Clinical Performance Study Protocol for Use of VENTANA PD-L1 (SP263)
CDx Assay in [redacted]

RD006691 study is a multicenter interventional clinical performance study with an In-vitro Diagnostic Device (IVD) , more specifically a Companion Diagnostic Device (CDx), not using only leftover samples. The IVD will be used 
to support patient screening for a pharmaceutical clinical trial that is running in parallel sponsored by pharma partner [redacted]). The performance study falls under IVDR article 58(2) sentence 1 and therefore falls under the same requirements as IVDR article 58(1a,b). Fresh biopsy samples will be used for this performance study.
The IVD *VENTANA PD-L1 (SP263) CDx Assay* (Class C IVD) is a qualitative immunohistochemical assay that determines the expression levels of programmed death ligand 1 (PD-L1) protein; it is indicated as an aid in identifying patients with non-small cell lung cancer (NSCLC) who may benefit from treatment with PD-L1 targeted therapy in combination regimens ([redacted]), under the above-referred pharmaceutical trial. The device bears the CE mark. 

Tumor specimens from approximately [redacted] patients undergoing screening under the pharmaceutical trial will be stained with *VENTANA PD-L1 (SP263) CDx Assay* at diagnostic (Dx) testing sites. Stained slides from each case will be interpreted by a qualified pathologist who will assign a PD-L1 IHC expression level at the [redacted]. Efficacy results from the pharmaceutical study will be used to evaluate the clinical performance of *VENTANA PD-L1 (SP263) CDx Assay* as a CDx device to identify patients with locally advanced, unresectable or metastatic NSCLC who may benefit from first line treatment with [redacted].

The objective of this study is to establish the clinical performance of VENTANA PD-L1 (SP263) CDx Assay as a companion diagnostic (CDx) for the identification of patients with NSCLC who may benefit from treatment with 
[redacted]. 
This clinical performance study protocol is being conducted in support of the [redacted] Study to determine the PD-L1 expression level of tumor specimens submitted for [redacted] Study enrollment screening. PD-L1 
expression level will be ussd for patient selection, stratification and study endpoint analyses in the [redacted] Study. Efficacy results from the [redacted] Study may serve as the basis for establishing the clinical performance of VENTANA PD-L1 (SP263) CDx Assay.

The current state of the art in medicine and/or diagnosis for patients with NSCLC includes IHC testing for PD-L1 expression to inform the appropriate course of treatment. Several PD-(L)1 inhibitors are currently approved by the FDA and EMA in first-line, PD-L1 high ([redacted]) NSCLC patients who are negative for actionable molecular biomarkers. Despite the benefits of PD-(L)1 inhibitors, more than half of patients with NSCLC do not respond to first line anti-PD-(L)1 therapy and most participants who do respond will typically progress within a year. Investigating treatment modalities that incorporate combinations of agents targeting different pathways in combination, including [redacted], within the immune cascade has the potential to provide additional 
benefit beyond that of PD-1 inhibition alone. (For a detailed discussion of the current standard of care for NSCLC patients and PD-L1/PD-1 blocking antibodies, [redacted]) 

As part of a co-development paradigm including both an investigational therapy and an investigational in vitro diagnostic (IVD) device, RTD, as the IVD device manufacturer and Sponsor of the clinical performance study for the IVD device, will be responsible for certain aspects of the investigational IVD device use within the [redacted] Study. As such, this Dx protocol supports the [redacted] Study by describing the procedures for how the patient samples that are collected as part of the [redacted] Study should be tested with the investigational VENTANA PD-L1 (SP263) CDx Assay at the Dx testing sites. The investigational VENTANA PD-L1 (SP263) CDx Assay will be used to determine PD-L1 IHC expression level of NSCLC tumor specimens collected from patients who are being screened for enrollment into the [redacted] Study. 

It is anticipated that tumor specimens from approximately [redacted] patients undergoing screening to participate in the [redacted] Study will be stained with VENTANA PD-L1 (SP263) CDx Assay at Dx testing sites. Stained slides from each case will be interpreted by a qualified pathologist who will assign a PD-L1 IHC expression level at the [redacted]. Cases will be stained and evaluated with VENTANA PD-L1 (SP263) CDx Assay at the Dx testing site(s) in the approximate order in which they are received. 
Participants must have a PD-L1 expression level of [redacted] per central laboratory to be eligible for the [redacted] Study. PD-L1 expression level at the [redacted] cutoff ([redacted]) will be one of the stratification factors for randomization to treatment arms. Primary endpoints are progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 [redacted]. 
Efficacy results from the [redacted] Study will be used to evaluate the clinical performance of VENTANA PD-L1 (SP263) CDx Assay as a CDx device to identify patients with locally advanced, unresectable or metastatic NSCLC who may benefit from first line treatment with [redacted].

Lung biopsies will be obtained in the framework of the pharmaceutical study.

Collection of tissue biopsy samples is considered part of standard clinical practice to determine the most appropriate therapeutic option for NSCLC patients. The possible complications of lung biopsies include Blood loss or blood clots, pain or discomfort, infection, pneumonia, pneumothorax and bleeding from the lung. In addition, there may be risks during the biopsy such as dizziness, localized mild pain, pressure or pain from the needle, soreness or tenderness at the biopsy site, swelling or redness and scarring at the biopsy site. In rare cases, you may develop an infection. Other unforeseen risks may occur. 

There is also the risk of a false positive or false negative test result. In the event of a false negative result, the patient may not have the opportunity to receive a potential benefit from the investigational therapy but would 
discuss alternative treatment with their doctor. In addition, a false positive result from the assay (i.e., incorrect assignment of a PD-L1 expression level [redacted]) could lead to enrollment of a patient who would otherwise have been excluded. In that event, the patient may be subjected to potential negative side effects of the treatment received in the context of the trial. 
 

There are also the risks associated with patient data privacy (possible breach in patient confidentiality).