Lung cancer Early Molecular Assessment trial

Non-small lung carcinoma (NSCLC) has a poor prognosis. At presentation 50-60%
of patients have stage I-III disease for which curative therapy is available.
But, in the majority of these patients the disease will metastasize and
systemic treatment is needed during the course of the disease. For metastasized
disease the 5-year overall survival rate is less than 5%.
Personalized treatment has become standard of care for metastasized NSCLC but
the proportion of patients for which targeted agents are available is still
modest. Next to targeted therapy currently immunotherapy is being introduced.
Targeted therapy is available for patients with EGFR and ALK gene aberrations
and many other targets are to be expected in the oncoming few years. For
patients with NSCLC wild-type ALK and EGFR, only chemotherapy is for first line
treatment that is often less effective than targeted therapy and has an
inferior toxicity profile. For patients that present with earlier stage disease
(stage I-III) currently no targeted agents have been approved. As of now, when
patients present with disseminated disease, molecular profiling is initiated.
The process of retrieving biopsy material from another hospital or collecting a
new biopsy, together with the molecular analysis itself can easily take up to 5
weeks. For approximately a quarter of patients, these samples are not available
in sufficient amount to perform predictive mutation analysis. Therefore a
substantial number of patients receives no targeted treatment. When however,
molecular profiles are available at an earlier stage of disease, more patients
who develop disseminated disease might benefit from personalized therapy
opportunities. Also because there is more time available we can perform the
molecular profiling in a cost-effective manner (that is sequentially and not
parallel), which will reduce the diagnostic costs. Although this strategy
resolves the delay to obtain a molecular diagnosis in the metastasized setting,
it won*t resolve the problem of insufficient material obtained with biopsy.
Therefore, we will use both tissue and blood-based genetic testing. We
hypothesize that early molecular screening will enable a timely switching to
targeted treatment and significantly improve survival and diagnostic
efficiency.

Primary Objective:
- To determine the percentage of patients with EGFR mutation, ALK translocation
and other genetic aberrations with an improved efficacy of molecular profiling
in all stages of NSCLC.
- To determine PD-L1 tumour proportion score in all stages of NSCLC

Secondary Objective(s):
- To define the diagnostic value of liquid- and tissue biopsy-based molecular
analysis.
- To investigate the change in diagnostic yield of tissue-based molecular
analysis when blood-based molecular analysis is an available alternative.
- To explore the reasons for insufficient tumor material available for
molecular profiling.
- To define the frequency of pre-defined genetic alterations using the LEMA
approach.
- To estimate the costs of the LEMA approach and the introduction of
liquid-based analysis
- To compare results of molecular analysis at baseline and follow up of NSCLC.
- To explore the epidemiology of the PD-L1 biomarker expression in all stages
of NSCLC.
- To determine PD-L1 tumour proportion score in EGFR mutant and ALK rearranged
NSCLC

In this prospective multicentre trial tumours of all patients presenting with
NSCLC will be profiled upfront, irrespective of disease stage and pathology
using both tissue and blood-based genetic testing. A minimal molecular
profiling is depicted but other targets will be included in due time. The study
is divided in two parts. In the first part participating centres will have a
run-in period of half a year in which molecular profiling is performed as is
currently standard of care. This period will be used to measure the impact of
increased awareness on the diagnostic process. During the second part of the
study a comprehensive upfront profiling according to local standards will take
place for all NSCLC patients. Liquid (blood) biopsies will be included in order
to increase the diagnostic yield for those patients where tissue biopsies are
not adequate. Patients will be treated according to standard of care, or
included in clinical studies where appropriate. Re-biopsies (both tissue and
liquid) will be advocated at the time of establishing disease
progression/disseminated disease, and personalized therapy will be initiated
according to the existing data from the molecular profiling.

The expected diagnostic process will change and theoretically the number of
biopsy procedure might be increased and therefore the chance of minor
complications. However, the improved molecular profiling is thought to expand
treatment opportunities. Patients will benefit from a direct switch to targeted
treatment upon progression.