Clinical Performance Study Plan for Ki-67 IHC MIB-1 pharmDx (Dako Omnis) on Early Breast Cancer Specimens used to identify subjects for enrolment in AstraZeneca*s Phase III CAMBRIA-1 trial (D8531C00002)

Ki-67 IHC MIB-1 pharmDx (Dako Omnis) is a qualitative immunohistochemical (IHC)
assay using Monoclonal Mouse Anti-Ki-67, Clone MIB-1 intended for use in the
detection of Ki-67 protein in formalin-fixed, paraffin-embedded (FFPE) breast
carcinoma using the EnVision FLEX visualization system on Dako Omnis.
Ki-67 IHC MIB-1 pharmDx (Dako Omnis) will be used as an aid in identifying
patients with early-stage breast cancer at intermediate or high risk of disease
recurrence for recruitment into the CAMBRIA-1 study.
Ki-67 IHC MIB-1 pharmDx (Dako Omnis) is designed to be run on the Dako Omnis
automated staining system (Dako Omnis) with Dako Omnis Software and the Dako
Link Omnis Workstation and Server software. Instruments and software are not
specific to the Ki-67 assay and will not be evaluated as part of the clinical
performance study.

This clinical performance study will evaluate the effectiveness of the Ki 67
IHC MIB-1 pharmDx (Dako Omnis) to identify estrogen receptor (ER)+/human
epidermal growth factor receptor 2 (HER2)- early breast cancer patients whose
tumours score Ki-67 >= 20%, using archival FFPE tumour tissue.
The objective of this study is to support the AstraZeneca CAMBRIA-1 clinical
trial (D8531C00002) by testing for Ki-67 expression in FFPE tumour specimens
from patients with ER+/HER2- early breast cancer in order to identify patients
with an intermediate or high risk of recurrence following standard of care
therapy.
This clinical performance study is intended to obtain clinical evidence for use
of this device as a (potential) companion diagnostic (CDx) to assess Ki-67
expression as one of the components to classify patients with ER+/HER2- early
breast cancer in order to identify patients with an intermediate or high risk
of recurrence that are eligible for treatment with camizestrant.

This interventional clinical performance study conducted as part of the
CAMBRIA-1 clinical study protocol (CSP), D8531C00002, therefore represents a
combined study, in which the diagnostic will be used for the selection of
specific patients (Section 15). CAMBRIA-1 is a prospective, 2-arm,
international, multicentre, randomised, open-label, Phase III study to evaluate
the effect of extended therapy with camizestrant with or without luteinising
hormone-releasing hormone (LHRH) agonist(s) compared to standard ET.
Approximately 5375 patients will be screened to randomise approximately 4300
patients with ER+/HER2- early breast cancer with intermediate or high risk of
recurrence, who have completed definitive locoregional therapy and at least 2
years and up to 5 years (+3 months) of standard adjuvant ET with or without a
CDK4/6 inhibitor, with no disease recurrence, in a 1:1 ratio to one of the
following arms: • Arm A: Continue the standard ET of investigator*s choice
(aromatase inhibitors [exemestane, letrozole, anastrozole] or tamoxifen,
standard dose per investigator, once daily) with or without LHRH agonist(s) •
Arm B: Camizestrant (150 mg, once daily) with or without LHRH agonist(s) •
Among other criteria defined in Section 5.1 of the CAMBRIA 1 CSP (D8531C00002),
patient eligibility will be determined based on tumour size, lymph node status,
grade of tumour, genomic signature assessment, Ki-67 testing, and use of prior
chemotherapy. Eligible patients will be pre-, peri-, or post-menopausal women,
or men, with at least one of the following: (a) T4 tumours (tumour of any size
with direct extension to the chest wall and/or the skin - ulceration or
macroscopic nodules), regardless of nodal status. (b) Pathological primary
invasive tumour size >5 cm regardless of nodal status. For patients who
received neoadjuvant systemic therapy (chemotherapy and/or ET), primary tumour
size >5 cm on breast imaging is allowed. (c) Pathological tumour of any size
with involvement in >=2 ipsilateral lymph nodes. Note: for patients who have
suspected involvement of locoregional lymph nodes, confirmation of nodal
disease by pathology, cytology, immunohistochemistry, and/or one-step nucleic
acid amplification is required. Patients with lymph nodes assessed by imaging
only are not eligible. For this study, locoregional lymph nodes include
ipsilateral lymph nodes (axillary, infraclavicular, supraclavicular, and
internal mammary), but exclude intramammary lymph nodes. Patients with
involvement of contralateral lymph nodes are not allowed. (d) Pathological
primary invasive tumour size >1 cm and <=5 cm with involvement of 1 positive
lymph node (or only micrometastatic disease) if at least one of the following
features is present: (i) Pathological grade 3 (ii) Pre-existing high risk of
recurrence per genomic signature assessment from medical record if in
compliance with local regulations and conducted in accordance with intended use
(see CAMBRIA-I CSP [D8531C00002] Section 4.1) (iii) Centrally assessed Ki-67
>20% via an AstraZeneca-provided laboratory test using archival sample where
country-specific IVD approvals are available, as required. (e) Pathological
primary invasive tumour size >1 cm and <=5 cm without involvement of any
ipsilateral lymph nodes if at least one of the following features is present:
(i) Pathological grade 3 (ii) Pre-existing high risk of recurrence per genomic
signature assessment from medical record if in compliance with local
regulations and conducted in accordance with intended use (see CAMBRIA-I CSP
[D8531C00002] Section 4.1) (iii) Centrally assessed Ki-67 >20% via an
AstraZeneca-provided laboratory test using archival sample where
country-specific IVD approvals are available, as required. (iv) Prior cytotoxic
chemotherapy for the current diagnosis of breast cancer. All patients,
regardless of qualifying criteria, will provide archival tissue for central
testing with Ki-67 IHC MIB-1 pharmDx (Dako Omnis).

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