Personalizing cancer medicine depends on the implementation of personalized diagnostics and
      therapeutics. Detailed genomic and gene expression signatures screening are likely to play a
      central role in this. Personalized Medicine has been widely depicted as a striking
      innovation, that is able to reform the standard approach to disease management, replacing the
      one-size-fits-all scheme of medicine with a single-patient-sized medical intervention.

      Personalized medicine promoters usually highlight its potential to combine a more effective
      health-care with costs containment, according to the following rules:

        -  monitoring of disease risks and more effective prevention;

        -  early intervention;

        -  selection of optimal therapy;

        -  reduction of trial-and-error prescribing and reduction of adverse drug reactions;

        -  exclusion of unnecessary drugs;

        -  therapeutic drug monitoring and disease progression/remission monitoring;

        -  increased patient compliance with therapy. In spite of expectations, many unsolved
           practical issues, from technical and scientific to ethical, legal and economic topics,
           are slowing down the translation of personalized medicine principles into medical
           practice. Furthermore, wide adoption of personalized strategies also has to deal with
           the peculiar rules, policy and reimbursement system of each country.

      Application of Personalized Medicine in the real world seems entangled by the unmet need to
      develop evidence-based guidelines.

      The benefits of personalized medicine in routine clinical practice have firstly emerged in
      oncology. The power of precision medicine in the field of anticancer therapy resides in the
      possibility to characterize the genomic profile of both the disease (eg somatic mutations in
      the tumor tissue or blood sample) and the patient (eg the germinal genomic profile). The
      first piece of information allows stratification of patients in responder and non-responder
      to specific drugs, improving efficacy and avoiding wasting of expensive medications as
      biological drugs. Personalized medicine for cancer can be classified in:

        -  targeted therapy (which bloks the growth of cancer cells by interfering with specific
           molecular targets of cancer cells) or

        -  immunotherapy (which use the body'immune system to fight cancer cells by stimulating the
           immune system) Targeted therapy belongs to Personalized Medicine approach and the study
           of genetic mutations on tumor tissue or blood sample (CTC or cfDNA ) are changing the
           scenario of the treatment approach of cancer patients.

      In clinical practice, the use of target therapies driven by mutation's assessment has
      radically changed the survival of patients affected by breast cancer, NSCLC, melanoma,
      colo-rectal cancer, while the clinical application of specific gene expression signatures is
      driving the choice of the best adjuvant strategy in early breast cancer.

      Despite the efficacy of such approach its use is restricted to a relatively small fraction of
      patients and the evaluation of mutation is conditioned by the primary site of the cancer,
      i.e. by the tumor histology. The current biological understanding leads to hypothesize that
      the cancer behavior is highly dependent from the underlying driver genetic alterations
      independently from the histology. It's widely demonstrated that such molecular alterations
      are detected regardless of the histology, and this has already modified the treatment
      approach of some cancers.

      Furthermore, several studies have demonstrated the efficacy of the choice of treatment
      according to genomic evaluation regardless of its histology with acceptable
      cost-effectiveness profile.

      In the context of precision medicine the Immuno-oncology is becoming Precision
      Immuno-oncology and the efforts of science are directed towards the identification of
      predictive biomarkers of response to immune checkpoint inhibitors.

      Promising biomarkers are Microsatellite Instability (MSI) and the tumour mutational load
      (TMB). In particular TMB is a quantitative biomarker that reflects the total number of
      mutations carried by tumor cells. TMB is well-known to reflect neoantigens burden potentially
      recognized by the immune system. This has been shown to correlate with better anti-PD-1
      response in particular for both pembrolizumab and nivolumab combined with ipilimumab .

      The same findings were demonstrated in the OAK study considering peripheral blood mutational
      load and response to atezolizumab.

      High tumor mutation burden (defined as tumors that have high ≥10 mutations/megabase, mut/mb)
      allows to identify 45% of patients who can benefit from immunotherapy regardless of PD-L1
      expression. So, ever keeping in mind that although many evidences are available, the
      relationship between histology and genomic alterations is still under definition, as well as
      the relationship between the latter and gene expression.

      The aim of the present investigation is to combine all of the information available to drive
      the therapy selection according to the genomic alteration profile. Therefore, the main
      objective of our study is to evaluate the efficacy of therapy according to genomic profile
      (TT - Tailored Treatment) versus Standard of Care (SoC). A molecular profile of the cancer
      will be evaluated on tumor tissue biopsy (using the Foundation One (with updated gene panel
      324 gene reflecting CDx) at the time of patient inclusion in the trial and on circulating DNA
      fragments (i.e. using FoundationOne Liquid test) at the time of patient inclusion in the
      trial and at progression of disease.

      This study is a Phase II, randomized, multicenter, Proof of Concept, clinical trial. Patients
      with progressive disease (recurrent and/or metastatic) of breast cancer, metastatic
      gastro-intestinal tumors, non small cell lung cancer (NSCLC) or others will be included.
      Patients should have completed at least 1 line of treatment and no more than 2 as defined by
      the current version of the AIOM guidelines. Patients are included if surgery is
      contraindicated.

      Patients could have received targeted therapy for metastatic disease. A molecular profile of
      the cancer will be evaluated on tumor tissue biopsy and on ctDNA of around 1280 patients at
      patient inclusion.

      After FO evaluations patients with actionable mutations, not previous identified with other
      methods, for which approved drugs according to histotype are available, will be excluded.

      Once identified molecular abnormalities (not only those that are disease-specific), that can
      be modulated with target or immunotherapeutic intervention available within the present
      study, patients will be randomized to receive:

      ARM A: Therapy at choice of physician, according to Standard of Care (SoC) ARM B: Tailored
      treatment according to genomic profile (Tailored Treatment, TT)

      The Molecular Tumor Board (MTB) will define the target therapy and immunotherapy while
      standard treatment will be decided by study physicians.

      Patients should remain in the treatment phase of the study until investigator assesses
      radiographic or clinical progressive disease, unmanageable toxicity, or study termination.

      Tumor assessments will be conducted every 12 weeks from the date of randomization until any
      of the above events occurs.

      Delays in treatment administration will not impact the timing of the tumor assessments. If a
      tumor assessment must be performed early/late, subsequent assessments will be conducted
      according to the original schedule of every 12 weeks from the date of randomization.

      At the time of the first progression of disease:

        -  blood sample will be collected to evaluate the molecular profile of the cancer on
           circulating DNA fragments (i.e. using FoundationOne Liquid test)

        -  Study treatment (SoC or TT) will be interrupted waiting for the evaluations for the
           Rescue/Switched Phase

      Tumor assessments must be conducted until progressive disease (PD for RECIST 1.1 or iCPD for
      iRECIST if clinically indicated), even if treatment has been discontinued due to
      investigator-determined PD or unacceptable toxicity.

      After discontinuation of study treatment for reason different from progressive disease and
      withdrawal of consent, tumor assessments will continue until progression.

      In addition, patients will be followed for survival until death, loss to follow-up,
      withdrawal of consent, or study termination.