Considerations for Neoadjuvant

Breast Cancer Trials

to Support Accelerated Approval
Tatiana M. Prowell, M.D.

Outline of Presentation
Accelerated Approval (AA) Regulation
Goals of neoadjuvant pathway to AA
Neoadjuvant trial design considerations

Appropriate patient populations

Endpoints
Randomization and blinding
Prespecified standard therapy
Issue of residual disease

Development approach: single vs. multiple trials

Conclusions and Discussion
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Accelerated Approval Regulations

FDA may grant marketing approval for a new
drug [or biological] product on the basis of
adequate and well-controlled clinical trials
establishing that the drug product has an effect
on a surrogate endpoint that is reasonably
likelyto predict clinical benefit... (21 CFR
314.510 and 21 CFR 601.41)
Require confirmation of clinical benefit (EFS/DFS or
OS) and include provision for withdrawal of indication
if fail to confirm clinical benefit
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The Slow Road From Drug Discovery

to FDA Approval
The example of trastuzumab development and approval:

1979: HER2 oncogene first described

1984: HER2 protein first discovered
1990: First animal studies of trastuzumab
1992: Phase I trial launched
1995: Randomized phase 3 MBC trial launched
May 1998: BLA filed for use in MBC
Sept 1998: FDA approval in MBC
March 2000: First adjuvant randomized phase 3 trial launched
Nov 2006: FDA approval in adjuvant setting

From phase 1 launch to approval in early-breast cancer:

14 YEARSand this is fairly typical
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What Is Clear
Current path to approval in early-stage disease
takes too long, especially for high-risk patients
with potential for cure.
We need to ensure widespread access to highly
effective drugs as quickly as we responsibly can.
Balancing needs of current and future patients

We need to incentivize study of pathways and

development of drugs for subtypes of breast
cancer patients with unmet need.
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Neoadjuvant Pathway to
Accelerated Approval
Goal: to market highly effective drugs sooner
Not a lesser standard or easy route to market for
marginal drugs
Target patients at high risk for recurrence and death
Utilize superiority designs
Design trials to detect a large improvement in pCR
Choose drugs with high likelihood of meaningfully
improving long-term outcomes

Concerns about Neoadjuvant

Pathway to Accelerated Approval
Delay between initial approval & confirmation of (or
failure to confirm) clinical benefit
Limited data on cumulative toxicity (e.g., neuropathy)
and rare/late toxicity (e.g., CHF, secondary malignancy)
Uncertainty about magnitude of improvement in pCR
needed to improve EFS/OS
May vary by breast cancer subtype
Some patients with pCR will relapse and many with residual
disease will not

Potential negative impacts on drug development

Assessing risks of drug studied first in early-stage breast cancer
Diminished drug development in advanced breast cancer
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Neoadjuvant Drug Approval Pathway

for New Drugs

Potential Neoadjuvant Drug Approval Pathways

Drugs with prior
approvals in breast
cancer or other cancer

Breakthrough
therapies

Drugs with ongoing

adjuvant breast cancer
trials

Neoadjuvant Approval

Patient Populations
Populations at high-risk of recurrence and death despite
best, modern systemic therapy
May be defined conventionally (stage, grade, receptor status,
etc.) or via validated genomic measures
Focus on triple negative (ER,PR,HER2-) and HER2+ pts
High risk population
Highest likelihood of pCR
Most compelling data that pCR predicts clinical outcome
Not appropriate for low-grade hormone receptor-positive
Less likely to attain pCR
More likely to have long-term survival with available therapy
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Randomization and Blinding

Should be RCTs
Add-on design
Ensures all patients receive standard therapy
Permits isolation of drug effect

Pathologists interpreting pCR should be blinded

Patients and investigators should be blinded
unless toxicity precludes

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Endpoints
Accelerated approval endpoint
pCR
Either ypT0 ypN0 or ypT0/Tis ypN0 acceptable to FDA
No invasive cancer in breast/nodes
DCIS may be allowed or not, but be consistent within trial

Regular approval endpoints

EFS/DFS or OS
Use EFS for neoadjuvant trial and DFS for adjuvant trial
Assess from date of randomization
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Standardization Of Therapy
Surgical approach to the axilla
Primary endpoint includes axillary nodal pathology

Criteria for and delivery of radiotherapy

Potential to impact EFS/OS

Standard of care systemic therapy

(e.g. trastuzumab x 1 yr total for HER2+, endocrine
therapy for HR+) specified in protocol for all patients

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Issue of Postop Residual Disease

No compelling data that additional chemo
improves outcome
Pre-specify any postop chemo and deliver to
all patients in both arms
An important topic for study in future
randomized trials

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Number of trials
Single Trial Model:
One large RCT to assess pCR & EFS/OS

Multi-Trial Model:
Accelerated approval based on smaller
RCT(s) demonstrating large absolute
improvement in pCR rate
Conversion to regular approval based on
large RCT(s) with DFS/EFS/OS as primary
endpoint
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Approval Timeline
Single Trial Model
pCR

Accelerated
Approval

EFS/OS

Regular
Approval

Multiple Trial Model

pCR

Accelerated
Approval

DFS/EFS/OS

Regular
Approval
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Single Trial Vs. Multi-Trial Model

Approach will vary based upon:
Extent of prior clinical data with the drug
Knowledge of efficacy/safety of drug class
Existing approvals for breast cancer, other
malignancies, or non-oncologic indications
Status of existing development in early-stage breast
cancer
Planned/ongoing adjuvant trial(s)
Fully accrued adjuvant trial(s)
Existing adjuvant indication (e.g., investigating a new
chemotherapy backbone)
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Single Trial
Requisites for a single trial
Powered to detect a clinically and statistically significant
improvement in EFS and/or OS
All patients should be accrued before pCR analysis
(except for futility)
Use ITT population for both pCR and EFS/OS analyses
Interim analyses acceptable for EFS/OS, but not pCR
Control type I error for pCR and EFS/OS
Should allocate a larger portion of alpha to EFS/OS and a
smaller portion to pCR endpoint

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Single Trial Model: Advantages

Efficacy
Ensures confirmatory trial will complete accrual
Confirmatory trial done in same population, including US patients
Clinical benefit data available sooner faster conversion to
regular approval or withdrawal of breast cancer indication
Improved estimate of effect size at time of accelerated approval
May help to validate pCR as an endpoint

Safety
Large body of data on safety compared to standard therapy
Early-stage population prevents confounding from disease
Rare AEs more likely to be identified at time of initial approval

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Single Trial Model: Disadvantages

Risk of exposing a large number of patients to treatment
that is more toxic and/or less effective
Longer wait to initial US approval compared to AA based
on smaller neoadjuvant RCT
Lack of data on use in adjuvant setting with implications
for drug labeling

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Multi-Trial Model
More appropriate for drugs with:
Extensive breast cancer efficacy/safety data
Evidence of unprecedented efficacy
A randomized adjuvant trial well underway
Early and frequent contact with the FDA is
strongly recommended.

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Multi-Trial Model: Advantages

Results of neoadjuvant trial may inform design of the
confirmatory trial
Provides greater assurance that results not due to
chance alone
Permits broad access to highly-effective drugs earlier
Provides data in adjuvant setting from a confirmatory trial
May provide opportunity to assess new drug combined
with or compared to other standard therapy in
confirmatory trial

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Multi-Trial Model: Disadvantages

A separate confirmatory trial may be hard to complete
successfully.
Accrual to adjuvant trial in US once drug is available after
accelerated approval
Implications of conducting confirmatory trial outside the US

Some challenges may be addressed by an international

adjuvant trial well underway at time of accelerated
approval, but
Will crossover be an issue?
Will patient dropout be an issue?

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Conclusions
Substantial improvement in pCR rate will be required to
maximize likelihood of clinical benefit
Risk/benefit ratio will be central to regulatory decisionmaking
Must balance risk of approval based upon unvalidated
surrogate vs. delay in access to a highly effective,
practice-changing drug in a high-risk population

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Panel Discussion

Discuss advantages/disadvantages of a single-trial versus a multitrial approach. Is one approach preferable to the other and why?
How can we address the feasibility issues of conducting an adjuvant
randomized trial once a drug is approved for a neoadjuvant
indication?
Are there other clinical trial strategies that should be considered?
How do we avoid negatively impacting drug development in
metastatic breast cancer?

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