ASPiRATION: Australian observational cohort study of comprehensive genomic profiling in metastatic lung cancer tissue
Abstract
ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia.
This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years.
Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.
Plain language summary
Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific ‘actionable’ gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new.
Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments.
The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia.
Clinical Trial Registration: ACTRN12621000221853 (ANZCTR)
Tweetable abstract
ASPiRATION is an Australian national prospective observational study assessing feasibility, clinical and economic value of comprehensive genomic profiling in newly diagnosed metastatic lung cancer.
Lung cancer accounts for more cancer deaths per year than any other cancer and the majority of patients have locally advanced or metastatic disease at initial clinical presentation. The most common type of lung cancer, non-small-cell lung cancer (NSCLC), is a heterogeneous disease with a wide diversity of genomic subtypes in which mutations or abnormal gene expression drive cancer cell growth. Approximately 20–25% of all metastatic non-squamous NSCLC harbour oncogenic driver mutations such as EGFR mutations, and ALK and ROS1 gene rearrangements. These alterations are recognised predictive biomarkers for established targeted therapy, and thus are considered actionable variants. Historically, patients with metastatic NSCLC were managed with empiric chemotherapy, until randomised trials demonstrated clinical superiority of targeted therapies over chemotherapy in patients with EGFR mutations [1–7] and ALK gene rearrangements [8,9]. Patients without an identified actionable variant are typically treated with immunotherapy with or without chemotherapy, resulting in a greater risk of serious toxicity compared with personalized targeted treatments [10], and ultimately potentially inferior outcomes. Guidelines recommend patients with actionable variants receive targeted therapy early in their disease course to enable maximum benefit [11].
The most common modalities used to identify actionable variants in NSCLC tissue in Australian clinical practice are single gene assays, such as COBAS sequencing for EGFR mutations, and immunohistochemistry (IHC) and/or florescence in situ hybridization (FISH) for ALK and ROS1 rearrangements. Standard of care (SoC) testing can identify a genomic alteration in approximately 21% of patients, including EGFR mutations (17%), ALK (3%) or ROS1 (1%) gene rearrangements [12,13]. However, multiple novel actionable variants including KRAS G12C, BRAF V600E, HER2/ERBB2 and EGFR exon 20 insertions, and MET exon 14 alterations, as well as RET, NTRK and NRG1 rearrangements [12,14,15], for which emerging targeted treatments are currently available or in clinical trials and in many instances recommended by international treatment guidelines, are not identified by the current SoC testing for Australian patients [16,17].
Although some molecular testing for newly diagnosed metastatic NSCLC is already SoC in Australia, the method and breadth of the molecular testing varies greatly between centres, including: sequential testing of actionable genomic alterations limited to EGFR, ALK and ROS1 (common in resource-constrained hospitals/health services); and small gene panels (approved by Australia's Medical Service Advisory Council from 1st November 2023 and until then the introduction of small gene panels in Australia has been limited to major hospitals and private vendors, and thus not universally available). This study is assessing the feasibility of a national tissue-based comprehensive genomic profiling program (that is not the current SoC in Australia nor most parts of the world) to assess for all actionable genomic alterations at diagnosis to ensure equitable opportunity to access targeted therapies. The study aims to generate evidence to support comprehensive testing becoming the SoC in Australia. Thus, it will provide evidence over and above limited gene panels and the SoC at the time of study commencement, sequential individual gene testing. Moreover, the study will provide information on molecular heterogeneity including co-mutations, and prospective data on the natural history and treatment response of these patient subgroups. Further novelty is added to this study by pairing the evaluation of a national screening program with substudies providing access to emerging targeted therapies.
Comprehensive genomic profiling
Comprehensive genome profiling (CGP) uses modern high throughput sequencing technologies, such as next generation sequencing assays, whole genome sequencing or whole exome sequencing, to screen for genomic alterations using DNA and RNA extracted from tumor tissue. CGP has entered clinical practice driven by clinical demand, and the associated investment has led to increased capacity for testing and reduced cost, but also to an arguably poorly regulated upsurge of direct-to-consumer marketing of screening tests. It remains unclear whether these tests confer clinical benefit since the majority of testing will not identify an actionable target, and more evidence-based guidance regarding appropriate patient selection and sample acquisition, timing of, and interpretation of CGP results is required. Despite these limitations, the use of CGP at diagnosis is expected to identify more actionable variants than SoC, and over time, is expected to become cheaper and faster than sequential testing for genomic alterations, thus enabling more patients to receive targeted treatment, and improve participation in clinical trials of novel targeted treatments.
CGP is expected to detect additional actionable variants in approximately 30% of patients. In addition, it is expected there will be instances in which patients will falsely test negative by SoC methods but will be identified to have an actionable variant by the more sensitive CGP testing methods [12,13]. Retrospectives studies of these methods have reported conflicting results, with some research demonstrating that CGP can correctly identify ROS1 alterations missed by FISH testing (i.e., false negative on FISH testing) [18,19] and also disprove some ROS1 alterations (i.e., false positive on FISH testing) [20]. This study aims to prospectively collect observational data to evaluate the capacity of CGP to identify additional actionable variants currently missed by SoC testing, and whether this can lead to increased access to targeted treatment options for lung cancer patients.
Limitations in implementation of tissue-based CGP
There are a number of factors that could limit feasibility of tissue-based CGP to inform first-line treatment for lung cancer: availability of sufficient tumor tissue to perform CGP, cost of testing, access to testing, as well as turnaround times to deliver CGP results to guide real-time treatment decisions.
Tissue availability
In lung cancer, tumor tissue biopsy can be challenging, or not possible, owing to the invasive nature and associated safety considerations of the procedures required to obtain diagnostic material. Successful CGP depends on the presence of adequate tumor cells within the sample, successful extraction of sufficient quantity and quality tumor DNA and RNA, and technical success of the assays performed, with multiple potential failure points throughout the process.
ASPiRATION (Australia New Zealand Clinical Trials Registry [ANZCTR] ACTRN12621000221853) will assess this by quantifying the rates of failure at various steps along the tumor sampling, CGP tissue processing and molecular analysis pathway.
A better understanding of reasons for failure will allow process improvement to increase success rates.
Molecular profiling turnaround times
Metastatic NSCLC is an aggressive malignancy, frequently requiring therapy to commence soon after diagnosis. To access reimbursed treatments, various processes have been developed locally throughout Australia to minimize delays between obtaining diagnostic tissue and receipt of SoC results. It is generally expected that a curated report should be available to the treating clinician within 2 weeks of biopsy in line with international best practice guidelines, but this is often much faster in high-volume centres and where there is clinical urgency.
In contrast, CGP is performed at few Australian sites, and is predominantly for research purposes or through a costly user-pays process through commercial vendors. This necessitates the additional steps of tissue retrieval, couriering to a CGP testing laboratory (in many cases internationally), followed by MTB discussion of results and issuing of a curated MTB report. It is expected, however, that the delay caused by these additional steps may be offset by the advantage of simultaneous testing for a comprehensive number of actionable variants, and that, in time, efficiencies from higher sample throughput, may permit CGP results to impact on first-line treatment decisions.
ASPiRATION will assess time-to-event data at all points along the referral and CGP analysis pathway, to identify barriers and direct process reviews to minimize turnaround times.
Methods & analysis
Study design
Australia-wide multi-centre prospective observational cohort study involving 17 participating hospitals. ASPiRATION is a sub-program of the Molecular Screening and Therapeutics (MoST) study. Treatment will be initiated at investigator discretion as clinically indicated while awaiting CGP results. Participants with actionable variants may be eligible to receive targeted treatments through associated substudies, clinical trials or other access programs. For associated MoST substudies of first-line targeted therapies, up to two cycles of standard treatment are permitted while awaiting CGP results (Figure 1).
CGP: Comprehensive genomic profiling; ECOG: Eastern Cooperative Oncology Group performance status of 0 or 1; FFPE: Formalin-fixed, paraffin embedded; MoST: Molecular Screening and Therapeutics; MTB: Molecular tumor board; NSCLC: Non-small-cell lung cancer; PBS: Pharmaceutical Benefits Scheme; SoC: Standard of care.
Target population
Adults with newly diagnosed, pathologically confirmed, non-squamous metastatic NSCLC, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate archival tumor tissue available to undergo CGP and SoC molecular testing. See Table 1 for full inclusion criteria.
| 1. Male or female patients, aged 18 years and older, with newly diagnosed, treatment naive, pathologically confirmed mNSCLC ○ Exception: patients with a typical pattern of disease recurrence following treatment with curative intent may not require a confirmatory repeat biopsy, unless the diagnosis is unclear, such as an isolated pulmonary nodule, in which case repeat biopsy should be considered per standard practice In exceptional circumstances, patients may be considered eligible without the need for histopathological confirmation of disease recurrence after approval from the ASPiRATION study chair or delegates; ○ Note: for mixed or other histologies: ▪ Eligible: • Mixed adenosquamous where adenocarcinoma is dominant • Carcinoma NOS favouring adenocarcinoma • Sarcomatoid carcinoma ▪ Ineligible: • Mixed small-cell lung cancer • Large cell neuroendocrine carcinoma |
| 2. ECOG performance status 0 or 1 |
| 3. Sufficient tissue for molecular screening |
| 4. Willing and able to comply with study requirements. It is the intention to screen patients who are in principle willing to consider participation in a MoST substudy if they are found to have an appropriate tumor biomarker and are still eligible for enrolment at the time of the treatment phase |
| 5. Current enrolment or participation in another clinical study with an unregistered investigational product during the last 12 months, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study, must first be discussed the Study Team before study enrolment |
| 6. Signed, written informed consent to participate in molecular profiling and linkage to Medicare data |
| 7. Do not have comorbidities or conditions (e.g. psychiatric) which may contraindicate participation and/or ability to receive any systemic therapy(s) |
| 8. Do not have other co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol |
| 9. Life expectancy of at least 12 weeks |
| 10. No history of another primary malignancy except for: ○ Malignancy treated with curative intent and with no known active disease within 2 years before consent to molecular screening and of low potential risk for recurrence ○ Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease ○ Adequately treated carcinoma in situ without evidence of disease |
Study procedures
Archival formalin-fixed, paraffin embedded (FFPE) diagnostic tumor samples from all participants will be retrieved from pathology laboratories as soon as possible after the participant signs informed consent. It is critical that sites expedite the turn-around times between consent, receipt of FFPE tumor material and CGP results, as it is the intention that CGP results will inform first-line systemic therapy.
Where archival tumor tissues are available from more than one occasion, the latest obtained sample will be retrieved whenever possible, unless the latest sample contains insufficient tissue for molecular screening.
See Table 2 for the full Schedule of Assessments.
| Pre-screening | CGP | Follow-up after CGP | Follow-up after CGP | |
|---|---|---|---|---|
| 6 and 12 months after consent to CGP | 3 monthly for 12 months, then 6 monthly up to 4 years after consent to CGP‡‡ | |||
| Clinician referral of patient | X† | |||
| Informed consent‡ | X | |||
| Archival biospecimen collection and processing | X | |||
| Blood sample for CGP§ | X | |||
| Blood sample for translational research¶ | X | |||
| Return of CGP results via MTB report to referring clinician | X# | |||
| Patient utility questionnaire (EuroQoL, EQ-5D-5L) | At consent, and return of CGP results†† | X†† | 24 months after consent to CGP†† | |
| Post CGP patient data collection | X‡‡ | X‡‡ | ||
| Post CGP adverse event reporting | X§§ | X§§ |
Comprehensive genomic profiling
CGP will be performed for 500 participants using the TruSight Oncology 500 panel (Illumina) at one of five MoST study sequencing laboratories in Australia and for the other 500 participants using the Foundation One Tissue CDx (Foundation One Medicine) in Cambridge, MA, USA. Assignment to sequencing platform/laboratory is based on logistical factors, such as archival tumor material source location, or balancing to maintain a 1:1 ratio of testing platform assignment.
Molecular review & variant classification
The outputs of CGP will be subjected to bioinformatics analysis and reviewed by MTBs for variant classification, assignment of an ‘actionability' category and recommendation for targeted therapy treatment options based on the published literature, participant clinical history and availability of therapeutic opportunities.
If several molecular targets are found, the MTB will make a recommendation based on the clinical profile of the participant and expected pathogenicity of each variant, including its importance in the context of other molecular characteristics and its role as a driver of tumor growth and progression.
Return of molecular profiling results
All participants, including those with no actionable variants, are informed of their tumor profiling results, as previously described [21]. The MTB report is provided to the referring clinician for discussion with the participant. The decision for subsequent treatment is made by the participant in consultation with their oncologist.
Example of the assessment result of an anonymous patient
A 61-year-old man, life-long non-smoker, new diagnosis of non-small-cell lung cancer, with bilateral pulmonary metastases and bone metastasis. Histopathology from a biopsy of the left lower lobe primary confirms TTF-1/Napsin A positive adenocarcinoma. ALK (D5F3 clone) and ROS1 (SP263 clone) IHC are negative, PD-L1 is 5% (SP263 clone), and an Idylla EGFR Mutation Test does not detect an EGFR mutation. CGP using the Illumina TSO500 panel detects an ERBB2 Y775dup activating mutation and a tumor mutational burden of 15.8 Mut/Mb. The molecular tumor board recommends the first-line, single-arm, phase II trial of trastuzumab emtansine in newly diagnosed mNSCLC with ERBB2 activating mutations as a clinical trial option.
Outcomes
The primary outcomes are:
the impact of CGP, as assessed by:
percentage of participants with actionable variants found using CGP and SoC testing methods;
percentage of participants receiving emerging targeted treatments, and
the feasibility of CGP, as assessed by:
time to receipt of results;
percentage of participants commencing treatment prior to receiving CGP results;
percentage of participants requiring repeat biopsy to obtain evaluable results by CGP and SoC testing.
Secondary outcomes include:
percentage of participants with a change in treatment recommendation based on CGP results;
percentage of participants participating in a clinical trial of an investigational agent;
clinical outcome measures, including time on first-, second- and third-line treatment and identification of each of the therapies received;
healthcare resource use and costs using linked Medicare data;
health-related quality of life measured using the EuroQoL EQ-5D-5L;
cost–effectiveness of CGP, by using the health-related quality of life, overall survival and healthcare resource utilisation data to facilitate prospective cost-utility analyses.
Tertiary and correlative studies will describe the natural history and treatment effects in rare molecular subsets and explore potential prognostic impact of co-mutations and other biomarkers of clinical outcomes and validate where possible.
Timelines
The ASPiRATION study commenced enrolment in December 2020 and is anticipated to complete recruitment in 2023.
Data collection methods
Remote collection of clinical data after CGP will be performed for all participants, including those who are not identified to have an actionable variant. Each participant's health status, including clinical outcomes, will be followed by accessing medical records of the participant's treating clinician, general practitioner, the participant directly, as well as via state-based cancer registries and national mortality registry (AIHW). Participants will be followed up every 3 months after consent to CGP for the first 12 months, then every 6 months for a minimum of 2 years and up to a total of 4 years.
Statistical methods
The study outcomes are descriptive and will generate data on the ability of CGP to identify participants with actionable variants that would not be detected by SoC testing, leading to personalized treatment recommendations. The primary analysis will describe the feasibility, efficiency and utility of implementation of CGP nationally.
Tables will report the number of patients satisfying the various conditions of interest. All key outcome percentages will be reported with 95% CIs (computed using the Wilson method). Durations will be reported as median, range, 25th/75th percentiles and mean (with standard deviation). Time to event outcomes will be summarized using the Kaplan–Meier method and compared using Cox proportional hazards regression where appropriate. Treatment response, duration and time-to-event outcomes will be reported overall and by groups. Results will also be reported according to genetic subgroup, as well as by treatment pathway received.
The sample size of 1000 was the maximum possible within resources available. For full cohort endpoints, we will be able to estimate percentages with 95% CI widths of at most +/-3.1%. Of the 1000 patients tested, we expect approximately 50% will have an actionable variant identified by CGP. The cohort will enable precise understanding of the feasibility of CGP (mean time to results +/-SD*0.03).
Health economic analysis
A cost-consequence analysis of CGP versus SoC testing will be undertaken from a health system perspective. Economic outcomes include: additional patients with an actionable variant; life years saved at 24 months; quality-adjusted life years (QALY) gained at 24 months. Healthcare use will be identified and measured through linkage to Medicare claims data (MBS/PBS) for all consenting screened participants, and through study records. Utility-based quality of life will be measured with the EuroQol EQ-5D-5L questionnaire at the time of consent, return of CGP results, 6, 12 and 24 months.
Mean and total volumes of healthcare use and costs will be tabulated for SoC and CGP with standard deviations. Mean values for survival, quality of life and QALYs will be tabulated with precision estimates. Differences between SoC and CGP will be reported with 95% CIs.
The health economic analysis will follow best practice guidelines [22] and a detailed study health economics analysis plan (HEAP) [23].
Trial oversight & monitoring
ASPiRATION, a subprogram of the MoST study, is an investigator-initiated, academic trial, conducted as a collaboration between the Thoracic Oncology Group of Australasia (TOGA), the NHMRC Clinical Trials Centre at the University of Sydney and the Australian Genomic Cancer Medicine Centre (AGCMC) trading as Omico. The NHMRC Clinical Trials Centre will be responsible for ethics and regulatory approvals, site coordination, medical oversight, acquisition of translational research bloods, health economic analysis and statistical analysis. The AGCMC will be responsible for study coordination, data acquisition and management. The NHMRC CTC and the AGCMC will each perform a complementary program of translational research. The study Sponsor is the University of Sydney, NSW, 2006, Australia.
The Trial Steering Committee (TSC) will oversee study planning, progress, review of information from related research, and implementation of recommendations from other study committees and external bodies (e.g., ethics committees). Changes and amendments to the protocol can only be made by the TSC. Ethics committee approval of protocol amendments is required prior to their implementation.
Ethics & dissemination
All patients will give written informed consent prior to study enrolment, including opportunity to provide optional consent for data collection for health economic analysis and collection of biospecimens (baseline blood and archival formalin-fixed paraffin embedded tissue) for future translational research. Informed consent will be performed in-person by trial staff at participating sites, or remotely via telehealth with trained trial staff.
Results will be disseminated in the clinical study report, presented at national and international conferences and scientific meetings and published (as aggregated data not identifying individual participants) in peer-reviewed journals. All study data will be stored in a secure area or on secure servers accessible only to authorised staff members.
Conclusion
Lung cancer is the leading cause of cancer death in Australia and worldwide, with a 5-year survival rate of only 21.6% [24], making it imperative to assess and implement all potential advances in clinical care. The ASPiRATION study is the first of its kind in Australia to generate high-quality, real-world data on the impact and value of CGP in delivering precision medicine and personalized healthcare for patients with advanced NSCLC. If confirmed to be feasible and of clinically utility, CGP will become incorporated in the diagnostic algorithm for all newly diagnosed Australian patients with advanced NSCLC.
Metastatic non-small-cell lung cancer (NSCLC)
Lung cancer remains the commonest cause of cancer death.
Non-squamous NSCLC is the most common histology, and comprises a range of molecular subtypes, with actionable variants arising from EGFR, ALK, ROS1, KRAS, BRAF, RET, NTRK, HER2, MET and NRG alterations in up to 50%.
Actionable variant testing
Standard of care (SoC) testing in Australia uses single-gene assays, limited multi-gene panels, immunohistochemistry, and fluorescence in-situ hybridization to identify EGFR, ALK and ROS1 alterations.
This approach is inefficient and will fail to identify a number of actionable variants treatable with emerging targeted therapies.
Comprehensive genome profiling (CGP)
CGP uses modern genome sequencing technologies to screen DNA and RNA extracted from tumor tissue for a much wider range of genomic alterations.
CGP is expected to identify a significant number of actionable variants missed by SoC testing, resulting in tailored treatment recommendations and improved clinical outcomes.
Study design
ASPiRATION is an Australian, multicentre, prospective cohort study which will enrol 1000 participants with newly diagnosed, treatment naive, metastatic, non-squamous NSCLC.
Study procedures
Participant tumor-tissue will undergo CGP in addition to SoC testing to identify actionable variants.
Results will be reviewed in a molecular tumor board and a curated report will be returned to the referring clinician with targeted treatment recommendations, where appropriate.
Participants may receive targeted therapies through ASPiRATION-specific substudies, other clinical trials, or access pathways.
Participants will be followed for a minimum of 2 years.
Study outcomes
The primary outcomes will assess the clinical impact (percentage of participants with actionable variants, percentage of participants receiving emerging targeted treatments), and feasibility of CGP (time to receipt of results, percentage of participants commencing treatment prior to receipt of results, percentage of participants requiring repeat biopsy to obtain evaluable results).
The secondary outcomes will assess other clinical outcomes, health resource use and costing, health-related quality of life and cost–effectiveness.
Implications
The data generated will assess the clinical impact and feasibility of adopting comprehensive genome profiling nationally.
Author contributions
AJ Mersiades drafted and critically reviewed the protocol, implemented the design and conduct of CGP infrastructure, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. BJ Solomon conceptualised the design, drafted and critically reviewed the protocol, supervised the conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. DM Thomas conceptualised the design, critically evaluated the protocol, supervised the design and conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. CK Lee drafted and critically reviewed the protocol, supervised the design and conduct of screening, and reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. MM Cummins drafted and critically reviewed the protocol, implemented the design and conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. L Sebastian drafted and critically reviewed the protocol, implemented the design and conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. ML Ballinger implemented and critically evaluated the protocol, supervised the design and conduct of CGP, refined data collection and information dissemination, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. E Collignon critically reviewed the protocol, implemented the design and conduct of CGP, including planning and execution of data collection, and reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. OMH Turnbull contributed to the conduct of CGP, including execution of data collection, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. S Yip contributed to the translational research design and components of the protocol, supervised design and implementation of translational research blood sample and data collection, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. RL Morton contributed to the health economic components of the protocol, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. C Brown contributed to the statistical components of the protocol, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. PJ Wheeler contributed to the conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. M Itchins contributed to the design and conduct of CGP, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. RJ Simes critically reviewed the protocol, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work. N Pavlakis conceptualised the design, drafted and critically reviewed the protocol, supervised the conduct of screening and substudies, reviewed and approved the final manuscript, and agrees to be accountable for all aspects of the work.
Acknowledgments
The authors wish to acknowledge the participants for their substantial contribution to the research, as well as the site investigators and research staff for contributing their time in the delivery of the study.
Financial disclosure
The study is supported by funding from the Australian government's Medical Research Future Fund (MRFF) Emerging Priorities and Consumer Driven Research initiative (application EPCD000005) and Roche Products, Pty. Limited (Australia) (ML42376). Prof Morton is supported by an NHMRC Investigator Grant #1194703. A/Prof Lee is supported by an NHMRC Investigator Grant #2009670.
The Australian Government and Roche Products Limited (Australia) are providing funding to help cover the costs of conducting this study. Neither the Australian Government or Roche will be involved in trial conduct or interpretation of study results. Oversight of the study and interpretation of the results will be performed by the Trial Steering Committee, led by the Study Chairs, and independent of the Australian Government and Roche. Roche will receive the final study report, including aggregated data. Roche may also receive de-identified patient level data. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
AJ Mersiades, MM Cummins, L Sebastian, ML Ballinger, E Collignon, OMH Turnbull, S Yip, C Morton, C Brown and PJ Wheeler have nothing to disclose. BJ Solomon reports honoraria and/or advisory board membership from Roche, Novartis, AstraZeneca, Pfizer, Merck, Bristol Myers Squibb, Takeda, Janssen, BeiGene, Eli Lilly and Amgen. DM Thomas reports that he is the CEO of Omico, and holds research grants or consultancy on behalf of Omico with AstraZeneca, Roche, Pfizer, Eisai, BeiGene, Bayer, Seattle Genetics, Merck, Illumina, Sunpharma, Elevation Oncology and RedX Pharmaceuticals. CK Lee reports speaking honoraria and/or travel support from AstraZeneca, Amgen, Takeda, Boehringer Ingelheim, Pfizer, Yuhan, Merck KGA, Roche and MSD; his institution received grants from Roche, AstraZeneca and Merck KGA. RJ Simes reports research grants held by his institution from AstraZeneca, Roche, Pfizer, BeiGene, Bayer, Merck, Elevation Oncology, BMS and Abbvie and is on the advisory board for FivepHusion. M Itchins reports honoraria from Pfizer, AstraZeneca, Takeda, Roche, Novartis, BMS, MSD and Bayer; she is an advisory board member of Pfizer, Takeda, Bayer, MSD, Amgen, Merck, Roche, BeiGene; reports consultancy for Roche and Merck; and holds a research grant from Pfizer, outside the submitted work. N Pavlakis reports speaking honoraria from Boehringer Ingelheim, Pfizer, Roche, Takeda, Pierre-Faber; he is an advisory board member of Boehringer Ingelheim, MSD, Merck, BMS, AstraZeneca, Takeda, Pfizer, Roche, Amgen, Beigene, Novartis, AllVascular; his institution received grants from Bayer, Pfizer and Roche, outside the submitted work.The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The protocol was approved by the St Vincent's Hospital Sydney Human Research Ethics Committee (reference, 2019/ETH03114), and the ethics committees for all participating sites. The authors state that they have obtained appropriate ethical approval for the study. In addition, informed consent will be obtained from all study participants at enrolment. The authors state that they have obtained verbal and written informed consent from the participant for the inclusion of their medical and treatment history within the provided example of an assessment result.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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