Clinical Performance Study Protocol for Use of the [redacted] PD-L1 [redacted] CDx Assay: Evaluation of PD-L1 Expression Levels in Non-small Cell Lung Cancer Specimens from Phase III Study [redacted]

[Redacted] (detailed in the [redacted] protocol [redacted]) is a phase III,
2-arm, randomized, double-blind, global, multicenter study assessing the
efficacy and safety of [redacted] compared with pembrolizumab, both in
combination with platinum-based
doublet chemotherapy, as a first-line treatment for patients with non-squamous
mNSCLC whose tumors express PD-L1 (tumor cell [TC] >=1%) without known
actionable genomic mutations (including but not limited to EGFR, ALK, and
ROS1). The scientific rationale for the design of
the [redacted] study is contained in Section 4.2 of the [redacted] protocol
[redacted].
Approximately 878 participants will be randomized into the [redacted] study in
a 1:1 ratio into the following arms:
* Arm A (experimental): [redacted] in combination with platinum-based doublet
chemotherapy, followed by [redacted] in combination with chemotherapy, or
* Arm B (control): pembrolizumab in combination with platinum-based doublet
chemotherapy followed by pembrolizumab in combination with chemotherapy

Randomized patients will be stratified [Redacted].

This diagnostic (Dx) study (RD007150) is a clinical performance study being
conducted in association with the [Redacted] study. PD-L1 testing (to support
patient enrollment into the [Redacted] study) will be performed at designated
central laboratories (referred to as Dx testing sites) with the investigational
[Redacted] PD-L1 [Redacted] CDx Assay under this Dx protocol. A PD-L1
expression level of >=1% TC, as determined by the [Redacted] PD-L1 [Redacted]
CDx Assay, will be one of the inclusion criteria for enrollment into
[Redacted]. Additionally, [Redacted] will be one of the stratification factors
used for randomization of patients into the treatment arms.

The primary objective of this study is to evaluate the clinical performance of
the [Redacted] PD-L1 [Redacted] CDx Assay in terms of its ability to identify
patients with non-squamous metastatic NSCLC (mNSCLC) who may benefit from
treatment with [Redacted] in combination with platinum-based chemotherapy, as
part of clinical trial [Redacted].
An additional objective of this Dx protocol is to evaluate the performance of
[Redacted] PD-L1 [Redacted] CDx Assay in staining FFPE NSCLC samples on the
[Redacted] instrument in a clinical use setting

[Redacted] is considered a drug (Rx)-diagnostic (Dx) combined trial, which is
the simultaneous evaluation of the efficacy and safety of an investigational
medicinal therapy ([Redacted] in combination with platinum-based doublet
chemotherapy) and the performance evaluation of an investigational in vitro
diagnostic (IVD), ie, the [Redacted] PD-L1 [Redacted] CDx Assay.

A PD-L1 tumor cell (TC) expression level >=1% (PD-L1 TC >=1%) will be required
for [Redacted] study (Rx) enrollment. the PD-L1 tumor cell expression levels
will be determined with the [Redacted] PD-L1 [Redacted] assay (investigational
IVD), meaning that the investigational device results will be used for patient
selection of the Rx trial. In this context, this is an interventional clinical
performance study, where the investigational [Redacted] PD-L1 [Redacted] CDx
Assay is being used as a companion diagnostic (CDx) device to identify
non-squamous mNSCLC patients who may benefit from treatment with the
investigational therapy in the clinical trial. In addition, [Redacted] will be
one of the stratification factors to randomize patients into treatment arms.

Stained slides will be interpreted by qualified pathologists, who will assign
the PD-L1 expression level (at the 1% and 50% TC thresholds) in accordance with
the [Redacted] PD-L1 [Redacted] CDx Assay scoring algorithm and interpretation
guide. In addition, for each case, a PD-L1 expression level will also be
assigned [Redacted] and [Redacted] will be recorded for exploratory purposes.
Performance of the [Redacted] PD-L1 [Redacted] CDx Assay will be evaluated as
described in Section 7 of this Dx protocol. In brief, the clinical performance
of the investigational IVD device will be measured by its ability to identify
the patients who are most likely to benefit
from the investigational therapy. Clinical performance will be considered
acceptable if the clinical biomarker-associated efficacy endpoint(s) are met.
Thus, the efficacy analyses specified in the pharmaceutical protocol will be
used to assess the benefit of the investigational therapy and the effectiveness
of the investigational IVD assay for patient selection. In addition, staining
performance of the investigational device will be assessed.

Lung biopsies will be obtained in the framework of the pharmaceutical study if
archival (leftover) samples are not available.
PD-L1 test result is one of the enrollment criteria for the pharmaceutical
study.

Collection of tissue samples is considered part of standard clinical practice
in this tumor indication to enable diagnostic testing in order to determine the
most appropriate therapeutic option. If a new tumor biopsy is needed to enable
investigational PD-L1 testing, the tissue will be obtained using a medically
routine sampling procedure. Patients will only undergo a new biopsy when risks
are considered medically appropriate by their treating physicians. Note that
the risk of a patient experiencing at least one complication during the biopsy
procedure is ~10%. The mortality rate for elective surgical lung biopsy for
patients with interstitial lung disease is <2%.

The risks to patients in both studies include false-positive results,
false-negative results, delayed
results, unevaluable results/loss of patient sample, and confidentiality
breaches.