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 used 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).