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Clinical Report Report Date: 26-Mar-2019

PATIENT PHYSICIAN SPECIMEN

PATIENT NAME: CHAN SIU MING REFERRAL SITE: ABC Hospital BLOCK ID: 123456789
HKID/PASSPORT NO.: A123456(7) CLINIC ID: 0001 SITE: Lung
GENDER: Female REFERRAL DOCTOR: Dr. LEE TAI MAN TYPE: FFPE
DATE OF BIRTH: 01-Jan-1961 COLLECTION DATE: 02-Jan-2019
SANOMICS LAB ID: TM18000001 ARRIVAL DATE: 14-Feb-2019
DIAGNOSIS: Non-Small Cell Lung Cancer REGISTRATION DATE: 16-Feb-2019

SUMMARY OF ACTIONABLE GENOMIC AND BIOMARKER FINDINGS

GENE GENOMIC FINDINGS§ VAF# BIOMARKER FINDINGS
EGFR T790M 14.08% Tumor Mutation Burden: TMB-High; 37.5 Muts/Mb
EGFR E746_A750del (exon 19) 5.14% Microsatellite Instability: MSI-High
ERBB2 Y772_A775dup
MYC Amplification
RET CCDC6-RET Fusion

# VAF= Variant Allele Frequency

§ Variants of Unknown functional/therapeutic Significance (VUS) are not included in this table.

FDA-APPROVED THERAPIES
GENOMIC FINDINGS THERAPY LIKELIHOOD OF RESPONSE^
EGFR T790M Osimertinib Enhanced Response
EGFR E746_A750del (exon 19) , T790M Afatinib Limited Response
EGFR E746_A750del (exon 19) , T790M Erlotinib Lack of Response
EGFR E746_A750del (exon 19) , T790M Gefitinib Lack of Response
ERBB2 Y772_A775dup Trastuzumab Emtansine Enhanced Response

TUMOR MUTATION BURDEN (TMB)

BIOMARKER FINDINGS THERAPY LIKELIHOOD OF RESPONSE^
Nivolumab Enhanced Response
Pembrolizumab Enhanced Response

TMB-High; 37.5 Muts/Mb Atezolizumab Enhanced Response

Avelumab Enhanced Response
Durvalumab Enhanced Response

MICROSATELLITE INSTABILITY (MSI)

BIOMARKER FINDINGS THERAPY LIKELIHOOD OF RESPONSE^
Nivolumab Enhanced Response
MSI-High
Pembrolizumab Enhanced Response

^ Clinical Correlation Recommended

Enhanced Response - Better than standard population response due to the presence or absence of specific markers.
Limited Response - Better than standard population response, but mitigated by the presence of conflicting markers.
Lack of Response - Likely to induce reduced or even no response compared to the standard population due to the presence of specific markers.

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DRUGS ASSOCIATED WITH POTENTIAL TOXICITY

GENOMIC FINDINGS THERAPY ZYGOSITY RELEVANCE FOR TOXICITY
DPYD*2A Irinotecan Homozygous Markers for toxicity detected
DPYD*2A Capecitabine Homozygous Markers for toxicity detected
UGT1A1*28 Fluorouracil Heterozygous Markers for toxicity detected

IN-TRIAL/OFF-LABEL DRUGS
GENOMIC FINDINGS THERAPY APPROVED INDICATIONS TRIALS
EGFR E746_A750del (exon 19) , T790M Ibrutinib Haematological Cancers NCT02321540
ERBB2 Y772_A775dup Afatinib Non-small Cell Lung Cancer (NSCLC) NCT02506517,
NCT03157089,
NCT02465060
ERBB2 Y772_A775dup Poziotinib None NCT03318939,
NCT03066206
ERBB2 Y772_A775dup Pyrotinib None NCT02834936,
NCT02500199
MYC amp Dinaciclib None NCT01434316
RET CCDC6-RET Cabozantinib Renal cell carcinoma NCT01822522
NCT01639508

VARIANTS OF UNKNOWN FUNCTIONAL/THERAPEUTIC SIGNIFICANCE

GENOMIC FINDINGS COSMIC IDS VARIANT ALLELE FREQUENCY (VAF)
RUNX1 R174Q COSM24805 5.23%

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FDA-Approved Therapies

Osimertinib Enhanced Response

Marker(s)
EGFR

Evidence Details
Osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is
approved for the treatment of EGFR Thr790Met positive metastatic non-small cell lung cancer (NSCLC) patients who have
progressed on previous EGFR-TKI therapy. Limited but strong clinical evidence has shown remarkable benefit to patients
with EGFR Thr790Met mutated tumors in terms of objective tumor response, disease control rate and progression free
survival, when compared with individuals with tumors lacking the mutation. A study assessing safety and efficacy of the
drug in patients reported confirmed overall response rate of 61%, disease control rate of 95% and PFS of 9.6 months in
patients with EGFR p.Thr790Met positive tumors vs. 21% (95% CI, 12 to 34), 61% and 2.8 months in pat ients with EGFR
p.Thr790Met negative tumors. Results from preclinical studies also associate benefit from Osimertinib to the presence of
EGFR p.Thr790Met mutations. [1,2] [2]

Marker Details
EGFR T790M (p.Thr790Met c.2369C>T NM_005228)
This mutation was detected with a variant allele frequency (VAF) of 14.08%.
This mutation has been reported as COSM6240 in COSMIC.
Oncogenecity established by in-vitro studies
The variant p.Thr790Met increases receptor autophosphorylation leading to enhanced kinase activity of EGFR in-vitro,
suggesting gain of function [3,4]. This variant usually occurs as a secondary mutation and confers resistance to first
generation EGFR tyrosine kinase inhibitors (TKIs) [5].

Drug Description
A third-generation, orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with
potential antineoplastic activity. Upon oral administration, AZD9291 covalently binds to and inhibits the activity of mutant
forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce
cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in
many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. AZD9291 preferentially inhibits
mutated forms of EGFR including T790M, a secondarily-acquired resistance mutation, and may have enhanced anti-tumor
effects in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent
is selective towards mutant forms of EGFR, its toxicity profile may be reduced when compared to non -selective EGFR
inhibitors which also inhibit wild-type EGFR.
Source: The National Cancer Institute's Cancer Drug Information

References
1 . Jänne PA et al. 2015. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 30;(372(18):):1689-99. [PMID: 25923549].
2 . Cross DA et al. 2014. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4(9):1046-61 [PMID:
24893891].
3 . Godin-Heymann N et al. 2007. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer
Res. 67(15):7319-26 [PMID: 17671201].
4 . Furuyama K et al. 2013. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci.
104(5):584-9 [PMID: 23387505].
5 . Yun CH et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-5 [PMID:
18227510].

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FDA-Approved Therapies

Afatinib Limited Response

Markers
EGFR

Evidence Details
Afatinib, a second-generation EGFR tyrosine kinase inhibitor (TKI), is approved for the first-line treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19
deletions or exon 21 (L858R) substitution mutations. It is not clear whether patients with p.Thr790Met respond to afatinib.
The LUX-Lung1 phase 2/3b trial assessed the efficacy of Afatinib vs placebo in Gefitinib/Erlotinib resistant NSCLC patients
(8 patients in this trial had the Thr790Met mutation, 4 in the Afatinib group and 4 in placebo). The study reported a better PFS
upon afatinib treatment compared to placebo (3.3 months, vs 1.1 months; p<0.0001), though there was no advantage in
terms of overall survival [10.8 months vs 12.0 months (hazard ratio 1.08; p=0.74)]. It also reported that none of the patients
showed complete response. While Afatinib has been suggested to be effective against the secondary mutation p.Thr790Met
preclinically, a study has recently reported cell lines with high copy number of this mutation to be resistant to Afatinib. This
study also presented a case, where a lung cancer patient with an EGFR exon 19 deletion mutation when treated with first line
Afatinib, acquired resistance to the drug due to the emergence of the Thr790Met mutation. Addition of Cetuximab to
Afatinib may be beneficial for patients who have progressed on EGFR TKI and chemotherapy, with similar response rates
observed in p.Thr790Met positive and negative tumors. [1-6] [4,7]

Marker Details
EGFR T790M (p.Thr790Met c.2369C>T NM_005228)
This mutation was detected with a variant allele frequency (VAF) of 14.08%.
This mutation has been reported as COSM6240 in COSMIC.
Oncogenecity established by in-vitro studies
The variant p.Thr790Met increases receptor autophosphorylation leading to enhanced kinase activity of EGFR in-vitro,
suggesting gain of function [8,9]. This variant usually occurs as a secondary mutation and confers resistance to first
generation EGFR tyrosine kinase inhibitors (TKIs) [10].

EGFR E746_A750del (exon 19) (p.Glu746_Ala750del c.2235_2249del NM_005228)

This mutation was detected with a variant allele frequency (VAF) of 5.14%.
This mutation has been reported as COSM6223 in COSMIC.
Oncogenicity established in in-vitro studies
The EGFR exon 19 alteration, p.Glu746_Ala750del, occurring within exon 19 of EGFR, has been shown to constitutively
activate EGFR leading to phosphorylation of the downstream effectors AKT and ERK1/2 in-vitro, indicating a gain of function
[11].

Drug Description
A third-generation, orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with
An orally bioavailable anilino-quinazoline derivative and inhibitor of the receptor tyrosine kinase (RTK) epidermal growth
factor receptor (ErbB; EGFR) family, with antineoplastic activity. Upon administration, Afatinib selectively and irreversibly
binds to and inhibits the epidermal growth factor receptors 1 (ErbB1; EGFR), 2 (ErbB2; HER2), and 4 (ErbB4; HER4), and
certain EGFR mutants, including those caused by EGFR exon 19 deletion mutations or exon 21 (L858R) mutations. This
may result in the inhibition of tumor growth and angiogenesis in tumor cells overexpressing these RTKs. Additionally, Afatinib
inhibits the EGFR T790M gatekeeper mutation which is resistant to treatment with first-generation EGFR inhibitors. EGFR,
HER2 and HER4 are RTKs that belong to the EGFR superfamily; they play major roles in both tumor cell proliferation and
tumor vascularization and are overexpressed in many cancer cell types.
Source: The National Cancer Institute's Cancer Drug Information

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References
1 . Ribeiro Gomes J et al. 2015. Combination of afatinib with cetuximab in patients with EGFR-mutant non-small-cell lung cancer resistant to EGFR inhibitors. Onco Targets
Ther 8:1137-42 [PMID: 26056478].
2 . Janjigian YY et al. 2014. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
Cancer Discov 4(9):1036-45 [PMID: 25074459].
3 . Bordi P et al. Overcoming T790M-driven acquired resistance to EGFR-TKIs in NSCLC with afatinib: a case report. Tumori 100(1):e20-3 [PMID: 24675505].
4 . Kim Y et al. 2012. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol. Cancer Ther. 11(3):784-91 [PMID: 22228822].
5 . Katakami N et al. 2013. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib,
gefitinib, or both. J. Clin. Oncol. 31(27):3335-41 [PMID: 23816963].
6 . Miller VA et al. 2012. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two
lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised
trial. Lancet Oncol. 13(5):528-38 [PMID: 22452896].
7 . Zhang S et al. 2015. Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation. Oncotarget. 6(8):5832-45. [PMID:
25714021].
8 . Godin-Heymann N et al. 2007. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer
Res. 67(15):7319-26 [PMID: 17671201].
9 . Furuyama K et al. 2013. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci.
104(5):584-9 [PMID: 23387505].
10 . Yun CH et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-5 [PMID:
18227510].
11 . Sakai K et al. 2006. Dimerization and the signal transduction pathway of a small in-frame deletion in the epidermal growth factor receptor. FASEB J. 20(2):311-3 [PMID:
16373402].

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FDA-Approved Therapies

Erlotinib Lack of Response

Markers
EGFR

Evidence Details
Erlotinib and Gefitinib are EGFR tyrosine kinase inhibitors (TKIs) approved for the first-line treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19
deletions or exon 21 (L858R) substitution mutations. Clinical evidence in lung cancer indicates p.Thr790Met to be an EGFR
mutation acquired after therapy with Erlotinib or Gefitinib. A clinical study in lung cancer identified p.Thr790Met as the most
prevalent mechanism of acquired resistance to EGFR TKIs like Erlotinib and Gefitinib. 63% of the patients (n=155) who
showed acquired resistance to Erlotinib or Gefitinib had this mutation (95% CI 55-70%). [1-11]

Marker Details
EGFR T790M (p.Thr790Met c.2369C>T NM_005228)
This mutation was detected with a variant allele frequency (VAF) of 14.08%.
This mutation has been reported as COSM6240 in COSMIC.
Oncogenecity established by in-vitro studies
The variant p.Thr790Met increases receptor autophosphorylation leading to enhanced kinase activity of EGFR in-vitro,
suggesting gain of function [12,13]. This variant usually occurs as a secondary mutation and confers resistance to first
generation EGFR tyrosine kinase inhibitors (TKIs) [14].

EGFR E746_A750del (exon 19) (p.Glu746_Ala750del c.2235_2249del NM_005228)

This mutation was detected with a variant allele frequency (VAF) of 5.14%.
This mutation has been reported as COSM6223 in COSMIC.
Oncogenicity established in in-vitro studies
The EGFR exon 19 alteration, p.Glu746_Ala750del, occurring within exon 19 of EGFR, has been shown to constitutively
activate EGFR leading to phosphorylation of the downstream effectors AKT and ERK1/2 in-vitro, indicating a gain of function
[15].

Drug Description
A quinazoline derivative with antineoplastic properties. Competing with adenosine triphosphate, erlotinib reversibly binds to
the intracellular catalytic domain of epidermal growth factor receptor (EGFR) tyrosine kinase, thereby reversibly inhibiting
EGFR phosphorylation and blocking the signal transduction events and tumorigenic effects associated with EGFR activation.
Source: The National Cancer Institute's Cancer Drug Information

References
1 . Paik PK et al. 2012. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol. Cancer
Ther. 11(11):2535-40 [PMID: 22896669].
2 . Zhou C et al. 2011. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive non-small-cell lung cancer (OPTIMAL, CTONG-
0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12(8):735-42 [PMID: 21783417].
3 . Wu JY et al. 2011. Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small
cell lung cancer. Clin. Cancer Res. 17(11):3812-21 [PMID: 21531810].
4 . Miller VA et al. 2008. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib.
J. Clin. Oncol. 26(9):1472-8 [PMID: 18349398].
5 . Sequist LV et al. 2007. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 12(1):90-8
[PMID: 17285735].
6 . Eberhard DA et al. 2005. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung
cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23(25):5900-9 [PMID: 16043828].

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7 . Zhu CQ et al. 2008. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J. Clin. Oncol.
26(26):4268-75 [PMID: 18626007].
8 . Tsao MS et al. 2005. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N. Engl. J. Med. 353(2):133-44 [PMID: 16014883].
9 . Li N et al. 2014. Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung
Cancer. PLoS ONE 9(7):e102777 [PMID: 25029199].
10 . Yu HA et al. 2013. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients
with EGFR-mutant lung cancers. Clin. Cancer Res. 19(8):2240-7 [PMID: 23470965].
11 . Pao W et al. 2005. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.
2(3):e73 [PMID: 15737014].
12 . Godin-Heymann N et al. 2007. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer
Res. 67(15):7319-26 [PMID: 17671201].
13 . Furuyama K et al. 2013. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci.
104(5):584-9 [PMID: 23387505].
14 . Yun CH et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-5 [PMID:
18227510].
15 . Sakai K et al. 2006. Dimerization and the signal transduction pathway of a small in-frame deletion in the epidermal growth factor receptor. FASEB J. 20(2):311-3 [PMID:
16373402].

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FDA-Approved Therapies

Gefitinib Lack of Response

Markers
EGFR

Evidence Details
Erlotinib and Gefitinib are EGFR tyrosine kinase inhibitors (TKIs) approved for the first-line treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19
deletions or exon 21 (L858R) substitution mutations. Clinical evidence in lung cancer indicates p.Thr790Met to be an EGFR
mutation acquired after therapy with Erlotinib or Gefitinib. A clinical study in lung cancer identified p.Thr790Met as the most
prevalent mechanism of acquired resistance to EGFR TKIs like Erlotinib and Gefitinib. 63% of the patients (n=155) who
showed acquired resistance to Erlotinib or Gefitinib had this mutation (95% CI 55-70%). [1-11]

Marker Details
EGFR T790M (p.Thr790Met c.2369C>T NM_005228)
This mutation was detected with a variant allele frequency (VAF) of 14.08%.
This mutation has been reported as COSM6240 in COSMIC.
Oncogenecity established by in-vitro studies
The variant p.Thr790Met increases receptor autophosphorylation leading to enhanced kinase activity of EGFR in-vitro,
suggesting gain of function [12,13]. This variant usually occurs as a secondary mutation and confers resistance to first
generation EGFR tyrosine kinase inhibitors (TKIs) [14].

EGFR E746_A750del (exon 19) (p.Glu746_Ala750del c.2235_2249del NM_005228)

This mutation was detected with a variant allele frequency (VAF) of 5.14%.
This mutation has been reported as COSM6223 in COSMIC.
Oncogenicity established in in-vitro studies
The EGFR exon 19 alteration, p.Glu746_Ala750del, occurring within exon 19 of EGFR, has been shown to constitutively
activate EGFR leading to phosphorylation of the downstream effectors AKT and ERK1/2 in-vitro, indicating a gain of function
[15].

Drug Description
An anilinoquinazoline with antineoplastic activity. Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including
the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase -dependent tumor growth.
Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor
autophosphorylation and resulting in inhibition of signal transduction. Gefitinib may also induce cell cycle arrest and inhibit
angiogenesis.
Source: The National Cancer Institute's Cancer Drug Information

References
1 . Paik PK et al. 2012. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol. Cancer
Ther. 11(11):2535-40 [PMID: 22896669].
2 . Zhou C et al. 2011. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutationpositive
non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12(8):735-42 [PMID: 21783417].
3 . Wu JY et al. 2011. Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small
cell lung cancer. Clin. Cancer Res. 17(11):3812-21 [PMID: 21531810].
4 . Miller VA et al. 2008. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib.
J. Clin. Oncol. 26(9):1472-8 [PMID: 18349398].
5 . Sequist LV et al. 2007. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 12(1):90-8
[PMID: 17285735].
6 . Eberhard DA et al. 2005. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic

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 SAMPLE
indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23(25):5900-9 [PMID: 16043828].
7 . Zhu CQ et al. 2008. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J. Clin. Oncol.
26(26):4268-75 [PMID: 18626007].
8 . Tsao MS et al. 2005. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N. Engl. J. Med. 353(2):133-44 [PMID: 16014883].
9 . Li N et al. 2014. Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung
Cancer. PLoS ONE 9(7):e102777 [PMID: 25029199].
10 . Yu HA et al. 2013. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res.
19(8):2240-7 [PMID: 23470965].
11 . Pao W et al. 2005. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.
2(3):e73 [PMID: 15737014].
12 . Godin-Heymann N et al. 2007. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer
Res. 67(15):7319-26 [PMID: 17671201].
13 . Furuyama K et al. 2013. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci.
104(5):584-9 [PMID: 23387505].
14 . Yun CH et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-5 [PMID:
18227510].
15 . Sakai K et al. 2006. Dimerization and the signal transduction pathway of a small in-frame deletion in the epidermal growth factor receptor. FASEB J. 20(2):311-3 [PMID:
16373402].

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Tumor Mutation Burden

Nivolumab, Pembrolizumab, Atezolizumab , Avelumab , Durvalumab

Enhanced Response

Marker
TMB High; 37.5 Muts/Mb

Evidence Details
Tumor mutational burden (TMB) is a measure of the mutation load in a tumor sample. The TMB for this tumor sample is
determined to be High. Recent studies have shown that TMB may be predictive of response to immunotherapy with increased
progression free survival observed in patients whose tumors have high TMB across multiple cancers [1-7]. The presence of low
TMB has been associated with lower rates of clinical benefit to immunotherapy when compared to high TMB in some clinical
studies [8-11].

References
1 . Goodman AM et al. 2017. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther. 16 (11):2598-
2608
[PMID: 28835386].
2 . Hellmann MD et al. 2018. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. [PMID: 29658845].
3 . Carbone DP et al. 2017. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 376 (25):2415-2426 [PMID: 28636851].
4 . Hendriks LE et al. 2018. Clinical utility of tumor mutational burden in patients with non-small cell lung cancer treated with immunotherapy. Transl Lung Cancer
Res. 7 (6):647-660 [PMID: 30505709].
5 . 2018. High TMB Predicts Immunotherapy Benefit. Cancer Discov. 8 (6):668 [PMID: 29661758].
6 . Yarchoan M et al. 2017. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 377 (25):2500-2501 [PMID: 29262275].
7 . Hellmann MD et al. 2018. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer
Cell. 33 (5):853-861.e4 [PMID: 29731394].
8 . Le DT et al. 2015. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 372 (26):2509-20 [PMID: 26028255].
9 . Rizvi NA et al. 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348 (6230):124-8 [PMID:
25765070].
10 . Snyder A et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371 (23):2189-99 [PMID: 25409260].
11 . Rosenberg JE et al. 2016. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with
platinumbased
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387 (10031):1909-20 [PMID: 26952546].

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Microsatellite Instability

Nivolumab, Pembrolizumab Enhanced Response

Marker
MSI-High

Evidence Details
This sample has tested positive for microsatellite instability.
Pembrolizumab is approved for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative
treatment options or microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. [1]
Nivolumab is approved for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. [2]
Patients with stage II MSI-H colorectal cancer show good prognosis and may not benefit additionally from adjuvant 5-FU therapy.
Clinical studies in stage II colon cancer have demonstrated that patients with dMMR (MSI-H) tumors receiving 5-FU had poor
overall survival (OS) and no improvement in disease free survival (DFS) compared with those randomly assigned to surgery alone
[3-6].

References
1. Keytruda FDA Label - https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s024lbl.pdf
2. Opdivo FDA Label - https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s055lbl.pdf
3. Benatti P et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005 Dec 1;11(23):8332-40. Erratum in: Clin Cancer Res. 2006 Jun 15;12(12):3868-
9. PubMed [PMID: 16322293].
4. Sinicrope FA. DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer. Nat Rev ClinOncol. 2010 Mar;7(3):174-7. doi: 10.1038/nrclinonc.2009.235. Review.
PubMed [PMID: 20190798]; PubMed Central PMCID: [PMC: 3767984].
5. Sargent DJ et al Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracilbased adjuvant therapy in colon cancer. J Clin Oncol. 2010 Jul
10;28(20):3219-26. doi: 10.1200/ JCO.2009.27.1825. Epub 2010 May 24. Erratum in: J Clin Oncol. 2010 Oct 20;28(30):4664. PubMed PMID: 20498393; PubMed Central PMCID:
[PM: C2903323].
6. ASCO Abstract 15S - http://ascopubs.org/doi/abs/10.1200/jco.2008.26.15_suppl.4008

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In-Trial/Off-Label Drugs

Ibrutinib

Marker(s)
EGFR

Evidence Details
Non-small cell lung cancers (NSCLC) positive for activating mutations in EGFR show an activation of downstream pathways
leading to increased cell proliferation and survival [1-4]. Preliminary evidence from preclinical studies suggests that Ibrutinib,
a BTK inhibitor could potentially inhibit EGFR mutant NSCLC [5-7]. Some studies have also indicated sensitivity to the drug
in cell lines resistant to first generation EGFR tyrosine kinase inhibitors (TKIs) [5,7], [8].
Preclinical studies have demonstrated anti-tumor activity of ibrutinib in NSCLC xenografts and cell lines [5 -7], [8] and
suggested that combination of MEK inhibitor, GSK1120212 and Ibrutinib could potentiate the effect of Ibrutinib against the
EGFR (p.Leu858Arg/p.Thr790Met) mutation in-vitro [6].

Marker Details
EGFR T790M (NM_005228 c.2369C>T p.Thr790Met)
This mutation was detected with a variant allele frequency (VAF) of 14.08%.
This mutation has been reported as COSM6240 in COSMIC.
The variant p.Thr790Met increases receptor autophosphorylation leading to enhanced kinase activity of EGFR in-vitro,
suggesting gain of function [9,10]. This variant usually occurs as a secondary mutation and confers resistance to first
generation EGFR tyrosine kinase inhibitors (TKIs) [11].

EGFR E746_A750del (exon 19) (NM_005228 c.2235_2249del p.Glu746_Ala750del)

This mutation was detected with a variant allele frequency (VAF) of 12.14%.
This mutation has been reported as COSM6223 in COSMIC.
The EGFR exon 19 alteration, p.Glu746_Ala750del, occurring within exon 19 of EGFR, has been shown to constitutively
activate EGFR leading to phosphorylation of the downstream effectors AKT and ERK1/2 in-vitro, indicating a gain of function
[12].

Clinical Trials
Trial ID Status Phase Title
NCT02321540 Active, not recruiting Phase 1/Phase 2
A Phase I/II Study of Ibrutinib in
Previously Treated
Epidermal Growth Factor
Receptor (EGFR) Mutant
Non-Small Cell Lung Cancer
Source: ClinicalTrials.gov, WHO's ICTRP and The National Cancer Institute's Cancer Clinical Trials

Drug description
An inhibitor of poly (ADP-ribose) polymerase (PARP) with potential antineoplastic activity. Niraparib inhibits PARP activity, oral
administration, ibrutinib binds to and irreversibly inhibits BTK activity, thereby preventing both B -cell activation and B-
cell-mediated signaling. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member
of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is required for B cell receptor signaling, plays a key role
in B-cell maturation, and is overexpressed in a number of B-cell malignancies. The expression of BTK in tumor cells is also
associated with increased proliferation and survival.
Source: The National Cancer Institute's Cancer Drug Information

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References
1 . Prenzel N et al. 2001. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8(1):11-
31 [PMID: 11350724].
2 . Dearden S et al. 2013. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann. Oncol. 24(9):2371-6
[PMID: 23723294].
3 . Roengvoraphoj M et al. 2013. Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small
cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat. Rev. 39(8):839-50 [PMID: 23768755].
4 . Giaccone G 2005. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J. Clin. Oncol. 23(14):3235-42 [PMID: 15886311].
5 . Gao W et al. 2014. Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells. J. Natl. Cancer Inst. 106(9) [PMID: 25214559].
6 . Wu H et al. 2015. Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells. Oncotarget
6(31):31313-22 [PMID: 26375053].
7 . Wang A et al. 2016. Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation. Oncotarget 7(43):69760-69769 [PMID: 27626175].
8 . ESMO_abstr32P
9 . Godin-Heymann N et al. 2007. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer
Res. 67(15):7319-26 [PMID: 17671201].
10 . Furuyama K et al. 2013. Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors. Cancer Sci.
104(5):584-9 [PMID: 23387505].
11 . Yun CH et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-5 [PMID:
18227510].
12 . Sakai K et al. 2006. Dimerization and the signal transduction pathway of a small in-frame deletion in the epidermal growth factor receptor. FASEB J. 20(2):311-3 [PMID:
16373402].

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TEST DESCRIPTION
OncoSnap® Pro NGS-based Tumor Profiling Service screens for somatic alterations in tumor tissue samples, enabling reliable
assessments of potential treatment options for cancer patients. To perform this screening, DNA is extracted from tumor tissue
samples, and then genomic alterations are examined by high-throughput next generation sequencing of a panel of well curated
466 target genes. The types of genomic alterations detectable by OncoSnap® Pro include single nucleotide variations (SNVs),
insertions or deletions (Indels), copy number alterations (CNAs) and fusions of selected genes. Tumor Mutation Burden (TMB) and
Microsatellite Instability (MSI) status is also determined. Exonic and selected intronic regions are sequenced for genes on the
OncoSnap® Pro gene panel as such coverage has been suggested to have clinical utility.

Tumor mutational burden (TMB) is measured by counting all synonymous and non-synonymous variants present at 1% allele
frequency or greater, and filtering out known and likely driver mutations according to published literature and database including
Catalogue of Somatic Mutations in Cancer (COSMIC) and OncoKB. The resulting mutation number is then divided by the coding
region corresponding to the number of total variants counted. The resulting number is communicated as mutations per Mb unit
(Muts/Mb). TMB-High was defined as at least 10 Mut/Mb and first Quartile of a specific tumor type population, others was defined
TMB-Low.

Using the 23 intronic homopolymer repeat loci, the somatic MSI status is inferred by interrogating all available genomic
microsatellites covered by the test within tumor samples against the matched normal. MSI status results may be reported as MSI-
High or MS-Stable.

According to the emerging clinical evidence that increased TMB may be associated with greater sensitivity to immunotherapeutic
agents. Immunotherapy was recommended for Patients with TMB-High or MSI-High. The assay will be updated periodically to
reflect new knowledge on cancer therapies and clinical trials.

PERFORMANCE SPECIFICATIONS
All Variant Types 98.8%1 (96.9%)2
1% ≤ VAF < 10% ≥ 99.7%
SNVs/Indels
Sensitivity VAF ≥ 10% ≥ 99.8%
Copy Number Alterations 95.5%
Fusion Rearrangements3 ≥ 99.9%
All Variant Types ≥ 99.9%1, 2
Specificity
SNVs/Indels ≥ 99.9%
All Variant Types 98.6%1 (99.0%)2
SNVs/Indels ≥ 99.9%
Positive Predictive Value
Copy Number Alterations ≥ 99.9%
Fusion Rearrangements3 ≥ 99.9%
SNVs/Indels ≥ 99.9%
Copy Number Alterations 96.2%
Concordance Fusion Rearrangements ≥ 99.9%
Tumor Mutation Burden4 98.6%
Microsatellite Instability5 99.0%
Remarks: Limit of Detection - 1% VAF for SNVs/Indels

1In-house analytical validation is calculated based on reference standards that cover multiple endogenous SNPs, insertions and deletion s, copy number variants
and fusion rearrangements, which are verified by ddPCR or NGS.
2In-house clinical validation is calculated using 20 FFPE samples of different tissue types, includes lung, colon, breast and ovary.
3Performance for fusion rearrangements with targeted intronic regions where these breakpoints frequently occur as reported in the COSMIC database
4Concordance of Tumor Mutation Burden is calculated based on linear regression with whole exome sequencing on clinical FFPE samples
5Concordance of Microsatellite Instability is calculated based on statistical comparison with gold standards: PCR-MSI and IHC-MMR on clinical FFPE samples

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GENE PANEL
Genes for the detection of SNVs, Indels and Copy Number Alterations (446 Genes)
ABL1 ABL2 ACVR1B ACVR2A ADAM29 ADGRA2 AKT1 AKT2 AKT3
ALK AMER1 APC APEX1 APOBEC3B AR ARAF ARFRP1 ARID1A
ARID1B ARID2 ASXL1 ATF1 ATM ATR ATRX AURKA AURKB
AXIN1 AXIN2 AXL B2M BAP1 BARD1 BCL2 BCL2L1 BCL2L11(BIM)
BCL2L2 BCL6 BCL7A BCOR BCORL1 BCR BIRC3 BIRC5 BLK
BLM BMPR1A BMX BRAF BRCA1 BRCA2 BRD4 BRIP1 BTG1
BTK CAMTA1 CARD11 CASP8 CBFB CBL CCND1 CCND2 CCND3
CCNE1 CD274(PD-L1) CD36 CD79A CD79B CDC73 CDH1 CDK12 CDK4
CDK6 CDK8 CDKN1A CDKN1B CDKN2A CDKN2B CDKN2C CEBPA CFTR
CHD2 CHD4 CHEK1 CHEK2 CIC COL1A1 CRBN CREB3L1 CREB3L2
CREBBP CRKL CRLF2 CSF1 CSF1R CSK CSNK1A1 CTCF CTNNA1
CTNNB1 CUL3 CXCR4 CYLD CYP17A1 CYP2D6 DAXX DDR1 DDR2
DICER1 DNMT3A DOT1L DPYD EGF EGFR EMSY EP300 EPCAM
EPHA2 EPHA3 EPHA5 EPHA7 EPHB1 ERBB2(HER2) ERBB3 ERBB4 ERCC1
ERG ERRFI1 ESR1(ER) ETV1 ETV4 ETV5 ETV6 EWSR1(EWS) EZH2
FAM135B FAM46C FANCA FANCC FANCD2 FANCE FANCF FANCG FANCL
FANCM FAS FAT1 FAT3 FAT4 FBXW7 FEN1 FEV FGF10
FGF12 FGF14 FGF19 FGF23 FGF3 FGF4 FGF6 FGF7 FGFR1
FGFR2 FGFR3 FGFR4 FGR FH FLCN FLI1 FLT1 FLT3
FLT4 FOS FOXL2 FOXO1 FOXP1 FRS2 FUBP1 FUS FYN
GABRA6 GATA1 GATA2 GATA3 GATA4 GATA6 GID4 GLI1 GLI2
GLI3 GNA11 GNA13 GNAQ GNAS GRIN2A GRM3 GSK3B H3F3A
HCK HDAC9 HGF HNF1A HRAS HSD3B1 HSP90AA1 HTATIP2 IDH1
IDH2 IGF1R IGF2 IKBKE IKZF1 IL7R INHBA INPP4B IRF2
IRF4 IRS2 ITK JAK1 JAK2 JAK3 JUN KAT6A KDM5A
KDM5B KDM5C KDM6A KDR KEAP1 KEL KIT KLHL6 KMT2A
KMT2C KMT2D KRAS LCK LIMK1 LMO1 LRP1 LRP1B LRP2
LYN LZTR1 MACC1 MAGI2 MAP2K1(MEK1) MAP2K2(MEK2) MAP2K4 MAP3K1 MAP3K13
MAP4K5 MCL1 MDM2 MDM4 MED12 MEF2B MEN1 MERTK MET
MGMT MITF MLH1 MPL MRE11 MS4A1 MSH2 MSH6 MST1R
MTOR MUTYH MYB MYC MYCL MYCN MYD88 NBN NCOA2
NCOR1 NEK11 NF1 NF2 NFE2L2 NFIB NFKBIA NKX2-1 NOTCH1
NOTCH2 NOTCH3 NOTCH4 NPM1 NR4A3 NRAS NRG1 NRG3 NSD1
NSD2 NTRK1 NTRK2 NTRK3 NUP93 PAK3 PALB2 PARK2 PARP1
PARP2 PARP3 PARP4 PAX5 PBRM1 PCA3 PDCD1(PD-1) PDCD1LG2 PDGFB
PDGFRA PDGFRB PDK1 PHF6 PIK3C2B PIK3CA PIK3CB PIK3CD PIK3CG
PIK3R1 PIK3R2 PKD2 PLA2G1B PLCG2 PMS2 POLB POLD1 POLE
PPP2R1A PRDM1 PREX2 PRKACA PRKAR1A PRKCI PRKDC PRSS1 PRSS8
PTCH1 PTEN PTK2 PTK6 PTPN11 QKI RAC1 RAD50 RAD51
RAD51B RAD51C RAD51D RAD52 RAD54B RAD54L RAF1 RANBP2 RARA
RB1 RBM10 RECQL REL RELA RELB RET RHBDF2 RHOA
RICTOR RIT1 RNF43 ROCK1 ROCK2 ROS1 RPTOR RUNX1 RUNX1T1
RXRA SDHA SDHB SDHC SDHD SETBP1 SETD2 SF3B1 SIK1
SLIT2 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SMARCD1 SMO SNCAIP
SND1 SOCS1 SOX10 SOX2 SOX9 SPEN SPINK1 SPOP SPTA1
SRC SRMS SRSF2 SS18 SSX1 STAG2 STAT3 STAT4 STK11
STK24 SUFU SYK TAF1 TBX3 TCF7L2 TEK TERT TET1
TET2 TET3 TFE3 TGFBR1 TGFBR2 TIE1 TIPARP TMPRSS2 TNFAIP3
TNFRSF14 TNFSF11 TNFSF13B TNK2 TOP1 TOP2A TP53 TP63 TPMT
TSC1 TSC2 TSHR TYK2 U2AF1 UGT1A1 USP6 VEGFA VGLL3
VHL WEE1 WEE2 WISP3 WT1 XIAP XPO1 XRCC2 XRCC3
YES1 YWHAE ZBTB2 ZNF217 ZNF703 ZNF750 ZRSR2

Genes for the detection of Fusion Rearrangements (41 Genes)

ALK AKT3 BCL2 BCR BRAF BRCA1 BRCA2 BRD4 DDR2
EGFR ERBB2(HER2) ERBB4 ETV1 ETV4 ETV5 ETV6 EWSR1(EWS) FGFR1
FGFR2 FGFR3 JAK2 KIT MET MSH2 MYB NOTCH1 NOTCH2
NRG1 NTRK1 NTRK2 NTRK3 PDGFB PDGFRA RAF1 RARA RET
ROS1 SS18 TMPRSS2 USP6 YWHAE

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LIMITATIONS AND DISCLAIMER

Treatment Decisions based upon test results
Drugs referenced in this report may not be suitable for a particular patient. The information in this report must be further interpreted along with
other diagnostic tests and all other relevant information regarding a particular patient, before the patient’s treating physician recommends a
course of treatment. Any treatment recommendation and/or decisions shall be made by the physician(s) and patient and not by Sanomics Ltd.
The selection of any, all or none of the drugs associated with potential clinical benefit (or potential lack of clinical benefit) resides entirely within
the discretion of the treating physician.

Interpretation of Variants
The therapeutic implications listed in the report are based on the interpretation derived as a result of analysis of up-to-date scientific literature
from various sources. The Human Genome Variation Society (HGVS) recommendations are adopted for presenting sequence variants in this
report. Interpretation of this report is based on the clinical diagnosis provided and certain other relevant clinical information provided. Some
findings listed in this report may be based on pre-clinical studies or studies not in the given patient’s tumor type. Inclusion of alterations is
dependent upon the assessment of their significance; hence not all alterations detected are listed in this report. An alteration that is not related
to tumor with VAF less than 5%, will be filtered before interpretation and curation. An alteration is considered actionable or significant if it can
be linked to potential response or resistance to a particular therapy, or prognosis or diagnosis or sub-typing of the disease. Alterations reported
may include somatic or germline (inherited) variants. The test does not distinguish between germline and somatic alterations, thus additional
testing may be warranted in certain cases where variants are suspected to be germline variants. OncoSnap® Pro is not validated for the detection
of germline or de novo variants that are associated with hereditary cancer risks.

Genomic Alterations Detection Limitations

Since somatic variants can be distributed unevenly in tumor tissues, negative results do not rule out the presence of somatic variants in all tumor
regions. The quality of sequencing and coverage varies between regions. Many factors such as homopolymers, GC-rich regions etc. influence the
quality of sequencing and coverage, which may result in lower sequence reads or lack of detection of a particular genetic lesion, such as Insertions
or deletions with low allelic fraction in homopolymer regions. OncoSnap® Pro analyzes SNVs and Indels with ≥1% VAF (see Performance
Specification table for sensitivity and specificity values).

Sample Quality and Analytical Sensitivity

Please note that the reported sensitivity and specificity might be affected due to conditions including but not limited to improper formalin fixing
of the tissue and storage of the FFPE blocks, insufficient quantity and sub-optimal quality of DNA extracted from tumor samples, and analytical
differences arising from varying sample types.

Tumor Content and Analytical Sensitivity

The OncoSnap® Pro requires tumor specimens with at least 20% tumor content. The sensitivity of the test can vary from sample to sample due
to tumor heterogeneity or sub-optimal estimation of tumor content after sample collection. Therefore, there is a possibility that somatic variants
are classified as germline variants or vice versa. The absence of accurate quantification of tumor content might result in variations in variant
calling.

Prediction of Clinical Response

The OncoSnap® Pro report does not guarantee that a suggested drug will be effective in the particular case. It also does not promise that a drug
with potential lack of effect will indeed provide no clinical benefit. The classification and interpretation of all mutations identified in this test is
based on currently available scientific information. Inclusion of variations is dependent on the assessment of their significance. This test is not
designed for clinical diagnostic purpose. It is strongly recommended that results should be communicated to the patient in a setting that includes
appropriate counselling, and interpreted with other clinical findings by a qualified doctor.

Compliance Statement
OncoSnap® Pro is a cancer genomics test that was developed by OrigiMed Co., Ltd. Processing of this test was performed and managed by
Sanomics Ltd., Hong Kong. The bioinformatics analysis was supported by OrigiMed Co., Ltd. The information on treatment regimens, correlations
between genetic variants and pharmaceuticals, clinical relevance of variants, available clinical trials and related publications were provided by
Strand Life Sciences Private Limited, which provided the information to qualified physicians for supporting clinical management, and such
information does not constitute any medical advice or prescription for patients.

Signature

____________________
Registered MLT Wong Siu Ming
Sanomics Ltd.

End of Report

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