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:
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.
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.
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.
