Implementation of Up-front ctDNA Into Lung Cancer Care and Development of Liquid Biopsy-based Decision Support Models - LM² Study

Официальное название

Implementation of Up-front ctDNA Analysis Into Lung Cancer Care and Development of Liquid Biopsy-based Decision Support Models - the Lungmarker² Study

Обзор

Despite scientific evidence, use of liquid biopsy (LB) in diagnosis and monitoring of lung cancer (LC) is limited since it requires major changes in diagnostic and care pathways. Analyzing tumor markers (TMs), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in blood (LB) can inform about the nature of the tumor, the most appropriate therapy, therapy response and resistance. Lungmarker2 is a multicenter, prospective, implementation and diagnostic cohort study. This study aims to implement up-front ctDNA analysis ('plasma first approach') into routine diagnostic work-up of all advanced stage LC patients in the Southeast of the Netherlands (the participating hospitals in the OncoZON region). Thereby, additional information about the molecular make-up of the tumor becomes available, the number of tissue Next-Generation Sequencing (NGS) analyses will decrease and time to therapeutic decision making is shortened. Next, using ctDNA, TM and other information, multi-parametric decision support models are built and validated that may support diagnosis, predict the outcome of the next imaging procedure and progression-free survival during follow-up. The final goal is to develop a super-resolution microscopy test that can detect PD-L1 expression on CTCs.

Подробное описание

RATIONALE: Despite scientific evidence, use of liquid biopsy (LB) in diagnosis and monitoring of lung cancer (LC) is limited since it requires major changes in diagnostic and care pathways. Analyzing tumor markers (TMs), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in blood (LB) can inform about the nature of the tumor, the most appropriate therapy, therapy response and resistance.

OBJECTIVE: To implement up-front ctDNA analysis ('plasma first approach') into routine diagnostic work-up of all advanced stage LC patients in the Southeast of the Netherlands (the participating hospitals in the OncoZON region) and to thereby validate that significantly more information about the molecular make-up of the tumor becomes available by introduction of up-front ctDNA. To establish that the number of tissue NGS analyses decreases and time to therapeutic decision making is shortened. To build and to validate, using ctDNA, TM and other information, multiparametric decision support models that may support diagnosis, predict the outcome of the next imaging procedure and survival during follow up. The final goal is to develop a super-resolution microscopy test that can detect PD-L1 expression on CTCs.

STUDY DESIGN: Multicenter, prospective, implementation and diagnostic cohort study.

STUDY POPULATION: 800 patients suspected of having lung cancer.

MAIN STUDY PARAMETERS/ENDPOINTS: ctDNA analysis, as additional source of genetic information, has been integrated into the diagnostic workup of LC patients and the medical benefits thereof are quantified, e.g. a significant higher percentage of patients with a driver mutation is identified by introduction of the plasma first approach. Multiparametric decision support algorithms based on imaging, TM and ctDNA analyses that identify small-cell LC (SCLC) and non-small-cell LC (NSCLC) have been developed and validated. Multiparametric decision support models have been developed that enable patient-specific timing of imaging procedures and predict survival during follow-up of LC patients. A super-resolution microscopy test for PD-L1 is developed and correlation with tumor tissue PD-L1 expression has been established.

NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP RELATEDNESS: At diagnosis, an extra 10 mL of blood are drawn during a routine venipuncture. Patients with advanced stage LC (stage IIIb/c or IV) undergo an extra venipuncture (40 mL).The longest follow up period for a patient is 36 months with a maximum of 20 blood draws. The volume per draw ranges from 10-40 mL. The risks of a venipuncture are negligible and the burden minimal. Those patients for whom a targetable mutation is found by ctDNA analysis benefit from the advantages of targeted therapy, i.e. better survival and less side effects of the treatment.

Первичные конечные точки

• Up-front ctDNA analysis is implemented into routine clinical care in the participating OncoZoN hospitals [Срок оценки: Up to 3 years]
• Evaluate the number of driver mutations detected by up-front ctDNA analysis compared to tumor NGS analysis [Срок оценки: Up to 3 years]
• Develop decision support algorithms for the diagnosis and monitoring of lung cancer patients [Срок оценки: Up to 3 years]

Вторичные конечные точки (2)

• Develop an analytical protocol for the analysis of PD-L1 expression on circulating tumor cells (CTCs) by super-resolution microscopy [Срок оценки: Up to 3 years]
• Evaluate the number of tumor NGS analyses and time to diagnosis when up-front ctDNA analysis is introduced [Срок оценки: Up to 3 years]

Критерии участия

Критерии включения

• Aged 18 or above and suspected of having lung cancer

Критерии исключения

• Presence of another malignant tumor, i.e. diagnosed with a tumor in the past 5 years

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Нидерланды · 5 центров

• Zuyderland Medical Center — Heerlen
• Maastricht University Medical Center — Maastricht
• Catharina Ziekenhuis Eindhoven — Eindhoven
• St. Anna Ziekenhuis — Geldrop
• Máxima Medisch Centrum — Veldhoven

Публикации

• Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic - implementation issues and future challenges. Nat Rev Clin Oncol. 2021 May;18(5):297-312. doi: 10.1038/s41571-020-00457-x. Epub 2021 Jan 20. PMID 33473219
• IJzerman MJ, de Boer J, Azad A, Degeling K, Geoghegan J, Hewitt C, Hollande F, Lee B, To YH, Tothill RW, Wright G, Tie J, Dawson SJ. Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late. Diagnostics (Basel). 2021 Jan 11;11(1):103. doi: 10.3390/diagnostics11010103. PMID 33440749
• Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, Bivona T, Diehn M, Dive C, Dziadziuszko R, Leighl N, Malapelle U, Mok T, Peled N, Raez LE, Sequist L, Sholl L, Swanton C, Abbosh C, Tan D, Wakelee H, Wistuba I, Bunn R, Freeman-Daily J, Wynes M, Belani C, Mitsudomi T, Gandara D. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study PMID 34246791
• de Kock R, Deiman B, Kraaijvanger R, Scharnhorst V. Optimized (Pre) Analytical Conditions and Workflow for Droplet Digital PCR Analysis of Cell-Free DNA from Patients with Suspected Lung Carcinoma. J Mol Diagn. 2019 Sep;21(5):895-902. doi: 10.1016/j.jmoldx.2019.05.003. Epub 2019 Jun 21. PMID 31229652
• Genet SAAM, Visser E, van den Borne BEEM, Soud MY, Belderbos HNA, Stege G, de Saegher MEA, Eduati F, Broeren MAC, van Dongen J, Brunsveld L, van de Kerkhof D, Scharnhorst V. Correction of the NSE concentration in hemolyzed serum samples improves its diagnostic accuracy in small-cell lung cancer. Oncotarget. 2020 Jul 7;11(27):2660-2668. doi: 10.18632/oncotarget.27664. eCollection 2020 Jul 7. PMID 32676167
• de Kock R, van den Borne B, Youssef-El Soud M, Belderbos H, Brunsveld L, Scharnhorst V, Deiman B. Therapy Monitoring of EGFR-Positive Non-Small-Cell Lung Cancer Patients Using ddPCR Multiplex Assays. J Mol Diagn. 2021 Apr;23(4):495-505. doi: 10.1016/j.jmoldx.2021.01.003. Epub 2021 Jan 22. PMID 33486072
• de Kock R, Knoops C, Baselmans M, Borne BVD, Brunsveld L, Scharnhorst V, Deiman B. Sensitive cell-free tumor DNA analysis in supernatant pleural effusions supports therapy selection and disease monitoring of lung cancer patients. Cancer Treat Res Commun. 2021;29:100449. doi: 10.1016/j.ctarc.2021.100449. Epub 2021 Aug 25. PMID 34481168
• de Kock R, Borne BVD, Soud MY, Belderbos H, Stege G, de Saegher M, van Dongen-Schrover C, Genet S, Brunsveld L, Scharnhorst V, Deiman B. Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients. Cancer Treat Res Commun. 2021;28:100410. doi: 10.1016/j.ctarc.2021.100410. Epub 2021 Jun 1. PMID 34107412

Идентификаторы

NCT: NCT06105177 · NL83276.100.22

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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