A performance evaluation study for the testing of DNA extracted from either tumor tissue biopsy samples or plasma, using the therascreen® EGFR Plus RGQ PCR Kit, from subjects with Non-Small Cell Lung Cancer, being screened for inclusion in Taiho Oncology, Inc*s Clinical Trial (Protocol No. 10073010).

About 10%-15% of Caucasian patients with non-small cell lung cancer (NSCLC) and
up to 50% of East-Asian patients with NSCLC have tumors harboring an epidermal
growth factor receptor (EGFR) activating mutations (i.e., L858R or exon 19
deletion mutations) . The current standard of care for these patients with
locally advanced or metastatic NSCLC is treatment with an EGFR tyrosine kinase
inhibitor (TKI). Several Phase 3 clinical trials have established the role of
first-generation (gefitinib and erlotinib) and second-generation (afatinib and
dacomitinib) EGFR TKIs as first-line treatment with similar median response
rates of 70%-75% and progression-free survival (PFS) ranging from 10-14 months,
which was a significant improvement compared to platinum-based chemotherapy.
The most frequent resistance mechanism to first-and second-generation EGFR TKIs
is the emergence of T790M EGFR kinase domain mutations. More recently, the
third generation EGFR TKI osimertinib active against T790M EGFRmt showed
superior efficacy when compared against erlotinib, with improved PFS (18.9
versus 10.2 months) and overall survival (OS) (38.6 versus 31.8 months).

Despite third-generation EGFR TKIs being highly effective in advanced EGFRmt
NSCLC, resistance to EGFR TKIs inevitably occurs leading to disease
progression. The current treatment options for EGFRmt NSCLC patients
progressing on treatment with third-generation EGFR TKIs are limited.
Chemotherapy with pemetrexed alone or in combination with cisplatin is
currently considered standard of care. However, the reported clinical outcome
is poor with approximately 25% ORR and median PFS of approximately 3 months
post osimertinib. One of the prevalent resistance mechanisms to
third-generation EGFR TKIs is an acquired C797S EGFR mutation which is observed
in 10%-25% of NSCLC patients progressing on osimertinib.

Study 10073010 is a first-in-human Phase 1/2 study, being conducted by Taiho
Oncology Inc, that is designed to determine the RP2D and efficacy of TAS3351 in
patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
harboring an acquired C797S EGFR mutation.

TAS3351 is a novel fourth-generation EGFR TKI designed to potently inhibit
triple-mutant EGFR in NSCLC patients. In addition to its activity against EGFR
sensitizing mutations (e.g. L858R or exon 19 deletion mutations) and the
acquired T790M resistance EGFRmt, TAS3351 also inhibits C797S EGFRmt observed
in patients progressing on third generation EGFR TKIs, while sparing EGFR
wild-type. In nonclinical studies, TAS3351 demonstrated dose-dependent activity
in vitro and in vivo in NSCLC models with co-occurrence of sensitizing EGFRmt
and T790M/C797S EGFRmt (data on file). Furthermore, TAS3351 has been shown to
be brain penetrant in nonclinical models. Approximately 25%-40% of patients
with NSCLC develop brain metastases and, due to limited treatment options, the
prognosis of patients with brain metastases remains poor. Thus, TAS3351 might
also provide a new treatment option for patients with EGFR deregulated NSCLC
who have brain metastases.
Based on these results, TAS3351, is expected to have antitumor activity in
NSCLC patients with tumors harboring an acquired C797S EGFRmt, a population
with an unmet medical need.

Mutations in the EGFR oncogene are found in human cancers. The presence of
these mutations correlates with response to certain tyrosine kinase inhibitor
therapies in patients with non-small cell lung cancer. Such mutations in the
EGFR oncogene are present in the general population of patients with NSCLC at a
frequency of approximately 10% in patients from the USA, Europe, or Australia
and up to 30% in patients from Japan and Taiwan.

The therascreen EGFR Plus RGQ PCR Kit is a real-time PCR (polymerase chain
reaction) test for the detection of 42 mutations in the EGFR cancer-related
gene using ARMS (Amplification Refractory Mutation System) and PCR clamp
technologies for the qualitative detection and identification of mutations in
the EGFR gene; exons 18, 19, 20, and 21. While both FFPE and plasma samples can
be used, only plasma generates a semi-quantitation of these mutations. The kit
allows the semi-quantification of G719X (X = A, S, or C; exon 18), T790M (exon
20), C797Sa and C797Sb (exon 20), S768I (exon 20), L858R (exon 21), and L861Q
(exon 21) in DNA samples extracted from human plasma.

For Taiho's Study (drug study):
Primary Objectives:
• Phase 1 Dose Escalation: To investigate the safety and determine the
recommended Phase 2 dose (RP2D) and dosing schedule of TAS3351.
• Phase 1 Dose Expansion: To explore the efficacy of TAS3351.
• Phase 2: To assess the efficacy of TAS3351.


For QIAGEN's Study (Device Study)
The primary objective is to demonstrate the effectiveness of the EGFR Plus
assay in identifying the population with C797S EGFRmt for the clinical study as
measured through the efficacy of the device and drug in combination. Efficacy
will be established based on the overall response rate (ORR) as defined in
Taiho*s clinical trial 10073010.

Drug Study

Study 10073010 is a first-in-human Phase 1/2 study, being conducted by Taiho
Oncology Inc, that is designed to determine the RP2D and efficacy of TAS3351 in
patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
harboring an acquired C797S EGFR mutation.
The study will consist of 3 parts:

• Part A1: Phase 1 Dose Escalation

The Phase 1 Dose Escalation is designed to evaluate 6 dose levels of TAS3351
from 50 to 700 mg/day using a Bayesian Optimal Interval (BOIN) design. The BOIN
design uses prespecified sample sizes and isotonic regression to pool
information across doses, resulting in a more efficient statistical estimate of
the MTD than a standard 3+3 design.9 The Bayesian Optimal Interval (BOIN)
design has a target DLT rate of 30% and an acceptable DLT interval from
24%-36%. The decision to escalate or de-escalate the dose of TAS3351 will be
based on the cumulative DLT rate at the current dose level and the
predetermined DLT rate threshold for dose escalation/de-escalation boundaries
as defined by the BOIN model. TAS3351 will be administered once daily (QD) on a
21-day cycle at a starting dose of 50 mg QD and escalated based on
tolerability to patients who harbor any EGFR mutation, with consideration of
lower increments than planned if clinically relevant toxicities are observed
(intermediate dose levels). In the event of unacceptable toxicities at Dose
Level 1, lower dose levels may be explored (eg, Dose Level -1). If PK,
pharmacodynamic, and/or safety data indicate, twice daily (BID) dosing of
TAS3351 may be explored. In order to appropriately characterize the PK profile
of TAS3351, there will be a PK lead-in with a single administration of TAS3351
followed by PK sampling 3 days prior to the start of continuous daily dosing of
TAS3351 for patients enrolled in the Dose Escalation Part A1 only.

• Part A2: Phase 1 Backfill Patients

When a dose level has been determined to be safe in Part A1 and preliminary
antitumor activity has been observed, up to 10 further patients may be enrolled
in that dose level (for a total of up to 20 backfill patients). A dose is
deemed to be safe in Part A1 if there is an acceptable DLT rate in that dose
level as per the BOIN design. Antitumor activity is defined as evidence of
tumor shrinkage in at least one of the patients at that dose level.
If no preliminary antitumor activity is observed in Part A1, the totality of
nonclinical in vitro and in vivo data as well as clinical PK data may be used
to inform selection of dose level(s) for *backfill* patients. This will include
IC50 values from various in vitro assays and/or the total exposure of TAS3351
and its active metabolite associated with tumor shrinkage in preclinical
xenograft mouse models to be used as thresholds for targeted efficacious Cmin
and/or AUC, respectively. The exposure linked with nonclinical activity is a
total TAS3351 and TAS-05-14317 Cmin of 40.3 nM. Clinical PK simulation will be
applied to project dosing regimen(s) which may achieve the targeted
threshold(s). The doses explored in the A2 part of the trial will be chosen in
consultation between the investigators and the Sponsor based on the above
safety and efficacy criteria as well as a
review of the PK data. *Backfill*patients enrolled are required to have a tumor
harboring a C797S EGFRmt. The additional information from these backfill*
patient cohorts will broaden the amount of safety and preliminary antitumor
activity data for TAS3351 at potential active dose levels to inform the
selection of the RP2D of TAS3351.

• Part B: Phase 1 Dose Expansion

The Phase 1 Dose Expansion part of the study will be initiated after an RP2D
and a dosing scheme has been identified in Part A. NSCLC patients with C797S
EGFRmt will be enrolled to explore the efficacy and confirm the safety of
TAS3351 at the RP2D in a larger patient population. Moreover, a second dose
level of TAS3351 may be evaluated in an additional cohort of patients in Part B
if promising antitumor activity is observed at another lower TAS3351 dose level
during Part A. In this case, patients enrolled in Part B will be randomized at
a 1:1 ratio between the two treatment arms to evaluate the optimal RP2D of
TAS3351 based on a comparative analysis considering the totality of efficacy
and safety data observed.

The results from Part B will confirm the RP2D of TAS3351 and are expected to
provide, in combination with the *Backfill* patients from Part A2, the proof of
concept for the efficacy of TAS3351 in NSCLC patients with the C797S EGFRmt.
Based on these results, the Phase 2 part of this study will be initiated.

Safety data will be summarized at the end of Parts A and B, and these results
will be submitted to all EU member states with study sites participating in
this study. The safety summaries will contain, at a minimum, the dose-finding
data, the dose selected for the next study phase, and all safety data.

In addition, further cohorts may be added by an amendment to explore the
activity of TAS3351 in further subgroup(s) of patients based on activity
observed in the Part A dose escalation and/or emerging scientific data. This
may include an additional cohort for EGFRmt NSCLC patients with brain
metastases to explore the efficacy of TAS3351 against CNS metastases or against
other type of EGFRmt, if promising results are observed during Part A of this
study.

• Part C: Phase 2 D

The Phase 2 part of the study will be an open-label, single-arm, Phase 2 study
to assess the safety and efficacy of TAS3351 in advanced NSCLC patients with
C797S EGFRmt who progressed on a prior treatment with another EGFR inhibitor.
Patients will receive TAS3351 at the RP2D and dosing scheme confirmed in Part
B and be evaluated for ORR based on RECIST v1.1 by Independent Central Review
(ICR) as the primary endpoint. A key secondary endpoint of this part of the
study will be duration of response (DoR) by ICR.

Device Study:

The therascreen EGFR Plus RGQ PCR Kit will be used to prospectively test
specimens in parts A2, B and C above to select patients who do not have local
results available for further screening for enrolment in the TAS3351 clinical
study and to confirm the local results for patients who have these local
results available. The test will also be used to retrospectively test samples
from part A1 above.

All patients will have a screening visit to ensure eligibility for the study.
Phase 1:
Following the screening visit there will be a PK Lead-In period for patients in
part A1 of the study where they will have a physical exam, vital signs taken,
blood drawn for chemistry, hematology, and coagulation testing, give a urine
sample, and have blood drawn for PK analysis and ECG*s performed.

Following this period, the study progresses in 21-day cycles. There are more
visits in cycle 1 than subsequent cycles.

In cycle 1 there are 3 visits (Cycle 1 day 1, day 8, and day 15). On all of
these visits patients will have their vital signs taken, and give blood for
chemistry and hematology testing. On 2 of these visits, patients will undergo a
physical exam, have blood drawn for chemistry and hematology, have pregnancy
testing (for WOCBP), and have blood drawn for PK analysis and ECGs. On one of
these visits (day 1) patients will also have blood drawn for coagulation, give
a urine sample, and have blood drawn for cfDNA biomarker testing.

In cycle 2 there are 2 visits (cycle 2 day 1 and day 8). On both of these
visits patients will have their vital signs taken, and give blood for chemistry
and hematology testing. On one of the visits (day 1), patients will undergo a
physical exam, have blood drawn for chemistry, hematology, and coagulation,
have pregnancy testing (for WOCBP), give a urine sample, have ECGs performed,
have blood drawn for PK testing, and have blood drawn for cfDNA biomarker
testing.

In cycle 3 and after patients only need to come in on the first day of each
cycle (i.e. cycle 3 day 1). At this visit patients will undergo a physical
exam, have their vital signs taken, have blood drawn for chemistry, hematology,
and coagulation, they will have a pregnancy test (for WOCBP) and give a urine
sample. They will also have a PK sample drawn (cycle 3 only), ECGs performed,
an ECHO or MUGA scan performed, and give a blood sample for cfDNA biomarker
testing.

Patients may have more visits depending on how long they remain in the study.
Throughout these cycles there is an optional biopsy sample that patients can
submit at any time and patients will have radiologic tumor assessments every 6
weeks after C1D1 (or after 12 months, these become every 9 weeks).

Phase 2:
Following the screening visit patients will start with cycle 1. In cycle 1
there are 2 visits (cycle 1 day 1 and day 8). On both of these visits patients
will have their vital signs taken, blood drawn for hematology and chemistry. On
one of the visits (day 1) patients will also have a physical exam, provide a
urine sample, a pregnancy test (for WOCBP), blood drawn for hematology,
chemistry, and coagulation as well as blood drawn for PK samples, ECG*s, and
blood drawn for cfDNA biomarker testing.

In cycle 2 and after patients only need to come in on the first day of each
cycle (i.e. cycle 2 day 1). At this visit patients will undergo a physical
exam, have their vital signs taken, have blood drawn for chemistry, hematology,
and coagulation, they will have a pregnancy test (for WOCBP) and give a urine
sample. They will also have a PK sample drawn (cycle 2 and 3 only), ECGs
performed, and give a blood sample for cfDNA biomarker testing.

Patients may have more visits depending on how long they remain in the study.
Throughout these cycles there is an optional biopsy sample that patients can
submit at any time and patients will have radiologic tumor assessments every 6
weeks after C1D1 (or after 12 months, these become every 9 weeks).