Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Immune System Diseases

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Hypersensitivity

Neoplasm, Residual

Pathologic Complete Response

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Immunomodulating Agents

Stage 3 NSCLC eligible for chemoradiotherapy

Stage 3 NSCLC eligible for neoadjuvant chemo-immunotherapy followed by surgery

Stage 3 NSCLC eligible for surgery followed by immunotherapy

ctDNA will be tested retrospectively, no treatment decisions will be made prospectively

ctDNA

T.Jeroen N Hiltermann, MD, PhD

Ed Schuuring, PhD

Jonathan Benzaquen, MD,PhD

Jennifer Griffonnet

Paul Hofman, MD,PhD

Jonathan Benzaquen, MD

Victoria Ferrari, MD

Jean Philippe Berthet, MD

Ferrari Victoria, MD

Nicola Martin, MD

Mustafa Abdo, MD

Martin Reck, MD, PhD

Remge Pieterman, MD

Alice Staats-Niemeijer, BSC

T.Jeroen Hiltermann, MD

Ed Schuuring, Dr

T.Jeroen Hiltermann, MD, PhD

Paul Hofman, MD, PhD

Improving personalized cancer treatments and finding the best strategies to treat each patient relies on using new diagnostic technologies. Currently, for non small cell lung cancer (NSCLC), the methods used to decide who gets additional post radical (surgery or definite chemo-radiotherapy) treatment are suboptimal. Some patients get too much treatment, while others do not get enough.

There is a new way to explore if there is any cancer left in a patient's body using circulating tumor DNA (ctDNA) detected in blood samples. This can help decide who needs more treatment. Even though many tests have been developed, it has yet to be determined which test performs best at relevant time points.

The GUIDE.MRD consortium is a group of experts, including scientists, technology, and pharmaceutical companies. The consortium is working on creating a reliable standard for the ctDNA tests, validating their clinical utility, and collecting data to help decide on the best treatment for each patient.

GUIDE.MRD-03-NSCLC is a part of the GUIDE.MRD project.

GUIDE.MRD-03-NSCLC is a part of WP3 of the overarching GUIDE.MRD project. Each study chair has a local clinical trial protocol where patients are recruited. After the end of recruitment, samples will be analyzed under the GUIDE.MRD consortium.

The overall aim of GUIDE.MRD is to investigate the clinical utility of ctDNA analysis to predict and guide the choice of multi-modal therapies prospectively. The fundamental steps towards this aim are assessment and benchmarking of the many available ctDNA diagnostics to identify the best-suited tests for clinical application. Clinical samples will be used to benchmark ctDNA diagnostics and assess their true clinical performance. The samples should reflect clinical situations where the ctDNA diagnostics are particularly useful, such as post-operatively, post-adjuvant, during chemotherapy, and longitudinally during post-treatment surveillance. In these situations, ctDNA diagnostics could be used to either monitor treatment response (in case of MRD after surgery or definite chemoradiotherapy) or to identify relapse at an early time point. Based on ctDNA information, medical treatment could be changed, or radiology could be used to reveal the location of residual disease.

The rationale for the observational clinical study GUIDE.MRD-03-NSCLC is to prospectively collect the clinical samples needed to enable assessment of the performance of ctDNA diagnostics in the setting of non small cell lung cancer (NSCLC). There are three main scenarios where ctDNA diagnostic is useful in NSCLC in a MRD setting:

For this study stage III NSCLC will be included treated with curative intent using:

1. chemo-radiotherapy (concurrent or sequential) followed by adjuvant immunotherapy. This patient group is particularly relevant because adjuvant therapy is recommended for all stage III patients (in some countries for those with PD-L1\>1% only), due to their high recurrence risk around 58%. Additionally, most of these do not need therapy at all, because they were already cured by chemo-radiotherapy alone, which leads to substantial overtreatment. Furthermore, the 58% of patients who recur despite both chemoradiotherapy and adjuvant immunotherapy, probably could benefit from further multimodal therapies. The challenge is, however, that currently there is no marker in clinical use that can identify those patients with residual disease and need for therapy. Circulating tumor DNA is potentially such a marker.
2. Neoadjuvant treatment followed by surgery (or radiotherapy with curative intent). In this setting up to 30% have a complete pathological response (pCR). These patients are probably cured by the neoadjuvant treatment alone, where surgery thus might have been avoided if the MRD biomarker would be sensitive enough. Patients that did not receive a pCR do worse with a median overall survival around 24 month even when they are treated with immunecheckpoint inhibitors adjuvantly. Better strategies for selecting patients and treatments are urgently needed here as well. Again ctDNA could be a marker that may help here when sensitive enough to select those that are negative for no adjuvant and those that are positive for ctDNA guided multimodality treatment.
3. Surgery followed by adjuvant chemotherapy and immunotherapy. Patients in this setting may be treated by immunotherapy adjuvantly only when PD-L1\>1% (FDA) or PD-L1\>50% (EMA). Also here recurrence risk is high around 50%. Additionally, most of these do not need therapy at all, because they were already cured by surgery alone, which leads to substantial overtreatment. Furthermore, the 50% of patients who recur despite both surgery and adjuvant therapy, probably could benefit from further multimodal therapies. The challenge is, however, that currently there is no marker in clinical use that can identify those patients with residual disease and need for therapy. Circulating tumor DNA is potentially such a marker.

However, currently, it is unknown, which, if any,of the many different ctDNA diagnostics developed in recent years have the required, performance to provide clinical utility in the management in these settings of stage III NSCLC.

Primary objectives:

To assess the performance of ctDNA diagnostics using samples collected at four to five -landmark time-points "baseline"; "post neoadjuvant treatment"; "post-surgery or chemoradiotherapy"; "post-adjuvant therapy" and "at the end of study or disease progression".Sensitivity, specificity, and positive and negative predictive values of the ctDNA diagnostics will be determined to enable a head-to-head performance assessment and benchmarking of ctDNA diagnostics.

Secondary objectives To assess the ctDNA stratified 3-year recurrence-free survival (RFS). To assess the lead time between ctDNA detection and clinical recurrence. To assess the capacity of the ctDNA diagnostics to predict response to neoadjuvant therapy.

To assess the capacity of the ctDNA diagnostics to predict response to adjuvant therapy.

Full blood samples processed into plasma, buffy coat,and serum Formalin-fixed paraffin-embedded tumor tissue

Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Stage III NSCLC

GUIding Multi-moDal thErapies Against MRD by LiquidBiopsies in Non Small Cell Lung Cancer- GUIDE.MRD-03-NSCLC

For head-to-head performance assessment and benchmarking of ctDNA diagnostics

for complete pathological response, disease progression, event free and overall survival

LungenClinic Grosshansdorf

Centre Hospitalier Universitaire de Nice

University Medical Center Groningen

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Hematinics

Liver Extracts

Claus L Andersen, PhD

Mads H Rasmussen, PhD

Armin Gerger, MD, PhD

Felix Aigner, MD, PhD

Nis Hallundbæk Schlesinger

Mads F Klein, MD, Ph.D

Jeppe Kildsig, MD

Lene H Iversen, MD, DMSc

Claudia Jaensch, MD, PhD

Kåre A Gotschalck, MD, Ph.D

Peter Bondeven, MD, PhD

Uffe S Løve, MD, PhD

Ole Thorlacius-Ussing, MD, PhD

Per Vadgaard Andersen, MD, PhD

Catherine Alix-Panabiéres, PhD

Thomas Bardol, MD

Thilo Hackert, MD, MBA

Nathaniel Melling, MD

Daniel J Smit, MD, PhD

Marco Gerling, MD

Ellen Heitzer, PhD

Klaus Pantel, MD

Matthias Löhr, MD

Improving personalized cancer treatments and finding the best strategies to treat each patient relies on using new diagnostic technologies. Currently, for colorectal cancer, the methods used to decide who gets additional post-surgery treatment are suboptimal. Some patients get too much treatment, while others do not get enough.

There is a new way to explore if there is any cancer left in a patient's body using circulating tumor DNA (ctDNA) detected in blood samples. This can help decide who needs more treatment after surgery. Even though many tests have been developed, it has yet to be determined which test performs best at relevant time points.

The GUIDE.MRD consortium is a group of experts, including scientists, technology, and pharmaceutical companies. The consortium is working on creating a reliable standard for the ctDNA tests, validating their clinical utility, and collecting data to help decide on the best treatment for each patient.

GUIDE.MRD-01-CRC is a part of the GUIDE.MRD project.

GUIDE.MRD-01-CRC is a part of WP3 of the overarching GUIDE.MRD project. Each study chair has a local clinical trial protocol where patients are recruited. After the end of recruitment, samples will be analyzed under the GUIDE.MRD consortium.

The overall aim of GUIDE.MRD is to investigate the clinical utility of ctDNA analysis to predict and guide the choice of multi-modal therapies prospectively. The fundamental steps towards this aim are assessment and benchmarking of the many available ctDNA diagnostics to identify the best-suited tests for clinical application. Clinical samples will be used to benchmark ctDNA diagnostics and assess their true clinical performance. The samples should reflect clinical situations where the ctDNA diagnostics are particularly useful, such as post-operatively, post-adjuvant, during chemotherapy, and longitudinally during post-treatment surveillance. In these situations, ctDNA diagnostics could be used to either monitor treatment response (in case of MRD after surgery) or to identify relapse at an early time point. Based on ctDNA information, medical treatment could be changed, or radiology could be used to reveal the location of residual disease.

The rationale for the observational clinical study GUIDE.MRD-01-CRC is to prospectively collect the clinical samples needed to enable assessment of the performance of ctDNA diagnostics in the setting of colorectal cancer (CRC). There are two main scenarios where ctDNA diagnostic is useful in CRC:

Stage III CRC (locally advanced, non-metastasized disease): This patient group is particularly relevant because adjuvant therapy is recommended for all stage III patients, due to their high recurrence risk, \~25%. Nevertheless, most patients do not recur, and most of these do not need therapy at all, because they were already cured by surgery alone, which leads to substantial overtreatment. Furthermore, the 25% of patients who recur despite both surgery and adjuvant therapy, probably could benefit from further multimodal therapies. The challenge is, however, that currently there is no marker in clinical use that can identify those patients with residual disease and need for therapy. Circulating tumor DNA is potentially such a marker. However, currently, it is unknown, which, if any, of the many different ctDNA diagnostics developed in recent years have the required performance to provide clinical utility in the management of stage III CRC. This clinical dilemma will be addressed with the first cohort of GUIDE.MRD-01-CRC.

Metastatic CRC with isolated liver metastases. Metastatic CRC with liver metastases is a unique tumor type in that surgical resection or complete ablation of the metastases, is the standard of care. In virtually all other tumor types, resection of liver metastases is considered only within clinical trials or in exceptional clinical circumstances. In contrast, resection, or ablation of colorectal cancer liver metastases (CRLM) are routinely performed with curative intention, and the overall 5-year survival is around 50%. Most relapses present within three years after operative intervention. The clinical benefit of adjuvant chemotherapy is currently a matter of debate, due to limited data from randomized controlled trials and recent results that indicate inferior overall survival (OS) in patients who received adjuvant therapy (JCOG0603). Based on these and earlier data (EORTC Trial 40983) that failed to show an OS benefit of adjuvant therapy after CRLM resection, it can be assumed that most patients are treated unnecessarily with chemotherapy, and those patients that could receive targeted agents are missed. No histological or clinical markers are available to guide decisions on adjuvant treatment. In this setting, ctDNA could be valuable to guide decisions on adjuvant chemotherapy (yes/no), the addition of biologicals such as anti-VEGF and anti-EGFR agents, targeted therapies in the case of BRAF mutations, or the presence of microsatellite instability (MSI), for example.

Primary objectives:

* To assess the performance of ctDNA diagnostics using samples collected at the two-landmark time-points "post-surgery" and "post-adjuvant therapy". Sensitivity, specificity, and positive and negative predictive values of the ctDNA diagnostics will be determined to enable a head-to-head performance assessment and benchmarking of ctDNA diagnostics

Secondary objectives

* To assess the ctDNA stratified 3-year recurrence-free survival (RFS)
* To assess the lead time between ctDNA detection and clinical recurrence
* To assess the capacity of the ctDNA diagnostics to predict response to adjuvant therapy

Full blood samples processed into plasma, buffy coat, and serum Formalin-fixed paraffin-embedded tumor tissue

Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Colorectal Cancer

GUIding Multi-moDal thErapies Against MRD by Liquid Biopsies in Colorectal Cancer - GUIDE.MRD-01-CRC

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Stage III NSCLC	NCT06111807	Lung Cancer Sta...	ctDNA	18 Years -	University Medical Center Groningen
Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Colorectal Cancer	NCT06111105	Colorectal Canc... Liver Metastasi...		18 Years -	University of Aarhus
Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Colorectal Cancer	NCT06111105	Colorectal Canc... Liver Metastasi...		18 Years -	University of Aarhus

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