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Essential Panel VIC 3149

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PATIENT PHYSICIAN SPECIMEN CASE

NAME SEX ORDERING PHYSICIAN EXT. SPECIMEN ID ACCESSION#

Roy Daubet Male Dr Annlelyn Beryl Ong-Cornel 22H1451 (University of Perpetual Help A22M0163DR
ARPON Medical Center)
FACILITY DATE
DATE OF BIRTH University of Perpetual Help DATE RECEIVED REPORTED
29/12/1966 MRN# Medical Center 18/09/2022 21/09/2022
- SPECIMEN TYPE
DISEASE DATE ORDERED REVIEW
Adenocarcinoma COPY TO Formalin-fixed paraffin-embedded tissue STATUS
of lung specimen Final
-
ADDRESS % TUMOR CELLULARITY REPORTED
No.55 70% BY
Concha Cruz Drive Dr. Vivek
BF Homes Rathi
Paranaque City 1720
Philippines

Report Summary
• • A variant of strong clinical significance detected -

TIER 1A, BRAF p.V600E - this variant has therapeutic significance in non-small cell lung carcinoma patients, with FDA approved
and NCCN/ESMO recommended therapeutic agents available, as described below.

• • Pertinent negatives - no clinically relevant mutations detected in EGFR, KRAS or MET, and no fusion transcripts detected in
ALK, ROS1, RET, NTRK1, NTRK2 or NTRK3.
• • PD-L1: TPS = 70% in this sample (on Ventana SP263)

IA IB IIC IID Trials

1 0 1 0 2

Clinical Implications

VARIANT SELECT
TIER DETECTED CLINICAL IMPACT CLINICAL
(GENE/SYNTAX) TRIALS

May benefit from: Vemurafenib or Dabrafenib

In Tumor Type: Non-small cell lung cancer

IA BRAF 2
p.V600E May benefit from: Dabrafenib + Trametinib

Malignant tumor of lung, Adenocarcinoma of lung, Non-small

In Tumor Type: cell carcinoma, Non-small cell lung cancer, Squamous cell

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

carcinoma of lung, Glioblastoma, or Large cell carcinoma of

lung

May benefit from: Pembrolizumab or Ipilimumab + Nivolumab

Squamous cell carcinoma of lung, Adenocarcinoma of lung,

In Tumor Type: Non-small cell lung cancer, Large cell carcinoma of lung, or
Non-small cell carcinoma

Bevacizumab-bvzr, Bevacizumab-awwb, Bevacizumab, or

May benefit from: Atezolizumab

Nonsquamous nonsmall cell neoplasm of lung,

In Tumor Type: Adenocarcinoma of lung, or Large cell carcinoma of lung

May benefit from: Dabrafenib

Squamous cell carcinoma of lung, Adenocarcinoma of lung,

In Tumor Type: or Large cell carcinoma of lung

May benefit from: Vemurafenib

Squamous cell carcinoma of lung, Adenocarcinoma of lung,

In Tumor Type: or Large cell carcinoma of lung

TP53
IIC No guidelines existing in the report. 0
p.P278A

Other Test Results

• • Cytopathology: Left lower lobe lung - atypical cells highly suspicious for malignancy, favour adenocarcinoma.

• • PD-L1 IMMUNOHISTOCHEMISTRY (performed by LifeStrands Genomics) -

VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody Assay:
-- Positive control results (Acceptable)
-- Negative control results (Acceptable)
-- Adequate tumour cells (>100 cells) are present
Description: Moderate and weak, occasionally strong partial and sometimes complete membranous staining in 70% of
tumour cells
Tumour Proportion Score: 70%

Clinical Interpretations

BRAF p.V600E c.1799T>A Tier IA NM_004333.4 VAF: 32.4% Depth: 12370

GENE: BRAF, serine/threonine-protein kinase B-raf, is a member of the Raf family of serine/threonine protein kinases, which signals
through the MAP kinase pathway to regulate cell proliferation and cell growth (PMID: 24737949, PMID: 29540830). BRAF mutations
and fusions have been identified in a variety of cancers, including, colorectal (PMID: 30122982), lung (PMID: 29729495), thyroid
(PMID: 12970315), and melanoma (PMID: 24737949), and a number of mutations have also been demonstrated to confer drug
resistance (PMID: 27478040).

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

VARIANT: BRAF V600E (previously reported as V599E) lies within the activation segment of the kinase domain of the Braf protein
(PMID: 15035987). V600E confers a gain of function to the Braf protein as demonstrated by increased Braf kinase activity,
downstream signaling, and the ability to transform cells in culture (PMID: 15035987, PMID: 29533785).

THERAPEUTICS: Currently, there are FDA approved and NCCN and ESMO guidelines recommended BRAF inhibitors approved for
treatment for advanced non-small cell lung cancer patients. 

Dabrafenib in combination with trametinib is FDA and EMA approved and NCCN and ASCO guidelines recommended for use in
non-small cell lung cancer harbouring BRAF V600E mutation as preferred first-line therapy or subsequent therapy following
disease progression on a non-BRAF-targeted regimen.

Dabrafenib in combination with trametinib is ESMO (PMID: 30285222, 2018, https://www.esmo.org/guidelines/lung-and-chest-

tumours/clinical-practice-living-guidelines-metastatic-non-small-cell-lung-cancer, 2020) guideline recommended for use in
non-small cell lung cancer harboring a BRAF Val600 mutation as first-line or second-line therapy.

Ipilimumab in combination with nivolumab and chemotherapeutic agents is NCCN (Non-Small Cell Lung Cancer, 3.2022) guideline
recommended for use in non-small cell lung cancer harboring a BRAF p.(Val600Glu) mutation as first-line or subsequent therapy
without PD-1/PD-L-1 inhibitor contraindication.

Some evidence indicates that metastatic non-small cell lung cancer harboring a BRAF V600 mutation may benefit from sorafenib
in combination with erlotinib, based on a retrospective study of 72 mixed ethnicity participants (PMID: 30642457, 2018).

Some evidence indicates that metastatic non-small cell lung cancer harboring a BRAF V600 mutation may benefit from
vemurafenib in combination with cobimetinib, based on a retrospective study of 72 mixed ethnicity participants (PMID:
30642457, 2018).

Atezolizumab in combination with chemotherapeutic agents is NCCN (Non-Small Cell Lung Cancer, 3.2022) guideline
recommended for use in non-squamous non-small cell lung cancer harboring a BRAF V600E mutation as first-line therapy
without PD-1/PD-L-1 inhibitor contraindication or as preferred subsequent therapy when PD-1/PD-L1 inhibitor naive.

TP53 p.P278A c.832C>G Tier IIC NM_000546.5 VAF: 40.3% Depth: 847

GENE: TP53, tumor protein p53, is a tumor suppressor (PMID: 30562755) and oncogene (PMID: 30577483) involved in cell cycle
arrest and apoptosis, and is the most frequently mutated gene in cancer (PMID: 10065147, PMID: 22713868). TP53 germline
mutations are common in Li-Fraumeni syndrome (PMID: 30239254) and somatic missense mutations are frequent in almost all
cancer types (PMID: 30224644) and are also implicated in chemoresistance (PMID: 9927204, PMID: 24065105, PMID: 27066457).

VARIANT: TP53 P278A lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). P278A results in a loss of
transactivation activity in yeast assays (PMID: 16861262), but has not been characterized in human cells and therefore, its effect
on Tp53 protein function is unknown.

THERAPEUTICS: Currently, there are no FDA approved or NCCN-Compendium recommended treatment options for patients
harbouring this variant.

 In a Phase I trial, the combination of Votrient (pazopanib) and Zolinza (vorinostat) improved progression-free survival and overall
survival in advanced solid tumor patients harboring TP53 hotspot mutations, and resulted in an increased stable disease rate of
45% (5/11), compared to a stable disease rate of 16% (4/25) in patients without detected TP53 mutations (PMID: 25669829). In a
Phase I trial, Adavosertib (MK-1775) treatment resulted in a prtial response in 3 and progressive disease in 2 of 6 patients with
advanced solid tumors harboring TP53 mutations (J Clin Oncol 38: 2020 (suppl; abstr 3624); NCT01748825).In a retrospective
analysis of a Phase I trial, Adavosertib (MK-1775) combined with a chemotherapy resulted in a 21% (4/19) response rate in
advanced solid tumor patients harboring a TP53 mutation and in those without a TP53 mutation, a 12% (4/33) response rate was
observed (PMID: 27601554). In a clinical study, VEGF/VEGFR inhibitor treatment resulted in improved rates of response (stable
disease over 6 months/partial/complete response, 31% vs 7%), time-to-treatment failure, and overall survival (both p<0.01)
compared to control in patients with TP53 mutant advanced solid tumors (n=106), but not in patients with TP53 wild-type tumors
(n=82) (PMID: 27466356). In a retrospective study, Avastin (bevacizumab) treatment was associated with increased progression-
free survival in cancer patients carrying TP53 mutations (PMID: 23670029).

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

Clinical Trials

Clinical Trials associated with this patient's genomic profile and tumor type as displayed below.

TITLE TRIAL IDENTIFIER PHASE VARIANT

Targeted Therapy Directed by NCT02465060 II BRAF

Genetic Testing in Treating Patients https://clinicaltrials.gov/show/NCT02465060 p.V600E
With Advanced Refractory Solid c.1799T>A
Tumors, Lymphomas, or Multiple
Myeloma (The MATCH Screening
Trial)

Study of Safety, Pharmacokinetics, NCT04249843 I BRAF

and Antitumor Activity of https://clinicaltrials.gov/show/NCT04249843 p.V600E
BGB-3245 in Participants With c.1799T>A
Advanced or Refractory Tumors

Significant Negative Findings

No clinically relevant variants detected in EGFR, MET or KRAS, and no fusion transcripts detected in ALK, ROS1, RET, NTRK1,
NTRK, NTRK3.

Tier III - Variants of Uncertain Significance

No variants were reported for this classification tier.

Other Comments

Current FDA approved treatments for specific genetic alterations in metastatic non-small
cell lung carcinoma-
ALK fusions - Crizotinib, ceritinib, alectinib, brigatinib, lorlatinib
BRAF V600E - Dabrafenib + trametinib
EGFR ex 19 del, L858Rm - Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib
EGFR ex 20 insertions - Amivantamab
EGFR nonresistant mutations other than exon 19deletions and L858R - Afatinib
EGFR T790M - Osimertinib
KRAS G12C - Sotorasib
MET exon 14 skipping - Capmatinib, tepotinib
RET fusions - Pralsetinib, selpercatinib
ROS1 fusions - Crizotinib, entrectinib

FDA approved tumour agnostic indications -

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

NTRK1 or NTRK2 or NTRK3 fusions - Entrectinib, larotrectinib

MSI-H, TMB-H - Pembrolizumab

FDA-listed genetic alterations contraindicated for specific treatments with TRK inhibitors -
NTRK1 and NTRK3 known acquired resistance mutations (eg, NTRK1 G595R and G667C; NTRK3 F617L, G623R, and G696A)

FDA-approved combination treatments with nontargeted therapies for specific genetic

alterations-
EGFR exon 19 deletions, L858R - Erlotinib + ramucirumab

Current NCCN recommended biomarkers for sequencing in NSCLC-

Mutations - BRAF, EGFR, HER2, KRAS, MET
Amplifications - MET
Fusions - ALK, NTRK1, NTRK2, NTRK3, RET, ROS1

Tier Definitions
Tier I-A: Approved therapy. Included in professional guidelines.
Tier I-B: Well-powered studies with consensus from experts in the field.
Tier II-C: Approved therapies for different tumour types or investigational therapies. Multiple small published studies with some
consensus. Inclusion criteria for clinical trials.
Tier II-D: Limited clinical or preclinical studies.
Tier III (VUS): Variants of Unknown Clinical Significance.
Tier IV: Benign or likely benign variants (not included in the report)

Test Information
REPORTED GENES: AKT1, AKT2, AKT3, ALK, AR, ARAF, BRAF, CD274, CDK4, CDKN2A, CHEK2, CTNNB1, EGFR, ERBB2, ERBB3, ERBB4, ESR1, FGFR1,
FGFR2, FGFR3, FGFR4, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MAP2K2, MET, MTOR, NRAS, NRG1, NTRK1, NTRK2, NTRK3,
NUTM1, PDGFRA, PIK3CA, PTEN, RAF1, RET, ROS1, RSPO2, RSPO3, SMO, TP53 CGW VERSION: CGW_v6.20 DATABASE DETAILS: The versions,
releases, builds, dates of the following databases were used to generate this report: Genomic Build: GRCh37.p13 | Genomic Annotation
Sources: NCBI RefSeq v105 | COSMIC: v96 | dbNSFP: 4.2c | ExAC: v1.0 | dbscSNV: v1.1 | ClinVar: 20220702 | NHLBI ESP: v.0.0.30 | gnomAD: r2.1 |
dbSNP: 149 ASSAY METHODOLOGY:

ASSAY METHODS: This is a laboratory developed test and has been extensively validated in-house utilising the Oncomine™ Precision targeted
next-generation sequencing assay, which is run on the ThermoFisher GenexusTM Integrated Sequencer to detect DNA and RNA based variants
in formalin-fixed paraffin embedded (FFPE) samples. The assay uses ThermoFisher’s proprietary AmpliSeq™ enrichment chemistry to enable
nucleic acid input sequencing. The Oncomine™ Precision assay is designed to detect multiple classes of variants including single nucleotide
variants (SNVs), multi-nucleotide variants (MNVs), small Insertions /Deletions (Indels), copy number variations (CNVs), and gene fusions. The
50 gene panel includes detection of hotspot mutations in 45 genes, CNV detection in 14 genes, and the detection of gene-fusions from RNA
in 18 genes.

DNA and RNA are extracted and quantified using the GenexusTM Purification System. The Sequencer performs library preparation, sequencing,
and secondary analysis. Multiplex primer design and sample barcoding leverage Ion AmpliSeqTM HD technology to generate results from
multiple samples in a single run.

SECONDARY ANALYSIS METHODS: DNA/RNA analysis was performed locally using GenexusTM analysis platform. Variant files i.e., VCF/BAM files
from this pipeline were then uploaded to the Clinical Genomics Workspace (CGW) from Pierian. Variant files were then parsed and combined
into compatible formats and analyzed using the CGW software platform using an in-house bioinformatics pipeline.

VARIANT CALLING: Variants are reported according to HGVS nomenclature (www.hgvs.org/mutnomen) and classified per the AMP
classification system into tiers IA, IB, IIC, IID, III, and IV. These tiers are stratified by clinical utility ('actionability' for clinical decision-making as
to diagnosis, prognosis, treatment options, and carrier status) and previously reported data in the medical literature. Variants found in
gnomAD (https:// gnomad.broadinstitute.org/) that have ≥1% minor allele frequency (except those that are also in Clinvar denoted as clinically

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

relevant, used in a clinical diagnostic assay, or reported as a mutation in a publication) are classified as known polymorphisms.

DNA/RNA VARIANTS (SNVS, INSERTIONS, DELETIONS, CNVS, AND GENE FUSIONS)

Based on the in-house validation using clinical samples and various types of reference standards, the assay can detect SNVs/Short Deletions
with 100% accuracy, sensitivity and specificity at ≥5% limit of detection. For the detection of Copy Number Variations (CNVs), the assays
demonstrated 100% accuracy, 98.6% sensitivity and 100% specificity (CNVs on NGS platforms is an estimate based on prediction algorithm
which consider multiple factors. The gene amplification of ≥5 is considered a true prediction on this platform). For Fusions, the assay
demonstrated 100% accuracy, 98.6% sensitivity and 100% specificity (based on high confidence fusion calls (≥10 copies).

Additional Notes:
• • Variants located outside of targeted regions will not be detected.
• • This assay is clinically validated for the detection of somatic variants in somatic tumor specimens.
• • It is possible that pathogenic variants may not be reported by one or more of the tools because of the parameters used. However, tool
parameters were optimized to maximize specificity and sensitivity.

OncoStrands™Essential Panel Gene List

DNA Hotspot Genes

AKT1 AKT2 AKT3 ALK AR ARAF BRAF CDK4 CDKN2A CHEK2 CTNNB1 EGFR ERBB2 ERBB3 ERBB4 ESR1 FGFR1 FGFR2 FGFR3 FGFR4 FLT3 GNA11
GNAQ GNAS HRAS IDH1 IDH2 KIT KRAS MAP2K1 MAP2K2 MET MTOR NRAS NTRK1 NTRK2 NTRK3 PDGFRA PIK3CA PTEN RAF1 RET ROS1 SMO TP53

Copy Number Variation (CNV) Genes

ALK AR CD274 CDKN2A EGFR ERBB2 ERBB3 FGFR1 FGFR2 FGFR3 KRAS MET PIK3CA PTEN

Fusion (RNA) Genes

ALK AR BRAF EGFR ESR1 FGFR1 FGFR2 FGFR3 MET NRG1 NTRK1 NTRK2 NTRK3 NUTM1 RET ROS1 RSPO2 RSPO3

DISCLAIMER:

This is a laboratory developed test, and its performance characteristics have been determined by LifeStrands Genomics. This Report was
generated using the materials and methods described above, which required the use of various reagents, protocols, instruments, software,
databases, and other items, some of which were provided or made accessible by third parties. A defect or malfunction in any such reagents,
protocols, instruments, software, databases, and or other items may compromise the quality or accuracy of the Report. The Report has been
created based on, or incorporates references to, various scientific manuscripts, references, and other sources of information, including
without limitation manuscripts, references, and other sources of information that were prepared by third parties that describe correlations
between certain genetic mutations and particular diseases (and/or certain therapeutics that may be useful in ameliorating the effects of such
diseases). Such information and correlations are subject to change over time in response to future scientific and medical findings. LifeStrands
Genomics makes no representation or warranty of any kind, expressed or implied, regarding the accuracy of the information provided by or
contained in such manuscripts, references, and other sources of information. If any of the information provided by or contained in such
manuscripts, references, and other sources is later determined to be inaccurate, the accuracy and quality of the Report may be adversely
impacted. LifeStrands Genomics is not obligated to notify you of any impact that future scientific or medical research findings may have on
the Report. The Report must always be interpreted and considered within the clinical context, and a physician should always consider the
Report along with all other pertinent information and data that a physician would prudently consider prior to providing a diagnosis to a
patient or developing and implementing a plan of care for a patient. The Report should never be considered or relied upon alone in making
any diagnosis or prognosis. The manifestation of many diseases is caused by more than one gene variant, a single gene variant may be
relevant to more than one disease, and certain relevant gene variants may not have been considered in the Report. In addition, many diseases
are caused or influenced by modifier genes, epigenetic factors, environmental factors, and other variables that are not addressed by the
Report (or that are otherwise unknown). This Report is based on a next generation sequencing assay which does not distinguish between
somatic and germline variants. If a germline variant is in question, further testing may be recommended. As such, the relevance of the Report
should be interpreted in the context of a patient's clinical manifestations. The Report provided by LifeStrands Genomics is provided on an AS
IS basis. LifeStrands Genomics makes no representation or warranty of any kind, expressed or implied, regarding the Report. In no event shall
LifeStrands Genomics be liable for any actual damages, indirect damages, and/or special or consequential damages arising out of or in any
way connected with the Report, your use of the Report, your reliance on the Report, or any defect or inaccurate information included within
the Report. Medical knowledge annotation is constantly updated and reflects the current knowledge at the time.

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PATIENT DOB DISEASE ACCESSION MRN REPORT DATE REPORT STATUS

Roy Daubet ARPON 29/12/1966 Adenocarcinoma of lung A22M0163DR - 21/09/2022 Final

Report electronically reviewed and signed out by: Dr Vivek Rathi

Date Reported: 21/09/2022

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