The Rome Trial From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy

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.