretation of trials analysed with informative censoring.

Efficacy-effectiveness gap

Definition

• Differences in outcomes between patients treated in ideal settings (i.e. RCTs) and those treated in the real world.

• Explained by multiple factors

– Patient characteristics likely explain some of the effect.

Treweek S et al. Eur J Cancer. 2015; 51(8): 907-14.

Solution?

• Validation of RCTs using well-designed observational studies is desirable to ensure patient safety and improved outcomes.

• Large scale population-based initiatives such as the American Society of Clinical Oncology CancerLinQ aims to provide a platform for real-world quality and comparative effectiveness analyses.