Comparison of RECIST 1.0 and 1.1 - Impact on Data Management

Kevin Shea Senior Solutions Architect C3i, Inc.

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Objectives

•  Describe RECIST •  Independent imaging review •  Manage external imaging data

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Agenda

•  Background •  RECIST

– Overview – Parameters – RECIST V 1.0 vs. 1.1

•  Independent Review •  Data Management Considerations •  Conclusions

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Background

•  Oncology clinical trials utilize imaging assessment as surrogate endpoint

•  Imaging involves variations in modality, techniques, and reader assessment, training

•  Standardization – variability, repeatability •  RECIST – well-adopted standard •  Data Management processes can be used to

monitor assessment data to track quality and safety

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RECIST Overview

•  Response Evaluation Criteria In Solid Tumors •  Establish referenceable, repeatable standards •  Based on WHO criteria (1981) •  Established 2000 (v.1.0), Updated 2009 (v.1.1) •  PII focus, PIII applicability •  Endpoints – ORR, PFS •  Well-adopted in ICLs •  Challenges at AROs and local imaging sites

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RECIST Parameters

•  Serial review – baseline to completion •  Quantify tumor burden •  Qualitative assessment of remaining lesions •  Lesion classification •  Consistent assessment categories •  Associate changes with efficacy

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Evaluation Process

•  Baseline – key to establish as comparator of subsequent timepoints –  Target – Sum of Longest Diameters –  Non-Target – document all other disease

•  Post-Baseline –  Target

•  Sum Diameters •  Compare to BSL/Prev TPs, Establish nadir

–  Non-Target – evaluate for substantial change –  New – Review for presence

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RECIST Lesion Classifications

•  Target – representative of disease, able to reproducibly measure and track over time

•  Non-target – all other lesions or sites of disease, tracked qualitatively

•  New – post-baseline presence of new disease

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RECIST Response Criteria

•  CR – Complete Response –  Disappearance of all target lesions

•  PR – Partial Response –  30% reduction in SLD

•  SD – Stable Disease –  Neither response or progression

•  PD – Progressive Disease –  20% increase in SLD –  Presence of new lesion

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RECIST End Points

•  Response – Timepoint response – Best overall response – Confirmation – 4-6 weeks (maybe required)

•  Progression – Target SLD > 20% of nadir – Non-target – unequivocal progression – Date of progression

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RECIST V 1.0 and 1.1

•  Uni-dimensional measurement •  Tumor burden based on sum of diameters •  Lesion classification scheme •  Response categories

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Consistencies

RECIST V 1.0 and 1.1 Differences

V 1.0 (2000)

•  Max 10 Target / Max 5 per organ

•  ≥ 10 mm LD (spiral CT) ≥ 20 mm LD (other)

•  Lymph Nodes not specified

V 1.1 (2009)

•  Max 5 Target / Max 2 per organ

•  ≥ 10 mm LD or 2x slice (extranodal)

≥15 mm SAD (nodal)

•  Lymph Nodes >10 mm pathological

≥ 15 mm measureable

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RECIST V 1.0 and 1.1 Differences

V 1.0 (2000)

•  CR – disappearance all lesions

•  Targ-PD – SLD ≥ 20% of nadir

NTarg-PD – unequivocal progression

•  New – not specifically

defined

V 1.1 (2009)

•  CR – disappearance all extranodal lesions, nodal < 10 mm

•  Targ-PD – SoD ≥ 20% and ≥ 5 mm from nadir

NTarg-PD – unequivocal progression w/substantial worsening

•  New – unequivocal, not based on imaging tech.

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Central Review of Images

•  Focus on consistency, repeatability •  Limited reader pool •  Training and review of cases •  BICR - typical process: dual reader w/

adjudication – Two primary readers – Adjudication for discordance on end points

•  Various quality processes incorporated

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BICR Process

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Site and Central Review

Imaging Site •  Clinical focus •  Do not generally utilize

RECIST •  Not blinded •  Access to all clinical data •  Limited protocol training

Central Review •  Focus on imaging •  RECIST w/ limited pool of

readers •  Blinded •  Limited access to clinical

data •  Image Review Charter

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Data Management Considerations

•  RECIST version challenges •  Site vs. Central Review data •  Central Review

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RECIST Version Challenges

•  Impact of migrating to v. 1.1 or maintaining v.1.0 and v. 1.1 studies

•  Target lesions –  Total number –  Number per organ

•  Lymph nodes •  Sum of Diameters •  Non-target progression •  New Lesions

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RECIST Version Impact

•  CRF Design •  Derivation procedures •  Edit checks •  Data quality reviews •  Emphasis on training and quality control •  Focus on non-target progression and new

lesions

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Site vs. Central Review

•  Comparison of endpoint results •  Concordance noted in previous studies •  Not based on consistent techniques •  Intra-study comparisons should be established

early

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Site vs. Central Review (2)

•  Develop processes to analyze: –  Previous study data –  Consistency of sites with central

•  Distinguish trends •  Establish “normal discordance” rate

–  Identify outlier sites •  Outlier sites can be reviewed further

–  Re-training –  Imaging technique

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Central Review Data

•  Win-Loss Adjudication Rates •  Intra-Reader Variability •  Inter-Reader Variability •  Monitor BICR discordance and adjudication •  Analyze variability

–  Tumor type –  Intervention

•  Evaluate quality between RECIST 1.0 and 1.1 studies

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Central Review Data (2)

•  Establish normal levels of variability and discordance for v. 1.0 and v. 1.1

•  Analyze for variables •  Assess for suitability in future studies •  Establish parameters for site and central

review data in future studies

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Conclusions

•  RECIST 1.1 – attempt to improve and simplify •  Comparisons between 1.0 and 1.1 data should be closely

monitored •  Follow-on studies may remain at v. 1.1 •  Fewer target lesions dictates attention to discordance and

variability •  Non-target progression and new lesions should be reviewed

for adherence to standard •  Incorporation of PET for confirmation should be considered •  Protocol-specific requirements may drive DM process and

QA controls

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Acknowledgements

I’d like to thank the following people for their help in preparing this presentation

•  Robert Ford •  Eric Perlman •  Tomomi Dyer

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