508-Prowell-Final Slides323543523462453452345234523452345

7/21/2019 508-Prowell-Final Slides323543523462453452345234523452345

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Considerations for NeoadjuvantBreast Cancer Trials

to Support Accelerated Approval

Tatiana M. Prowell, M.D.

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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 ofadequate and well-controlled clinical trials

establishing that the drug product has an effect

on a surrogate endpoint that is reasonablylikelyto predict clinical benefit... (21 CFR

314.510 and 21 CFR 601.41)

Require confirmation of clinical benefit (EFS/DFS orOS) 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 patientswith 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 ApprovalGoal: to market highly effective drugs sooner

Not a lesser standard or easy route to market formarginal 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

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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 pCRneeded 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 cancer7


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Neoadjuvant Drug Approval Pathway

for New Drugs

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Potential Neoadjuvant Drug Approval Pathways

Neoadjuvant Approval

Drugs with prior

approvals in breastcancer or other cancer

Drugs with ongoing

adjuvant breast cancertrials

Breakthrough

therapies

? ? ?

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Patient Populations

Populations at high-risk of recurrence and death despitebest, 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+, endocrinetherapy for HR+) specified in protocol for all patients

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Issue of Postop Residual Disease

No compelling data that additional chemoimproves 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 smallerRCT(s) demonstrating large absolute

improvement in pCR rate

Conversion to regular approval based onlarge RCT(s) with DFS/EFS/OS as primary

endpoint

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Approval Timeline

Accelerated

Approval

AcceleratedApproval

Regular

Approval

Regular

Approval

Single Trial Model

Multiple Trial Model

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pCR EFS/OS

pCR

DFS/EFS/OS


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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 significantimprovement 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 treatmentthat 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 inconfirmatory trial

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Multi-Trial Model: Disadvantages

A separate confirmatory trial may be hard to completesuccessfully.

Accrual to adjuvant trial in US once drug is available afteraccelerated approval

Implications of conducting confirmatory trial outside the US

Some challenges may be addressed by an internationaladjuvant trial well underway at time of acceleratedapproval, 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 decision-

making

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 multi-

trial approach. Is one approach preferable to the other and why?

How can we address the feasibility issues of conducting an adjuvantrandomized 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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