# Presentation: 822507

## Clinical Trial Designs for First-line Hormonal Treatment of Metastatic Breast Cancer

- Susan Honig, M.D.
- Patricia Cortazar, M.D.
- Rajeshwari Sridhara, Ph.D.

## Acknowledgements

- John Johnson
- Alison Martin
- Grant Williams
- Julie Beitz
- Richard Pazdur

- Gang Chen
- George Chi
- Ning Li
- Dianne Spillman
- Ann Staten

## Purpose

- To discuss the rationale and basis for past approvals of hormonal therapy for metastatic breast cancer
- To solicit input from the Committee in order to improve and standardize our approach

## Hormone Drug Approval: Historical Perspective

- Should be distinguished from cytotoxic drug therapy
- Toxicity
- Basis for approval of hormonal agents derived from NDAs for megestrol acetate, tamoxifen

## Megestrol acetate (Megace)

- Approved 7/76 for “the palliative treatment of advanced carcinoma of the breast...”
- Basis of approval
- Response rate (RR) in Phase II studies
- Database of 116 patients
- No information available about time to progression (TTP), survival (OS)
- Historical controls

## Tamoxifen

- Approved 12/77; many supplements
- Basis of approval:
- RR in 14 Phase II studies
- RR in literature reports from 9 other studies
- Database 1164 patients
- No information available about TTP, OS
- Historical controls for the initial approval

## Recent Approval Requirements for Hormonal Drugs

- Randomized clinical trials required
- Response rate adequate endpoint
- Surrogate endpoint acceptable for treatments with modest toxicity
- Response is attributed to drug effect, as cancer rarely shrinks without treatment
- Used as FDA’s primary endpoint for traditional approval, not subpart H

## Approval Requirements for Hormonal Drugs

- Survival not required
- Lack of a demonstrated survival advantage for the control compared to no therapy
- Non-inferiority for survival is a safety, not efficacy, endpoint
- TTP submitted, but not used as the sole basis of approval

## Historical Standards for Approval

- Non-inferiority based on response rate
- Lower limit of the 2-sided 95% CI for the difference in response between Drug A and Drug B should be _< _10%
- “Similarity” for TTP, OS
- Total database of about 1000 patients

## Historical Standards for Approval

- Comparator frequently tamoxifen (RR 20%)
- Difference in response rate interpreted as
- Ruling out inferiority by an absolute difference of 10%			OR
- Ruling out a loss of half of tamoxifen’s effect

## Recent Approvals

- Will be summarized by Dr. Cortazar

## 	Hormonal Treatment of 		Metastatic Breast Cancer

- Approval Overview

## Hormonal Drugs Approved in 2nd line Metastatic Breast Cancer

- Comparator: Megestrol acetate
- 1° Endpoints: Response rate, TTP
- Approvals:  	Anastrozole
- 				Letrozole
- 				Exemestane

## Hormonal Drugs Approved in 1st line Metastatic Breast Cancer

- Tamoxifen
- Toremifene
- Anastrozole
- Letrozole

## Toremifene: Fareston®  1st line Metastatic Breast Cancer 

- Approved: October 1995
- Trials: 3 randomized Phase 3
- Comparator: Tamoxifen
- Sample size: 1526 patients in all trials
- 1° Endpoints: Response rate, TTP
- Designed to show non-inferiority in RR

## Non-inferiority Trial Design

- 	Protocol definition for non-inferiority was in terms of the lower bounds of the 95% C.I. for RR and TTP:
- Difference in RR (Tor – Tam) was not more than 10% worse than tam.
- TTP lower limit at least 0.80.

## Toremifene 1st line MBC Efficacy Results

## Statistical Issues

- Nordic Trial did not meet the protocol definition of non-inferiority (L.C.I. more than 10%)
- Nordic Trial had significantly worse TTP with TOR
- Lack of explanation for deviance in results
- Approved because of non-inferiority in RR and TTP in 2 of 3 trials

## Anastrozole: Arimidex® 1st line Metastatic Breast Cancer 

- Approved: September, 2000
- Trials: 2 randomized Phase 3
- Comparator: Tamoxifen
- Sample size: 1021 patients in all trials
- 1° Endpoints: Response rate, TTP
- Designed to show non-inferiority

## Non-inferiority Trial Design

- 	Non-inferiority was defined in terms of the lower bounds of the 95% C.I. for RR and TTP:
- Margin for RR was 10% (difference in RR A – Tam more than – 10%).
- Margin for TTP was 20% (HR Tam:A should be more than 0.80).

## Anastrozole 1st line MBC Efficacy Results

## Letrozole: Femara® 1st line Metastatic Breast Cancer 

- Approved: December, 2000
- Trial: 1 randomized Phase 3
- Comparator: Tamoxifen
- Sample size: 916 patients
- 1° Endpoint:  TTP
- Designed to show superiority

## Letrozole 1st line MBC Efficacy Results

## Recent Approvals

- Anastrozole
- RR: Non-inferior to tamoxifen
- TTP:
- Superior in study 030 [N  350; 88% ER(+)]
- Non-inferior in study 027 [45% ER(+)]
- Letrozole the first to demonstrate superiority with statistical significance for RR and TTP
- N=916; 66% ER(+)
- No direct comparison of these agents
- Potential class effect?

## Issues to consider: TTP

- Should TTP be the new primary endpoint for breast cancer?
- Pros
- Is TTP intrinsically more meaningful than RR?
- Cons
- Neither of the aromatase inhibitors may be acceptable for non-inferiority comparison. Neither has reproducibly demonstrated a TTP advantage.
- No data available for TTP for other comparators
- Sample size needed for a TTP non-inferiority analysis may be very large

## Issues to consider: TTP

- Required information for TTP non-inferiority analysis
- How to estimate treatment effect of comparator from historical data
- Point estimate of the hazard ratio?
- 95% CI?
- More conservative or more liberal boundary?
- What fraction of the effect should be retained?

## Issues to consider: Response Rate

- Is response rate still an acceptable primary end point?
- Does RR sufficiently identify efficacy in this setting?

## Issues to consider: Response Rate

- Is non-inferiority to tamoxifen (or other approved first-line agent) still an acceptable basis for approval?
- Pro: FDA has no comparative efficacy standard in most cases
- Con: Letrozole’s RR > tamoxifen’s RR

## Issues to consider: Response Rate

- Alternatively, is superiority to tamoxifen required?
- By superiority in a direct comparison to tamoxifen		OR
- By non-inferiority comparison to letrozole

## Issues to consider: Response Rate

- Required information for RR non-inferiority analysis, letrozole as comparator
- Treatment effect size (RR 30% for letrozole)
- What fraction of the effect should be retained?
- Rule out 10% absolute difference in RR
- Rule out RR < 20%
- Retain 50% of the letrozole RR
- Rule out RR < 15%
- Retain some fraction of the letrozole advantage over tamoxifen
- Letrozole RR - tamoxifen RR = 10%
- Retain 50% or 75% of this difference
- Rule out RR < 25%

## Additional Concerns: Choice of endpoint

- Response rate
- Must exclude patients with bone-only disease
- TTP
- ODAC discussed difficulties in assessing TTP 6/99
- Strengthened by blinded trials

## Additional Concerns: Choice of endpoint

- Response rate
- Must exclude patients with bone-only disease
- TTP
- ODAC discussed difficulties in assessing TTP 6/99
- Strengthened by blinded trials

## Additional concerns: Non-inferiority trial designs

- “Sloppiness obscures differences”
- Robert Temple, M.D.

## Additional concerns: Non-inferiority trial designs

- Independent substantiation of results particularly important for non-inferiority
- Special attention to study conduct important
- Inclusion of patients with ER unknown status contributes to lack of observed difference
- Inclusion of patients with bone-predominant disease makes response assessment difficult
- Must adapt inclusion criteria as potential predictive factors are validated (her2-neu?)

## Additional concerns:Future applications

- Ongoing trials of new hormonal agents
- Possibility that OS with letrozole will be greater than OS with tamoxifen

## Statistical Considerations in Clinical Trial Designs for First-line Hormonal Treatment of Metastatic Breast Cancer

## Outline

- Active Control
- Terminology
- Assumptions
- Non-inferiority Designs
- Sample Sizes (power = 0.8, one-sided  = 0.025)
- Perspective Issues
- Issues for Discussion

## Active Control versus Drug “X”

- Tamoxifen (T)
- Letrozole (L)

## Terminology

- Superiority
-     = Drug ‘X’ better than Active Control
- “Non-inferiority”
-      = ‘X’ not much less effective than 			 Active Control
-       ‘Was Not Different’ or ‘Similar’

## Assumptions

- ‘L’ has an effect (compared to placebo)
- Can reliably estimate ‘L’ effect size
-        * ‘L’ effect size compared to ‘Placebo’
-        * ‘L’ effect size compared to ‘T’
-        * or ‘T’ effect size compared to ‘Placebo’
- Control (‘L’) effect in the future study population will be same as in the historical population.

## Non-inferiority Trial Design Considerations

- Endpoint - Response Rate
-                    - Time to Progression
- Control Effect
-  % Retention

## Estimates of True Control Effect

- Lower 95% C.L.
- ( << 0.025)

- Lower  % C.L.
- ( = 0.025)

- Point Estimate
- ( >> 0.025)

## Endpoint: Response Rate

## Endpoint - Response Rate Sample Sizes - Point Estimate of Letrozole Effect Relative to Placebo

## Endpoint - Response RateSample Sizes - Point Estimate of Letrozole Effect Relative to Tamoxifen

## Endpoint - Response Rate Sample Sizes -  Lower 95% C.L. of Letrozole Effect Relative to Placebo 

**Fixed Margin Approach of  ******** 10%, N = 660**

## Endpoint: Time to Progression

## Endpoint - Time to Progression Sample Sizes - Point Estimate of Active Control Effect Relative to Tamoxifen

## Endpoint - Time to Progression Sample Sizes - Lower 95% C.L. of Active Control Effect Relative to Tamoxifen

**Letrozole**

**Anastrozole**

## Endpoint - Time to Progression Sample Sizes -  % Lower C.L. of Active Control Effect Relative to Tamoxifen, & preserving  = 0.025 

**Letrozole**

**Anastrozole**

## Summary: Endpoint Response Rate, 50% of Active Control Effect Retained

## Summary: Endpoint Time-to-Progression, 50% of Active Control Effect Relative to Tamoxifen Retained

## Sample Size For Superiority Trial With Tamoxifen As The Comparator

- Assuming: _**Response Rate as the Endpoint**_,
- Tamoxifen Response Rate = 20%,
- Drug ‘X’ Response Rate = 30%,
- Total Sample Size = _**586 patients**_ (power = 0.8,  = 0.025)
- Assuming: _**Time to Progression as the Endpoint**_,
- Median TTP for Tamoxifen = 6.0 months,
- Median TTP for Drug ‘X’ = 9.4 months,
- Total Sample Size = _**200 events**_ (power = 0.8,  = 0.025)

## Perspective Issues

- Effect size of Letrozole estimated from _**One**_, large, well conducted, randomized study
-  Convincing evidence of Superiority
-  Is the effect size over estimated?
-  Effect size w.r.t. TTP is L *vs*. T and not L *vs*. Placebo
- No estimated effect size of Tamoxifen w.r.t TTP
- If Non-inferiority trials - Replication mandatory
- If Non-inferiority trials - more patients
- If Non-inferiority trials and TTP endpoint - more patients

## Issues for Discussion

- Superiority (compared to Tamoxifen or Letrozole)
*   **versus *
-     Non-inferiority (compared to Letrozole)
- % of Letrozole effect to be retained
- Endpoint: Response Rate *versus* Time to Progression; Survival ??
- Given the sample sizes, is it feasible to conduct a non-inferiority study?

## Summary: Comparators

- Tamoxifen frequently used
- Is letrozole superior?
- Are all aromatase inhibitors superior?
- Anastrozole superior to tam in study 030, 1st-line
- No direct comparison of different aromatase inhibitors

## Summary: Endpoints

- Traditionally, RR
- A change to TTP will require
- Non-inferiority to letrozole or superiority to tamoxifen, because of available dataset
- Larger sample size

## Questions to the Committee

## Slide 59