RECIST Overview

Introduction What is RECIST? RECIST Endpoints in Berenice Definitions Methods of Assessment Schedule of Assessments Evaluation of Tumour Response Minimum Source Data Requirements Summary

Response Evaluation Criteria In Solid Tumours What is RECIST? Response Evaluation Criteria In Solid Tumours A set of published rules that define when cancers improve (respond), stay the same (stable) or worsen (progress) during treatment Standardises solid tumor response evaluation => uniform reporting of clinical study outcomes Response Evaluation Criteria in SolidTumors (RECIST) Version 1.1 (Eisenhauer et al. 2009).

Berenice RECIST Efficacy Outcome Measures Clinical response, defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) prior to surgery. The clinical response rate is defined as the proportion of patients in the ITT population who achieve a CR or PR prior to surgery. Tumor response will be assessed prior to each new cycle of therapy by clinical examination and/or, mammography, and/or other methods of evaluation as per local practice. Response will be assessed by the investigator as per local practice based on the principles of Response Evaluation Criteria in SolidTumors (RECIST) Version 1.1 (Eisenhauer et al. 2009). The RECIST eCRF pages in Berenice are for collection of RECIST outcomes in the NEOADJUVANT period only

Definitions – Target Lesions Selected at baseline All measurable lesions Minimum of 1 maximum of 10 No more than 5 per organ Representative of all involved organs Selected based on size and suitability for accurate repeated measurements Unidimensional measurements (longest diameter) required for each target lesion at all assessed time points.

Definitions – Non Target Lesions Selected at baseline All other lesions that are not selected at baseline Excess measurable lesions ( e.g. when 10 have already been identified as target lesions) All non-measurable lesions Measurements are not required

Definitions – Non Measurable Lesions All other lesions including Small lesions < 20mm with conventional techniques of <10mmwith spiral CT Bone lesions Previously irradiated lesions Ascites, pleural effusions, cystic lesions etc.

Definitions – New Lesions Any lesion present on a follow up tumour assessment that was not present at baseline NTL = New Target Lesion

Methods of Assessment Target Lesions Non- Target Lesions and New Lesions Recommended CT (preferred) MRI Accepted Clinical Examination Chest X Ray Mammogram Ultrasound X Ray Endoscopy

Methods of Assessment Important to use the same imaging/examination methods to follow lesions Baseline method must be followed as much as is practical throughout the trial Bone scan, PET scan, angiography, tumor markers and cytology/histopathology are not acceptable methods as part of the RECIST framework

Schedule of Assessments Baseline Tumour Assessments Follow Up Assessments Unscheduled Tumor Assessments Clinical tumor assessment will be performed as per local medical practice based on the principles of RECIST version 1.1 criteria. During the adjuvant treatment period, patients should be assessed for recurrence at least every 3 months (Cycle 9, Cycle 13, Cycle 17, and Cycle 21), and at the study completion or early termination visit.

Evaluation of Response Complete Response (CR) All target lesions have disappeared completely (diameters =0) Partial Response (PR) Sum of the long diameters (LD) of the target lesions have shrunk by >/= 30% compared to the sum of long diameters at baseline Progressive Disease (PD) Sum of the LD for the target lesions have grown by >/= 20% compared to the smallest sum of the previously recorded LD Note: not necessarily baseline Stable Disease (SD) Neither sufficient shrinkage for PR or growth for PD i.e. conditions of PD, CR and PR are not satisfied Not Evaluable (NE) Any missing target lesion data As assessed by investigator

New Lesion Visit Response The presence or absence of new lesions must be recorded at each tumor assessment visit Detection of a new lesion = progressive disease (PD) If in doubt, confirm the presence before recording on eCRF

Overall Visit Response Combination of TL response, NTL response and presence, absence of new lesions RECIST overall response categories If patient has PD of TL, NTL or an appearance of a new lesion, the overall response will be a PD ( PD always overrides) If TL or NTL assesment is NE, then the overall assessment will also be NE unless there is clear evidence of progression e.g. a new lesion.

Confirmation of Response A responder is defined as a patient who has a confirmed CR or PR What do we mean by confirmed? Initial overall visit response of CR or PR Confirmation of response ( overall visit repsnise of CR or PR) at the next scheduled tumor assessment visit ( no less than 4 weeks later) Why do we confirm responses? to avoid overestimating the response rate observed.

Minimum Source Data Requirements Target Lesions and Non Target Lesions at baseline and follow up Site and location Date of assessment and method used Any lesion interventions (e.g. irradiation/surgery) Longest diameter measurements ( target lesions only) Reasons for any missing or non evlauable assessments Reasons for any inconsistencies between radiology report and patient notes Details of any new lesions ( site, location, date of assessment and method used) Overall assessment of non target lesion response (RECIST response as calculated by investigator) Investigator’s opinion of response

Summary RECIST is used to standardise tumour response evaluation Baseline documentation of tumour burden in terms of Target and Non – Target Lesions Target lesions are selected on the basis of their size and suitability for accurate repeated measurements Tumour assessments must be performed in accordance with visit schedule to avoid bias All patients must be followed for progression even if Discontinued randomised treatments Started another anticancer treatment

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