COPE is a biology driven protocol with 2 independent, multicentric, two-arm non-comparative randomized (2:1) phase II trials in 2 distinct populations: colorectal cancer patients and non-small-lung cancer patients.

For each phase II trial, patient will be randomized between two arms with two patients randomized in arm A for one patient randomized in arm B:

• Arm A (Experimental - initial MTB providing therapeutic recommendation based on tumor sequencing and then follow-up combining standard imaging and ctDNA analysis)
• Arm B (Standard - initial MTB providing therapeutic recommendation based on tumor sequencing and then follow-up based on standard imaging).

Primary tumor tissue, if accessible at all, does not always provide enough information to stratify individual patients to the most promising therapy. Re-analysis of metastatic lesions by needle biopsy is possible but invasive, and limited by the known intra-patient heterogeneity of individual lesions. These hurdles might be overcome by analyzing circulating tumor DNA (liquid biopsy), which in principle might reflect all subclones present at that specific time point and allow sequential monitoring of disease evolution.

Once tumor's genetic profiling is available, patients will be discussed within a multidisciplinary tumor board (MTB) which aims at discussing the genomic profiles and at providing a therapeutic decision for each patient. This MTB involves clinical oncologists, molecular biologists and clinical or biological project manager.

All the patients carrying an actionnable alteration will be proposed to receive a matched drug or to enter in a matched clinical trial depending on the possibility of inclusion at the time of molecular report.

the investigators hypothesize that implementing sequential circulating tumor DNA analysis can improve management of patients with advanced cancer and therefore their survival.

Inclusion Criteria:

1. Age ≥ 18 years,
2. Histology: colorectal cancer, non-small cell lung cancer,
3. Locally advanced/unresectable and/or metastatic solid tumor,
4. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Appendix 1),
5. Measurable disease according to RECIST 1.1 (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST v1.1). At least one site of disease must be uni-dimensionally > 10 mm,
6. No previous systemic treatment for advanced disease,
7. Availability of suitable paraffin embedded (FFPE) archive tumor material or at least one target lesion that can be biopsied for research purpose,
8. Eligible to first-line systemic therapy,
9. Patient with a social security in compliance with the French law,
10. Voluntary signed and dated written informed consent prior to any study specific procedure.

Exclusion Criteria:

1. Inability to swallow,
2. Major problem with intestinal absorption,
3. Previous allogeneic bone marrow transplant,
4. Previous or current malignancies of other histologies within the last 2 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin and prostate cancer,
5. Evidence of severe or uncontrolled systemic disease (uncontrolled hypertension, active bleeding diatheses, or active Hepatitis B, C and HIV),
6. Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in a clinical trial or which would jeopardize compliance with the protocol,
7. Individuals deprived of liberty or placed under guardianship,
8. Pregnant or breast feeding women,
9. Previous enrolment in the present study,
10. Any contraindication to first-line systemic therapy.