APPLICATION OF PERSONALISED HEALTHCARE IN

ONCOLOGY PRACTICE: A DIAGNOSTIC AND TREATMENT

CHALLENGE

LITERATURE REVIEW

Personalised Oncology Treatment: Navigating Cancer Treatment Options Based on Tumour

Characteristics

For many years, patients with cancer have had limited treatment options, with cancer diagnoses and
treatments based upon the location of origin and the histologic classification of the tumour. As
technology advances and researchers learn more about cancer, molecular characteristics are becoming
an increasingly important part of diagnosis and treatment.1 This literature review focuses on one of
newest weapons in the oncologist's arsenal: comprehensive genomic profiling (CGP), a tool for broadly
detecting a tumour's specific molecular features and using that knowledge to target potentially matching
cancer therapies. The application of CGP in the management of rare malignancies (ie, cancers of
unknown primary, intrahepatic cholangiocarcinoma, uterine sarcoma) will be also be discussed in this
review to support the cases presented in this program.

Each person has about 25,000 different genes that are made up of about 3 billion DNA units.2 Over the
past few decades, genomic sequencing has become more readily available, and high-throughput
sequencing technology is now capable of sequencing an entire human genome in a matter of hours.1,3
Oncologists have the opportunity to use next-generation sequencing (NGS) to identify a personalised
medicine approach for patients with many different forms of cancer based on genetic information
rather than just cancer type.3 Identifying specific genetic information may also help to identify patients
who are eligible to enrol in clinical trials investigating new therapies across the spectrum of cancer.

Precision Oncology

Biomarkers identified through NGS may help diagnose cancer, inform prognosis, anticipate a patient's
response to therapy, and assess outcomes.1,4 Today, the precision oncology approach aims to match a
tumour's molecular characteristics to targeted drugs that can improve outcomes (eg, a targeted tyrosine
kinase inhibitor [TKI] in a patient with lung cancer) instead of relying on nontargeted therapies (eg,
chemotherapy for lung cancer). New clinical trial designs are also including NGS to identify specific
genetic variants for study. The rarity of many genetic mutations complicates clinical trials, because a
certain number of enrolled patients is required for analysis. Even so, several studies have been
performed or are underway that are using NGS to seek actionable tumour mutations. "Umbrella" trials
evaluate targeted agents against a range of mutations in a single cancer type: such trials include
LUNG-MAP (squamous cell lung cancer), ALCHEMIST (non-small cell lung cancer [NSCLC]), and
BATTLE (NSCLC). "Basket" trials also evaluate targeted agents, but against multiple kinds of tumours;
examples include NCI-MATCH (patients with solid tumours, with disease that has progressed after at
least 1 standard therapy, or for whom there is no standard therapy) and SUMMIT (HER kinase
inhibition in HER2- and HER3-mutant cancers).1 Finally, for patients whose cancers have no known
effective treatment, the possibility of a treatment based on the cancer's molecular characteristics may
offer some hope. Indeed, the prospective, phase 2 CUPISCO trial is randomising patients with cancer

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of unknown primary site (CUP) to either standard chemotherapy or to targeted treatment or
immunotherapy based on genetic alterations in their tumours; however, the results are not expected for
a few years.

Precision Oncology Therapies

Currently available targeted drugs (ie, therapies selected on the basis of the molecular characteristics of
a patient's tumour) may be:

1. Officially approved as a cancer treatment

2. Off-label treatment (eg, the drug is approved for specific molecular findings in another type of
cancer)
3. Experimental (ie, only available within a clinical trial)

The clinician must consider drug availability, approval, patient preferences, and cost when making
treatment recommendations. Furthermore, all treatment decisions should be made following a joint
discussion between the patient and the physician, with the expert advice of a multidisciplinary
molecular tumour board when possible. There are currently several models of molecular tumour boards,
but generally, the board first reviews the patient's NGS test results to form a recommendation of either
an approved or investigational treatment and/or enrolment in available clinical trials/compassionate use
programmes.6

Next-Generation Sequencing

NGS is a faster sequencing method than the original Sanger method and works by detecting differences
between a patient's genome and a reference (normal) genome. NGS can detect variants including
insertions or deletions in a specific DNA sequence or an array of sequences. Simultaneous evaluation of
both DNA and RNA from the same cell has also recently become available. NGS is performed via
DNA sequencing, RNA sequencing, single-cell RNA and DNA sequencing, and using samples from
liquid biopsy.3

DNA Sequencing

DNA can be sequenced by synthesis, pyrosequencing, or ligation. In sequencing by synthesis, small

genomic sections are flagged by man-made target sequences. Then, single bases with a fluorescent tag
are added to initiate a complementary DNA strand. A fluoroscopy microscope is used to capture the
light off of the fluorescent tags to map the genome base by base. In pyrosequencing, the process also
begins with target sequences, but then individual nucleotides are added that are bound to
pyrophosphate. As nucleotides are incorporated into the DNA template, pyrophosphate is released and
generates light that is captured by a camera. In ligation sequencing, short sections of nucleotides called
oligonucleotides are bound to one another. Each oligonucleotide has 8 bases, 2 of which are used as
starter probes. The end of each of the probes is attached to a fluorescent dye. The primer is bound to
the adapter sequence, and subsequent primer probes are attached to the adapter sequence and ligated to
the primer sequence through an enzyme called DNA ligase. The signal from the fluorescent dye is
detected and recorded. After several ligation cycles, the DNA strand is denatured. The process starts
over with another primer that is off by one base from the previous primer. The testing produces raw

2
data from several reads of the strands; these data must be analysed before any conclusions can be
drawn.3

RNA Sequencing

RNA can be extracted from cells or tissue and then converted into complementary DNA via reverse
transcription. Those chains are amplified through polymerase chain reaction with fluorescent
complements. The data can be sequenced similarly to DNA by adding nucleotides and reading out with
fluoroscopy. RNA sequencing can provide information about RNA expression and can detect fusions
and alternative splicing. However, DNA sequencing is usually preferred to detect mutations.3

Single-Cell RNA and DNA Sequencing

Sequencing material from a single cell begins with generating a single-cell suspension. Various methods
are available, and the end result is either DNA or RNA, which can be sequenced as described above.
The advantage of single-cell sequencing is that it allows for assessment of tumour heterogeneity and
separate cell types (eg, immune cells).3

Liquid Biopsy

DNA may be obtained from blood samples from plasma or from circulating tumour cells. The
minimally invasive, liquid biopsy was first performed with allele-specific polymerase chain reaction
and flow cytometry. However, NGS panels are now being used more often to focus on known
mutations.3

Genomic Alterations

Recent information from the American Medical Association about genomic screening indicates that,
when screening healthy populations, > 3% of people will have actionable or pathogenic variants, and >
95% will have actionable pharmacogenomic variants.5 Below is an explanation of the types of
alterations detected by NGS.

Single-Nucleotide Variants

DNA sequence alterations can affect the activity, localisation, or expression of a gene, which may
affect its function. Typically, alterations that increase the expression of oncogenes or decrease the
activity of tumour suppressor genes are considered actionable. It is not always known whether
single-nucleotide variants (SNVs) will affect function, and in that case, they are classified as variants of
unknown significance. SNVs are thought to be a common mechanism of resistance to small-molecule
inhibitors.3

Copy Number Variants

3
Larger deletions or amplifications are called copy number variants. These can be difficult to interpret
since the large regions that are amplified or deleted contain multiple genes. Additionally, this is an area
where it is important to be mindful of the limitations of NGS. Amplification on NGS often represents
higher copy number alterations, but a lack of amplification on NGS does not exclude the possibility of
lower-level copy gain. Many NGS platforms also have challenges with reporting deletions, partly
because of the difficulty in detecting deletions in tumours with low cellularity.3

Gene Fusions

Gene fusions are common in cancer and increase the activity of genes that are known to play a role in
promoting tumours. Fusions have been reported primarily in hematologic malignancies, but also in bone
and soft tissue sarcomas.3

If NGS demonstrates more than one copy number alteration and both are actionable, then the one with
the strongest evidence of response to therapy should be targeted. Additionally, the mutation with the
highest allelic frequency is also typically targeted.3

CGP evaluates most cancer-related genes in a single test. This is preferred over single-gene (hot-spot)
panels, which target regions of known cancer genes, but may miss up to 20% of clinically important
mutations. And though hot-spot panels are very sensitive, the clinical significance of lower-level
mutations is uncertain.7

Oncogenic Mutations

The data generated from genomic sequencing are complex and the interpretation is still evolving.
Typically, the reported results will include genomic findings of interest and pertinent negative findings,
approved therapeutic options, any other biomarkers or alterations that were identified, and clinical trials
that may be appropriate.8

Although not an exhaustive list, the following are examples of molecular aberrations that are found
across multiple types of cancer:

● BRCA1/2 mutations are well known as oncogenic drivers of breast, ovarian, and prostate cancers.
Targeted therapies for BRCA-mutated cancers include the PARP inhibitors olaparib, rucaparib,
and niraparib9,10,11
● HER2/ERBB mutation or overexpression occurs in many types of cancer including lung, breast,
gastric, and colorectal cancer. Several HER2-targeted therapies are available including
trastuzumab, lapatinib, tucatinib, and neratinib. Additionally, the novel antibody-drug conjugate
trastuzumab deruxtecan recently received accelerated approval in the United States for the
treatment of unresectable or metastatic HER2+ breast cancer in patients who had received at least
2 prior HER2-based regimens for metastatic disease12

4
 ● NTRK gene fusions (involving NTRK1, NTRK2, NTRK3) are oncogenic drivers of both adult and
paediatric malignancies, and NTRK mutations have been identified in colorectal cancer, lung
cancer, melanoma, breast cancer, basal cell carcinoma, and acute myeloid leukaemia. Patients can
be treated with first-generation TKIs (ie, larotrectinib, entrectinib), and such treatment is
associated with high response rates (> 75%) and durable disease control. The cancer will
eventually become resistant to therapy, but some of these resistance mutations can be overcome by
treatment with second-generation TKIs (ie, LOXO-195 and TPX-005) that are currently in clinical
trials13
● The EGFR exon 19 and exon 21 mutations activate the tyrosine kinase domain to accelerate
tumour development, and targeted EGFR TKIs have been used successfully to treat these tumours
in NSCLC. Targeted therapies include gefitinib, erlotinib, afatinib, osimertinib (approved for
T790M mutations), and dacomitinib. Of note, though both EGFR and KRAS mutations are
oncogenic driver mutations commonly found in lung cancer, they are mutually exclusive14
● ALK rearrangements have been identified in multiple cancers including lymphoma, NSCLC,
neuroblastoma, glioblastoma, renal cell carcinoma, breast cancer, colon cancer, and thyroid cancer.
Targeted TKIs (eg, crizotinib, alectinib, and ceritinib) used in patients with lung cancer have
dramatically improved patient survival14,15,16
● ROS1 mutations are thought to be present in several types of NSCLC. These mutations cause a
defective receptor tyrosine kinase that is structurally similar to the ALK protein. Targeted
therapies to treat ROS1 mutations include crizotinib, cabozantinib, and ceritinib14,17
● BRAF mutations include the BRAF V600E point mutation and BRAF fusions. These mutations are
found in central nervous system tumours, colorectal cancer, lung cancer, melanoma, non-Hodgkin
lymphoma, thyroid cancer, and ovarian cancer. Targeted therapies include encorafenib,
vemurafenib, and dabrafenib14,18
● KRAS mutations are prognostic biomarkers associated with lung, colorectal, and pancreatic
cancers. There are currently no targeted therapies available to treat KRAS mutations14,19,20
● IDH1 is a mutation seen in cholangiocarcinoma. Targeted therapy is available with ivosidenib (see
"patient scenarios" below)
● FGFR is a mutation seen in cholangiocarcinoma. Targeted therapies include pemigatinib and
erdafitinib (see "patient scenarios" below)
● MET mutations are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and
head and neck cancers. MET inhibitors include crizotinib, tivantinib, cabozantinib, and foretinib21
● Programmed death-ligand 1 (PD-L1) is a predictive biomarker for immune checkpoint inhibitor
therapy; however, PD-L1 expression may vary between the primary tumour and its metastases and
can also vary within an individual. Thus, even patients with tumours that do not express PD-L1
may still benefit from anti-PD-1 checkpoint inhibitors (eg, pembrolizumab, nivolumab,
atezolizumab, avelumab). These agents have been used in metastatic melanoma, NSCLC, and a
wide range of other tumours4,22
● Microsatellite instability (MSI) and tumour mutation burden (TMB) are biomarkers that have been
studied and are reported for some NGS assays. Generally, patients with high levels of MSI in
certain solid tumours may be good candidates for treatment with immune checkpoint inhibitors.
TMB is a pan-tumour biomarker that provides information about the overall number of mutations
within a tumour and is emerging as promising way to predict patients' likelihood of response to
immunotherapy. In a study of patients with colorectal cancer with high MSI tumours, all patients
with high TMB responded to immunotherapy while only 22% of patients with low TMB (< 37
mutations/Mb) responded to immunotherapy4,23,24

Ordering Testing

CGP may not yet be widely available and may or may not yield actionable information. When positive,
however, these results could significantly affect patient management, especially when selecting therapy.

5
Additionally, CGP data can also provide information about the patient's sensitivity to particular
therapies or the likelihood of developing resistance. Genomic studies have mostly been done in
advanced disease (eg, metastatic, locally advanced, or locally recurrent), and these have yielded a range
of approved therapies used to treat specific mutations, as described above.

Clinicians should discuss the goals of CGP with the patient prior to initiating testing. CGP testing may
be useful for diagnosis, for personalised medicine (ie, selecting therapies based on the presence or
absence of a mutation or selecting therapies for patients with acquired resistance who are not
responding to current therapy), or to direct patients to experimental therapies/clinical trials. Though
resources are available online to assist patients in understanding test results, clinicians should be
prepared to discuss somatic findings with their patients as well as any findings that may have hereditary
implications. Tumours tested using tumour-only platforms cannot determine whether an alteration is
somatic or germline, so germline counselling should be considered. If BRCA1 or BRCA2 mutations are
found during tumour-only testing, germline BRCA1/2 testing should be performed even if there is no
family history. Formal genetic counselling should be employed when appropriate.3

As genomic testing has become more widely available, medical guidelines are increasingly including it
as part of diagnostic and/or treatment algorithms. As an example, in the United States, the National
Comprehensive Cancer Network (NCCN) revised the guidelines for prostate cancer in March 2020; the
expert panel now endorses germline genetic testing for patients with prostate cancer who have a positive
family history; high-risk, very high-risk, regional, or metastatic prostate cancer regardless of family
history; Ashkenazi Jewish ancestry; or intraductal histology. The guidelines recommend that germline
testing include MLH1, MSH2, MSH6, and PMS2, as well as BRCA1/2, ATM, PALB2, and CHEK2;
however, clinicians may instead consider ordering a CGP that includes known and (as yet) unknown
genetic mutations (ie, identifying potential therapeutic targets). The NCCN also notes that clinicians
may consider testing additional genes depending on the clinical context since these test results may
impact family planning, even when no targeted therapies are currently available (eg, HOXB13).25

Somatic vs Germline Mutations

Germline mutations like those found in hereditary cancers (eg, germline BRCA mutations) occur in all
cells in the body. Somatic mutations are mutations that only occur inside the tumour. To determine
whether a mutation is somatic or germline, patients would ideally have NGS from both tumour and
normal tissue; however, there are panels that combine tumour-only sequencing with bioinformation to
decide which alterations are somatic. Thus, it is important for the clinician to know which reporting
approach is being used for a given CGP as a patient could have germline alterations that are not
reported in tumour-only sequencing.3

NGS Testing Limitations

NGS testing has limitations. First, the sensitivity of testing is affected by tumour cellularity. Second,
while fresh frozen solid tumour tissue provides good quality samples for sequencing, these tissue
samples are normally formalin-fixed and embedded in paraffin for pathology and storage. This can
degrade DNA and RNA, although newer tests may be able to overcome this limitation. Third,
heterogeneity exists among different tumours within the same patient and even within the same tumour.
Metastatic tumours can also differ from the primary tumour. Though liquid biopsies are noninvasive
and can reflect the various DNA alternations in a patient, they also have limitations. The DNA sample

6
is small and may miss small amounts of mutant DNA. Certain alterations, such as copy number
changes, may also be harder to pinpoint using liquid biopsy methods.3

Commercial Testing Platforms

The table below shows several commercial panel tests used to evaluate tumour-specific genomic
alterations. These platforms cover most actionable alterations and are designed to meet clinical needs
regardless of cancer tumour type.3,8,27,28 The choice of which testing platform to use depends on
several factors including the number of genes requiring examination (narrow vs broad panel testing),
availability, cost, and convenience for patient (in-person laboratory testing vs testing done from the
patient's home). The tests are listed in descending order by the number of genes assessed.

Platform (Manufacturer) Number of Genes Assessed Mutations

RNA sequencing: copy number

GPS Cancer (NantOmics) 20,000 genes + RNA alterations, gene fusions, MSI,
TMB

DNA sequencing: copy number

TempusXT (Tempus) 596 alterations, gene fusions, MSI,
TMB

DNA sequencing: copy number

alterations, MSI, TMB
Caris CDx (Caris Life Sciences) 592
RNA sequencing: gene fusions,
mRNA variants

DNA sequencing: copy number

PCDx (Paradigm) 500 alterations, gene fusions, MSI,
TMB

DNA sequencing: copy number

CancerPlex (Kew) > 400 alterations, gene fusions, MSI,
TMB

DNA sequencing: copy number

FoundationOne CDx (Foundation
324 alterations, gene fusions, MSI,
Medicine)
TMB

Oncomine Comprehensive Assay DNA sequencing: copy number

161
(ThermoFisher) alterations, gene fusions

DNA sequencing: single

SureSelect Cancer All-In-One
98 nucleotide variants, indels, copy
Solid Tumor Assay (Agilent)
number alterations, translocations

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 DNA sequencing: copy number
Guardant360 (Guardant) 76
alterations, 6 gene fusions

DNA sequencing: copy number

FoundationOne Liquid
70 alterations, specific gene fusions
(Foundation Medicine)
for lung cancers, MSI

Some cancer centres have developed private NGS platforms. One of these is the Memorial
Sloan-Kettering-Integrated Mutation Profiling of Actional Cancer Targets (MSK-IMPACT) assay. It
can detect all protein-coding mutations, copy number alterations, selected promoter mutations, and
structural rearrangements in 468 genes. The US Food and Drug Administration (FDA) approved the
test in 2017.14 To date, it has been used to sequence tumours from > 20,000 patients with cancer,
including a unique cohort of 10,000 patients with advanced cancer. The use of patient-matched normal
controls has allowed the team behind the assay to compile a catalogue of definitively somatic mutations
for every tumour sequenced.14,29 An advantage of the MSK-IMPACT assay is that it can analyse both
tumour and matched normal tissue and blood to identify both somatic and germline mutations.14

Patient Scenarios in Rare/Advanced Cancers and the Use of Genomic Testing

Cancer of Unknown Primary Site (CUP)

CUP is, by definition, metastatic cancer, and these patients have a poor prognosis. Diagnosis and
workup should include a thorough physical examination; blood and biochemical analyses; and imaging
of the thorax, abdomen, and pelvis. European Society for Medical Oncology (ESMO) guidelines state
that most CUP are not sensitive to therapy and the median overall survival for these patients is < 1 year.
The recommended treatment for patients with CUP depends on the disease subtype and may include
one or several of the following: surgical resection, debulking, radiation therapy, androgen-deprivation
therapy, and chemotherapy.30 As mentioned above, the CUPISCO trial is randomising patients with
CUP to either standard chemotherapy or to targeted treatment or immunotherapy based on genetic
alterations in their tumours with results expected in a few years.31

Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (IHCC) is one of three types of cholangiocarcinoma, a group of bile

duct cancers. IHCC, which accounts for < 10% of cases, begins in the small bile ducts within the liver.
Perihilar cholangiocarcinoma begins in the hilum and is the most common form of cholangiocarcinoma.
All other cases are termed distal cholangiocarcinomas because they start in bile ducts outside the liver.
IHCC does not cause symptoms in the early stages, so it is not typically diagnosed until it has spread to
other tissues. Common symptoms include jaundice, itching, dark-coloured urine, anorexia, weight loss,
abdominal pain, and light-coloured and greasy stools.32 Though many genetic mutations are associated
with cholangiocarcinoma, FGFR2 fusions and IDH1/2 mutations are commonly seen in IHCC.32,33
Because resection is only an option if the disease is diagnosed early, very few patients are appropriate
surgical candidates. Thus, IHCC is normally treated with systemic gemcitabine and cisplatin
chemotherapy.33,34 Targeted therapies against EGFR and VEGF have not proven successful, and clinical
trials are challenging due to the rarity of this disease.33

About 15% of patients with IHCC harbour FGFR2 fusions. In the global, open-label, phase 2
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FIGHT-202 trial, pemigatinib (a selective oral inhibitor of FGFR 1, 2, and 3) was evaluated in 146
patients who had previously received at least 1 therapy. Study results were reported at the 2019
European Society for Medical Oncology (ESMO) Congress; the study achieved its primary endpoint,
demonstrating responses in 35.5% of patients with FGFR2 fusions/rearrangements and a median
duration of response of 7.5 months. Because this was presented at a medical conference, detailed
measures of statistical significance were not provided. The most common adverse event was
hyperphosphataemia, with dose reductions or interruptions required in 3 patients. The study is limited
by its open-label design.34 This drug was recently approved in the United States for treatment of
patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a
FGFR2 fusion or other genomic rearrangement. The drug received accelerated approval based on
overall response rate (ORR) and duration of response in the FIGHT-202 trial; continued approval may
be contingent upon confirmatory trials.36 This agent was not approved in Europe at the time of writing.

Erdafitinib, a kinase inhibitor for patients with locally advanced or metastatic urothelial cancer with a
susceptible FGFR3 or FGFR2 genetic alternation and progression of disease on platinum-based
chemotherapy, is being studied in clinical trials including patients with a variety of advanced solid
tumours with the FGFR alteration, for whom standard antineoplastic therapy was no longer effective.37,
38 As of the date of this program release, erdafitinib was approved on the basis of an open-label,
single-arm study that enrolled 87 patients with locally advanced or metastatic urothelial carcinoma with
disease that had progressed on or after at least 1 chemotherapy regimen and who had FGFR3 gene
mutations. During the study, the ORR was 32.2% (95% CI: 22.4%, 42%; P value not specified). The
study is limited by the small number of participants.38

Recently, results from the phase 3 ClarIDHy trial were reported at the 2019 ESMO Congress. A total of
185 patients with advanced, nonresectable, IDH1-mutated cholangiocarcinoma were treated with
ivosidenib, and the risk of disease progression or death was reduced by 63% with this treatment.
Progression-free survival was 1.4 months with placebo vs 2.7 months with ivosidenib (hazard ratio
[HR] = 0.37; P < .001). At 12 months, 22% of ivosidenib-treated patients were progression free.
Commonly reported adverse events were nausea, diarrhoea, and fatigue. The study is limited by the
small number of patients and the short duration of follow-up.34 Ivosidenib is approved to treat acute
myeloid leukaemia, but it is not yet approved for the treatment of IHCC in the United States or in the
European Union.35

Uterine Sarcoma

Though most patients with sarcoma do not have a strong family history of cancer, sarcomas often
represent cancer predisposition syndromes; these are associated with well-defined germline genetic
aberrations. Commonly seen mutations include c-KIT mutations, PAX3/7-FKHR translocations, and
EWS-FLI translocations.39 In uterine sarcoma, a rare form of cancer, malignant cells form in the
muscles of the uterus or in other tissues that support the uterus. Risk factors for uterine sarcoma include
previous radiation treatment to the pelvis and treatment with the drug tamoxifen for breast cancer.
Common symptoms associated with uterine sarcoma include abnormal bleeding, pain or a feeling of
fullness in the abdomen, frequent urination, and bleeding after menopause. Uterine sarcoma may be
treated with surgery, radiation therapy, chemotherapy, and hormone therapy.40 Targeted treatment for
uterine sarcoma may also become possible as more information is discovered about drivers of this form
of cancer. Indeed, a prospective study of tumours from 107 women with uterine sarcoma identified the
following loss-of-function mutations: TP53 (56%), RB1 (51%), and ATRX (31%). Other alterations
detected included homozygous deletions of BRCA2 and PTEN changes.41

9
For patients with NTRK gene fusion mutations, the TRK inhibitors entrectinib or larotrectinib may
prove useful. Entrectinib received accelerated approval from the FDA in August 2019 to treat patients
≥ 12 years of age with solid tumours that have an NTRK gene fusion without a known acquired
resistance mutation, that are metastatic, or where surgical resection is likely to result in severe
morbidity and who have progressed following treatment or have no satisfactory standard therapy. It is
also approved to treat metastatic NSCLC in patients whose tumours are ROS1 positive. Entrectinib's
efficacy was demonstrated in an integrated analysis of 3 different phase 1/2 trials that included 54
patients with multiple tumour types (eg, sarcoma; NSCLC; and breast, thyroid, and colorectal cancers)
enrolled in 1 of 3 single-arm clinical trials. The ORR was 57% (95% confidence interval [CI]: 43%,
71%; P value not provided), and the response duration was ≥ 6 months in 68% of patients and ≥ 12
months in 45% of patients. Common adverse events include fatigue, constipation, dysgeusia, oedema,
dizziness, diarrhoea, nausea, increased weight, cough, pyrexia, and vision disorders. The trial is limited
by the small number of patients. The analysis is limited by the fact that data from 3 different trials were
combined.42

Larotrectinib was evaluated in a phase 1/2 "basket" study that included TRK-fusion positive tumours of
all types. The trial enrolled 55 patients aged 4 months to 76 years. The ORR was 75% (95% CI: 61%,
85%) by independent review and 80% (95% CI: 67%, 90%) by investigator assessment. After 1 year,
55% of treated patients were progression free. The drug was well tolerated, with < 5% grade 3 or 4
adverse events.43 The drug is approved in Europe for adult and paediatric patients with solid tumours
with an NTRK gene fusion who have locally advanced or metastatic disease, or where surgical resection
is likely to result in severe morbidity and who have no satisfactory treatment options. Approval was
based on data from 3 multicentre, open-label, single-arm clinical trials: LOXO-TRK-14001, SCOUT,
and NAVIGATE, which were ongoing at the time of the drug's approval. A total of 125 patients were
enrolled, and the median time on treatment for the overall safety population was 7.7 months (range
0.03–40.7 months). Commonly reported adverse reactions included fatigue, increased liver
transaminases, dizziness, constipation, nausea, anaemia, and vomiting, and 3% of patients discontinued
treatment due to adverse effects. Pooled efficacy results showed that, in patients with solid tumours
(excluding primary CNS tumours), the ORR was 72% (95% CI: 62%, 81%; P value not provided) and
in patients with solid tumours (including primary CNS tumours), the ORR was 67% (95% CI: 57%,
76%; P value not provided). These trials are limited by their open-nature design.45

Additional Resources

Clinicians can consult the following resources to aid in interpreting genomic testing results:

● Personalized Cancer Therapy (MD Anderson Cancer Center): personalizedcancertherapy.org 3

● Precision Medicine Knowledgebase (Weill Cornell Medicine): https:/pmkb.weill.corn… 3
● OncoKB (Memorial Sloan Kettering Cancer Center): http:/oncokb.org 3
● The QIAGEN OncoLand oncology database is also available for cancer researchers to explore
public and private cancer genomic data https://digitalinsights.qiagen… 44

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REFERENCES

[1] Technology Networks. Next-Generation Sequencing (NGS): Stimulating the Next Generation of
Cancer Diagnostics and Treatment.https://www.technologynetworks…. Updated May 23, 2019. Accessed
February 6, 2020.

[2] Dana Farber.https://blog.dana-farber.org/i…. Updated November 1, 2018. Accessed February 7,

2020.

[3] Avila M, Meric-Bernstam F. Next-Generation Sequencing for the General Cancer Patient. Clin Adv
Hematol Oncol. 2019;17:447-454.

[4] Oncology Nurse. An Overview of Existing and Emerging Biomarkers in Oncology.

http://www.theoncologynurse.co…. Accessed February 7, 2020.

[5] American Medical Association. Precision medicine infographic.https://www.ama-assn.org/sites….

Accessed February 6, 2020.

[6] Association of Community Cancer Centers (ACCC). Multidisciplinary Molecular Tumor Boards:
Two Models.https://www.accc-cancer.org/ho…. Updated June 28, 2019. Accessed February 7, 2020.

[7] Kew. Why Comprehensive Genomic Profiling?https://kewinc.com/genomic-profili…. Accessed

February 7, 2020.

[8] FoundationOne. Sample Report.https:/www.startwithst…. Accessed February 7, 2020.

[9] LYNPARZA (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals

LP; May 2020.

[10] RUBRACA (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology; May 2020.

[11] ZEJULA (niraparib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline;

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April 2020.

[12] Leiser M. Targeted therapy shows promise or HER2-mutant NSCLC, other solid tumors. Updated
March 25, 2020. Accessed June 15, 2020.https://www.healio.com/news/he….

[13] Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev
Clin Oncol. 2018;15:731-747.

[14] Saito M, Momma T, Kono K. Targeted therapy according to next generation sequencing-based
panel sequencing. Fukushima J Med Sci. 2018;64:9-14.

[15] Radiopaedia.org. Anaplastic lymphoma kinase (ALK) gene rearrangements.

https://radiopaedia.org/articl…. Accessed February 7, 2020.

[16] Yau NK, Fong AY, Leung HF, et al. A Pan-Cancer Review of ALK Mutations: Implications for
Carcinogenesis and Therapy. Curr Cancer Drug Targets. 2015;15:327-336.

[17] Radiopaedia.org. ROS1 mutation.https://radiopaedia.org/articl…. Accessed February 7, 2020.

[18] Radiopaedia.org. BRAF.https://radiopaedia.org/articl…. Accessed February 7, 2020.

[19] Radiopaedia.org. KRAS mutation.https://radiopaedia.org/articl…. Accessed February 7, 2020.

[20] Wellmark. Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer.
https://www.wellmark.com/Provi…. Updated September 2019. Accessed February 7, 2020.

[21] NIH. MET gene. Accessed June 15, 2020.https://ghr.nlm.nih.gov/gene/MET.

[22] Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM. Biomarkers for
Immunotherapy: Current Developments and Challenges. Am Soc Clin Oncol Educ Book.
2016;35:e493-503.

12
[23] Bodker JS, Sonderkaer M, Vesteghem C, et al. Development of a Precision Medicine Workflow in
Hematological Cancers, Aalborg University Hospital, Denmark. Cancers (Basel). 2020;12:pii E312.

[24] Schrock A. Chemotherapy or immunotherapy? TMB may help predict best treatment choice for
some metastatic colorectal cancer patients. May 20, 2019. Accessed May 29, 2020.
https://www.foundationmedicine….

[25] NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 1.2020–March 16,
2020../www.nccn.org. Accessed March 26, 2020.

[26] FoundationOne. FoundationOne®CDx.https://assets.ctfassets.net/v…. Accessed February 7, 2020.

[27] Agilent. SureSelect Cancer All-In-One Custom and Catalog NGS Assays.
https://www.agilent.com/cs/lib…(single%20pages).pdf. Accessed February 7, 2020.

[28] Kew. Cancerplex.https://kewinc.com/cancerplex-over…. Accessed February 7, 2020.

[29] Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from
prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703-713.

[30] Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Pentheroudakis G. Cancers of Unknown
Primary Site: ESMO Clinical Practice Guidelines. Ann Oncol. 2015;26(suppl 5):v133-v138.

[31] ESMO. DNA Profiling May Hold Key to Better Treatment Options in Carcinoma of Unknown
Primary.https://www.esmo.org/newsroom/…. Updated September 28, 2019. Accessed February 7, 2020.

[32] National Institutes of Health. Cholangiocarcinoma.https://ghr.nlm.nih.gov/condit…. Updated March

31, 2020. Accessed April 1, 2020.

[33] Zhao DY, Lim KH. Current biologics for treatment of biliary tract cancers. J Gastrointest Oncol.
2017;8:430-440.

13
[34] Helwick C. ClarIDHy and FIGHT-202 Trials Show Positive Results in the Treatment of Patients
With Biliary Tract Cancer.https://www.ascopost.com/issue…. December 10, 2019. Accessed April 2,
2020.

[35] TIBSOVO (ivosidenib tablets) [prescribing information]. Cambridge, MA; Agios Pharmaceuticals,
Inc.; May 2019

[36] PEMAZYRE (pemigatinib) [prescribing information]. Wilmington, DE: Incyte Corporation; April
2020.

[37] Bahleda R, Italiano A, Hierro C, et al. Multicenter phase I study of erdafitinib (JNJ-42756493),
oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid
tumors. Clin Cancer Res. 2019;25:4888-4897.

[38] BALVERSA (erdafitinib) ]prescribing information]. Horsham, PA; Janssen Pharmaceutical

Companies; April 2020.

[39] Gupta A, Malkin D. Sarcomas and cancer predisposition syndromes.

http://sarcomahelp.org/article…. Accessed April 1, 2020.

[40] National Cancer Institute. Uterine Sarcoma (PDQ®) - Patient Version. Updated June 12, 2019.
Accessed May 28, 2020.https://www.cancer.gov/types/u….

[41] Hensley ML, Chavan SS, Solit DB, et al. Genomic landscape of uterine sarcomas defined through
prospective clinical sequencing. Clin Cancer Res. 2020 Apr 16 [Epub ahead of print].

[42] ESMO. FDA approves entrectinib for the treatment of NTRK fusion-positive solid tumours in
adults and adolescent patients. August 20, 2019. Accessed May 29, 2020.
https://www.esmo.org/oncology-….

[43] Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive
cancers. J Hematol Oncol. 2018;11:78.

[44] QIAGEN. QIAGEN OncoLand.https://digitalinsights.qiagen…. Accessed February 7, 2020.

14
 [45] VITRAKVI (larotrectinib). [Summary of Product Characteristics]. Leverkusen, Germany: Bayer
AG; September 19, 2019.

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