Clinical Performance Study for PD-L1 IHC 22C3 pharmDx on Non-Squamous Non-Small Cell Lung Cancer Specimens.

The purpose of this clinical performance study is to investigate the use of the
PD-L1 IHC 22C3 pharmDx in Daiichi Sankyo*s Phase 3 clinical trial
TROPION-Lung07 to identify advanced or metastatic non-squamous non-small cell
lung cancer (NSCLC) patients with programmed death-ligand 1 (PD-L1) expression
at tumor proportion score (TPS) <50% and stratify randomization by PD-L1
expression (TPS <1% vs. 1%-49%).
TROPION-Lung07 is a global, multicenter, randomized, open-label Phase 3 study
designed to compare the efficacy of datopotamab deruxtecan (Dato-DXd) in
combination with pembrolizumab with or without platinum-based chemotherapy in
subjects with advanced or metastatic non-squamous NSCLC without actionable
genomic alterations and are PD-L1 TPS <50%. The study is designed to evaluate
whether progression-free survival (PFS) and overall survival (OS) in the
subject population can be improved when the standard of care (SOC) treatment
(pembrolizumab with or without platinum therapy) is combined with Dato-DXd.

PD-L1 IHC 22C3 pharmDx will be used as a test object under clinical research
for use of the device as a companion diagnostic in the TROPION-Lung07 trial.
The corresponding clinical research objectives of the device are aligned to the
study objectives of the clinical trial. PD-L1 IHC 22C3 pharmDx will be used for
prospective testing of freshly collected or archived formalin-fixed, paraffin
embedded tumor tissue specimens (resection or biopsy). Results from PD-L1 IHC
22C3 pharmDx will confirm patient eligibility for enrollment into the trial and
may be used for registrational purposes of the therapeutic and companion
diagnostic.

PD-L1 IHC 22C3 pharmDx has undergone analytical validation studies by the
manufacturer. PD-L1 IHC 22C3 pharmDx will be used to select non-squamous NSCLC
patients eligible for the TROPION-Lung07 trial based on their tumor PD-L1
expression level at TPS <50% and randomization stratification by PD-L1
expression (TPS <1% vs. 1%-49%). To measure the objectives and endpoints of the
clinical trial, the companion diagnostic test results from PD-L1 IHC 22C3
pharmDx are required to identify subjects with non-squamous NSCLC with PD-L1
TPS <50% for enrollment eligibility.

This is a clinical performance study of PD-L1 IHC 22C3 pharmDx on non-squamous
non-small cell lung cancer specimens. PD-L1 IHC 22C3 pharmDx will be used to
select non-squamous NSCLC patients eligible for the TROPION-Lung07 trial based
on their tumor PD-L1 expression level at TPS <50% and randomization
stratification by PD-L1 expression (TPS <1% vs. 1%-49%).

This is a global, multicenter, randomized, open-label, Phase 3 study designed
to evaluate the efficacy and safety of Dato-DXd in combination with
pembrolizumab, with or without 4 cycles of platinum chemotherapy versus
pembrolizumab in combination with pemetrexed and platinum chemotherapy, in
subjects with no prior therapy for advanced or metastatic non-squamous
non-small cell lung cancer (NSCLC), whose tumors have programmed death-ligand 1
(PD-L1) expression (tumor proportion score [TPS]) <50% and do not contain known
actionable genomic alterations.

PD-L1 IHC 22C3 pharmDx will be used to select non-squamous NSCLC patients
eligible for the TROPION-Lung07 trial based on their tumor PD-L1 expression
level at TPS <50% and randomization stratification by PD-L1 expression (TPS <1%
vs. 1%-49%).

The IVD test results from PD-L1 IHC 22C3 pharmDx will be used
for patients selection using PD-L1 expression level TPS <50% cutoff and patient
stratification at TPS <1%, and TPS = 1-49%. 

Risk Determination of Indirect Harm Caused by PD-L1 IHC 22C3 pharmDx Use in
TROPION-Lung07 Trial

The investigational use of the PD-L1 IHC 22C3 pharmDx in this Phase 3 study of
Dato-DXd and pembrolizumab with or without platinum chemotherapy in subjects
with no prior therapy for advanced or metastatic PD-L1 TPS < 50% non-squamous
NSCLC does not present a potential for serious risk to the health and safety of
the study participants.

A Misdiagnosis (i.e., false positive or false negative result) Leading to
Inappropriate Disease Management for the Patients

In the event of a false strong positive PD-L1 result (TPS >=50%), patients would
not be eligible for TROPION-Lung07 study and could be administered non-trial
SOC, which would have been the default option had they not screened for the
study. Thus, a false strong positive result would not lead to increased patient
risk relative to what they would have experienced had they not screened for
this study.
If the event of false PD-L1-negative result (TPS <1%) or false weak positive
(TPS = 1% - 49%),the most common result will be that patients who would
normally receive SOC therapy would instead receive investigational drug
Dato-DXd and pembrolizumab with or without platinum therapy. However, the
patient may fail to potentially benefit from the clinical trial. This could
result in comparatively less efficacy and may expose the patient to marginal
differences in toxicity. Also, this would result in approximately two thirds of
such subjects being exposed to marginal additional toxicity and/or efficacy of
Dato-DXd.
Overall, the risk to the subject incurred by any false results depends on the
risk of the investigational or comparative drugs. Whether any risk is
reasonable or not depends on the medical benefit risk profile of the
investigational drug and the clinical trial design. Therefore, the consequence
of indirect harm to the patient due to an erroneous test result based on the
trial design and treatments provided will be further assessed by the IRB.

Risk Associated with Biopsy Procedures

As stated in the clinical trial protocol, if archived tissue is not available,
a fresh tissue sample is required for PD-L1 testing as determined by PD-L1 IHC
22C3 pharmDx by the clinical testing laboratory. The common risk of a biopsy
procedure is pain, a risk of bleeding and/or infection. There is a risk of
regional spread of cancer cells when the needle is removed from the tumor.
Anesthesia (numbing medication) is commonly used for this type of procedure and
there is a risk of complication from anesthesia.

Additional biopsies may be permitted for testing with PD-L1 IHC 22C3 pharmDx.
However, PD-L1 rescreening is not permitted if a subject is PD-L1 TPS >=50% as
determined by central laboratory testing; retest is only permitted if no valid
result is obtained. The risks associated with invasive sampling are not
expected to exceed the risks of non-trial SOC, i.e., the biopsy procedures that
will be used in this trial are similar to routine biopsy collection procedures.
The biopsy procedures when used are similar to those used per routine
collection procedures. Further, patients as part of the study screening would
have signed an informed consent that includes the risks associated with biopsy
procedures. Thus, additional safety risks (beyond what patients in this
advanced disease setting face in routine SOC) will not be posed by the sampling
procedure that may be requested for this study.

A medical expert would assess the risks associated with re-biopsy of a
particular patient and determine whether or not it would be in the patient*s
best interest to proceed.