Trial Title:
PLAsma Genomic Testing in Patients With Advanced Non-Small Cell Lung Cancer: The PLAN Study
NCT ID:
NCT05542485
Condition:
Non-small Cell Lung Cancer
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
ctDNA liquid biopsy - Roche Avenio Assay
Description:
The intervention will involve plasma ctDNA testing for patients with a radiological
suspicion for newly diagnosed advanced NSCLC
Summary:
This is a multi-centre, prospective, translational study investigating the use of plasma
genotyping for initial genomic testing in newly diagnosed advanced/locally advanced
non-squamous NSCLC.
In this study, patients will have a plasma genotyping assay completed following
confirmation of suspected diagnosis of non-squamous NSCLC at institutional Rapid Access
Lung Cancer Clinics (RALCC), alongside standard tissue-based biopsy and genotyping.
Detailed description:
Background Genomic Testing in Non-Small Cell Lung Cancer Tissue genotyping of
therapeutically actionable alterations is a standard diagnostic requirement for patients
with advanced non-squamous NSCLC. Tissue genotyping represents a gold standard, with both
a sensitivity and specificity for identifying common genomic alterations of >90%. NSCLC
represents a genomically diverse cancer. Detection of genomic alterations has progressed
over the past decade, now including detection of mutations such as KRAS, EGFR, ERBB2,
BRAF, MET and fusions including ALK, ROS1, NTRK and RET genes, as well as co-occurring
mutations on tissue samples. The ability to detect these mutations has led to discovery
of molecularly defined subsets of NSCLC, and a rapid growth in the development of
targeted therapies. Actionable oncogenic driver mutations, which lead to uncontrolled
cell growth, are detected in up to 64% of lung adenocarcinomas. The most commonly
observed oncogenic driver mutation in NSCLC is KRAS, observed in up to 30% of cases,
which has led to the development of agents such as sotorasib and adagrasib to target KRAS
G12C mutations after failed first line systemic therapies. The development of EGFR
tyrosine kinase inhibitors (TKIs) such as osimertinib, gefitinib or erlotinib, and ALK
directed therapy with crizotinib, alectinib and ceritinib has led to significant
improvement in survival in patients with NSCLC over the past decade, and shifted the
focus to developing improved detection methods of these mutations for first-line targeted
therapy. Each actionable mutation detected has led to the rapid expansion of available
therapeutic options beyond those mentioned above and changed the landscape of lung cancer
treatment.
The majority of NSCLC is diagnosed at an advanced stage (stage III or IV), and it is
often diagnosed with a core biopsy or cytology specimens. Oncology and pathology
societies recommend that molecular testing turnaround times not exceed 10 working days
yet up to 30% of these specimens are insufficient to allow for tissue genotyping
necessitating repeat biopsy. Patients may thus clinically deteriorate while waiting for
genomic test results. In those patients who have insufficient samples on initial biopsy
and require repeat intervention, this can prolong the time from diagnosis to treatment by
more than 28 days. The methods by which these mutations are detected are continually
evolving, including DNA sequencing, DNA allele-specific testing, RNA sequencing,
fluorescent in situ hybridization (FISH) to detect fusion genes, and next generation
sequencing (NGS). Both DNA and RNA sequencing have been shown to detect actionable
mutations, but certain large panels can miss small exon skipping or fusion alterations,
and thus a sequential approach may be warranted. In certain mutations, RNA sequencing can
detect a higher proportion of MET exon 14 skipping. Frequently a hotspot panel is used to
detect a range of commonly occurring mutations, and if negative for these mutations,
single gene sequencing can be done for less common mutations, which is time consuming and
can further delay treatment. NGS has become the gold-standard method to detect actionable
mutations, and was recommended by the European Society for Medical Oncology (ESMO) in
2020 in advanced non-squamous NSCLC, as well as in other malignancies including
cholangiocarcinoma, prostate and ovarian cancers. NGS provides a broader test platform,
and can assess many more potential gene alterations. The MOSCATO trial assessed the use
of high throughput genomic analyses including NGS and showed improved outcomes in
advanced cancer. Specifically in NSCLC, NGS has shown significantly improved outcomes, by
identifying patients who will derive the greatest benefit from targeted therapies,
therefore reducing toxicity related to ineffective therapies with certain mutations.
Plasma genotyping in non-small cell lung cancer Plasma genotyping, or 'liquid biopsy,' is
a relatively new technology in which circulating tumour DNA (ctDNA), shed into the
bloodstream by tumours, is detectable by next generation sequencing. This technology,
while associated with a slightly lower sensitivity (80%), has >96% concordance for tissue
testing of EGFR, ALK, ROS1 and BRAF mutations. In addition, the median turnaround time is
just 7-10 days, without the associated risks and costs of invasive biopsy. Recent studies
have shown the dynamic nature of tumour cells including the development of resistance
mechanisms in EGFR-mutated tumours. As such, many cancer centres, including some based in
Ireland, have used liquid biopsy as a means of surveillance for these resistance
mechanisms over time rather than submitting a patient to multiple repeat biopsies. More
recently many centres in North America and Europe have utilised liquid biopsy for
assessing genomic alterations for targeted therapies in lung cancer upfront at the time
of tissue sampling, thereby reducing the time to treatment commencement. This approach is
supported by several high-level papers, including the NILE study, a prospective study of
282 patients with advanced untreated NSCLC that showed concordance between tissue and
plasma genotyping and a significantly faster turnaround time from 15 to 9 days. A single
centre study in the USA showed that concurrent plasma and tissue testing in NSCLC
increased the detection of actionable mutations by 15%, and hence increased the number of
patients receiving targeted therapies.
As well as the oft needed requirement for repeat biopsy due to a lack of tumour tissue
for NGS, patients with advanced NSCLC often have a poor ECOG performance status which can
limit the possibility of primary invasive procedures or repeat tissue sampling, and in
some cases, the location of the tumour site may not be amenable to biopsy. In the event
that tissue can be retrieved by invasive procedure, storage of these samples, for example
with formalin fixation, can lead to false positive results on next generation sequencing.
Invasive sampling is often associated with high cost, due to the number of clinicians,
and supportive staff available. Blood sampling is minimally invasive during the initial
diagnosis, bypasses the time required to schedule bronchoscopy or radiologically-guided
biopsies and allows immediate processing of samples. Although the use of plasma
genotyping has expanded in recent years, it is likely that it would remain an additional
tool alongside tissue genotyping, as tissue samples can provide morphology and elucidate
primary sites of disease.
Rationale We propose this study to evaluate the feasibility of a plasma-based circulating
tumour DNA mutation testing pathway using NGS and initiated at the Rapid Access Lung
Cancer Clinic (RALCC) for patients with suspected NSCLC in Ireland. This proof of
principle initiative aims to establish a robust patient pathway for systematic somatic
mutation testing in patients with NSCLC in Ireland using plasma-based testing. Plasma
will be tested for circulating tumour DNA mutations using a validated NGS-based assay, at
one of two testing laboratories in Ireland. Proving feasibility through a clinical trial
in Ireland is crucial to inform successful applications for authorisation of liquid
biopsy to the National Clinical Cancer Programme and to inform clinical trials that aim
to identify novel therapies for Irish patients. We believe an upfront plasma-based
pathway would lower median turnaround time in the Irish context. Liquid biopsy testing of
patients in the RALCC for tumour mutations should ensure that more patients have access
to precision medical therapies. Moreover, this approach is likely to significantly
improve the identification rate of patients with NSCLC actionable genomic alterations,
with resultant benefits for these patients in terms of cancer treatment. This study will
also report on the currently unknown frequency, characteristics, disease course, and
treatment patterns of somatic mutations in an Irish population with NSCLC.
Hypothesis Upfront plasma-based tumour genotyping of patients with advanced NSCLC with
the goal of guiding treatment selection is feasible to implement and will reduce the time
to treatment compared with tissue genotyping.
Planned Analysis This proof of principle initiative aims to establish a robust patient
pathway for systematic somatic mutation testing in patients with NSCLC in Ireland using
plasma-based testing. Plasma will be tested for circulating tumour DNA mutations using a
validated NGS-based assay, at one of two testing laboratories in Ireland. The Cancer
Molecular Diagnostics (CMD) laboratory at St James's Hospital will perform the tumour
test on using an in- house Roche AVENIO ctDNA Expanded panel (Basel, Switzerland). The
Histopathology Department at Beaumont Hospital will use an in-house Roche AVENIO ctDNA
Expanded panel on the Illumina MiSeq NGS platform (California, USA). Both assays will be
validated on a training tumour set. In parallel to ctDNA testing, tumour biopsy tissue
testing will be carried out as per standard of care. Liquid biopsy results will be
reviewed by the treating clinician for treatment decision purposes however the treatment
decision will remain at the discretion of the treating medical oncologist.
It is recognised that liquid and tissue biopsy both have an excellent specificity (>95%).
However, liquid biopsy may have a lower sensitivity in the region of 80%. As such, there
may be genomic alterations identified on tissue biopsy not identified on liquid biopsy
and less likely - vice-versa. In that event, the genotyping which has reported a genomic
alteration will be considered the most clinically relevant results as the likelihood of a
false positive result is very low (< 5%). However, final treatment decision will remain
at the discretion at the treating medical oncologist.
Criteria for eligibility:
Study pop:
Patients with a radiological suspicion of a new diagnosis of stage IV NSCLC will be
considered for inclusion in this study
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
1. Radiological suspicion of advanced or locally advanced non-small cell lung cancer
2. Age ≥18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
4. Ability of subject to understand and the willingness to sign a written informed
consent document.
Second arm additional criteria
5. Planned for systemic treatment with either single agent immunotherapy (IT) or
combination chemotherapy/IT
6. No prior systemic therapy for advanced NSCLC
Exclusion Criteria:
1. Squamous cell subtype NSCLC histology
2. Small cell carcinoma histology
3. Patients who have received systemic anti-cancer treatment
Gender:
All
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Beaumont Hospital
Address:
City:
Dublin
Country:
Ireland
Status:
Recruiting
Contact:
Last name:
Jarushka Naidoo, MB
Phone:
018092032
Email:
davidoreilly22@rcsi.ie
Facility:
Name:
St. James' Hospital
Address:
City:
Dublin
Country:
Ireland
Status:
Recruiting
Contact:
Last name:
Parthiban Nadarjan, MB
Facility:
Name:
University Hospital Limerick
Address:
City:
Limerick
Country:
Ireland
Status:
Recruiting
Contact:
Last name:
Gregorz Korpanty, MB PhD
Start date:
August 6, 2023
Completion date:
December 1, 2025
Lead sponsor:
Agency:
Royal College of Surgeons, Ireland
Agency class:
Other
Source:
Royal College of Surgeons, Ireland
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05542485
