LA MEDICINA DI PRECISIONE TESSUTO-AGNOSTICA:
UN APPROCCIO EMERGENTE
Studi clinici in corso
FIRST EXPERIENCE : IMPACT 1
Tsimberidou 2014
• COMBINATION THERAPY Many patients are unlikely to respond to monotherapy
• THE CHOICE OF DRUGS … Everolimus weakly affects the PI3K/Akt/mTOR pathway; patients with PI3K/ Akt/mTOR alterations often have coexisting alterations in RAF/MEK that confer resistance… many patients had hormone
receptor abnormalities; response to hormone monotherapy in pretreated patients with advanced disease is unlikely….
• NOT OVER SECOND LINE …Heavily pretreated metastatic cancer … As the number of prior therapies increases, the expected progression-free survival will decrease…
DISTRIBUTION OF ACTIONABLE ALTERATIONS
Presented By Olivier Tredan at 2017 ASCO Annual Meeting
ON GOING
TRIAL MOSCATO
TRIAL
FRANCE 74 genes POSITIVE RANDOMIZED
SHIVA TRIAL FRANCE NEGATIVE RANDOMIZED
PROFILER FRANCE + cfDNA POSITIVE NON
RANDOMIZED
WINTHER USA FMI + mRNA ON GOING RANDOMIZED
NCI-MATCH USA NGS ON GOING RANDOMIZED + IMMUNO
TAPUR USA NGS ON GOING NON
RANDOMIZED
+ IMMUNO
IMPACT 2 USA FMI ON GOING RANDOMIZED + CROSS OVER
Key points
(critical evaluation of previous trials)
1. Numbers of detectable alterations 2. Numbers of actionable mutations 3. Tissue sample versus ctDNA
4. Line of treatment (earlier is better) 5. Combination treatment
6. Immunotherapies
7. Beyond the genomics … trascriptomics
8. Beyond the clinical trial : THE PATIENTS : the cross over …
The ROME trial: from histology to target
…from the previous trial design…
The ROME trial: from histology to target
A multi-basket trial
The ROME trial: from histology to target
SPONSOR Department of Clinical and Molecular Medicine, Sapienza University of Rome and Istituto Superiore di Sanità, Fondazione per la Medicina Personalizzata, Rome
CRO Clinical Trial Center, Fondazione per la Medicina Personalizzata, Rome, Italy
The ROME trial: from histology to target
Prospective Randomized 2 arms Phase II trial:
Therapy at choice of physician (TCP) vs Tailored treatment (TT)
Pts affected by progressive disease
Patient with recurrent/metastatic breast, gastrointestinal cancer (excluding colon-rectal cancer), lung cancer or other neoplasia, excluding in first line patients with well-established actionable targets for which approved and marketed targeted drugs are available (i.e. lung cancer with EGFR mutation, or ALK translocation, B-RAF mutant melanoma, GIST with KIT mutations or breast cancer with HER2 amplification).
Patients must have biopsable lesion to perform Foundation One evaluation and will be randomized to targeted therapy vs SOC
Primary endpoint: ORR of TCP vs TT (RECIST v1.1 criteria) Secondary Endpoint:
OS of TCP vs TT , TTF, TTNT
The ROME trial: from histology to target
FoundationOne CDx
A single test that analyzes all
guideline-recommended genes in solid tumors, including companion diagnostic indications with a direct path to therapy.
Results include MSI and TMB with the option to add PD-L1 testing to help inform immunotherapy
decisions.
nCounter® Breast Cancer 360™ Panel
• The nCounter Breast Cancer 360 panel and data analysis service provides a unique 360 degree view of gene
expression for the breast tumor microenvironment and immune response.
• Expertly curated, comprehensive
content includes 770 genes across 23 key breast cancer pathways and
processes
• Expanded evaluation of breast cancer
subtypes includes: PAM50 Signature,
Triple Negative Breast Cancer Signature,
and Claudin-Low Signature
nCounter® PanCancer IO 360 Gene Expression Panel
The PanCancer IO 360 Gene
Expression Panel is a unique 770 gene expression panel for research use
only (RUO) that combines vital
components involved in the complex interplay between the tumor,
microenvironment and immune response in cancer allowing for a multifaceted characterization of
disease biology and interrogation of
mechanisms of immune evasion.
nCounter® PanCancer Immune Profiling Panel
Perform multiplex gene expression
analysis with 770 genes from 24 different immune cell types, common checkpoint inhibitors, CT antigens, and genes
covering both the adaptive and innate
immune response.
Molecular Tumor Board
& Virtual Consultation System for Therapeutic Decision
From a standard pre-defined therapy to a personalized treatment
INCLUSION CRITERIA
• Patients able and willing to provide a written informed consent to participate to the study
• Patient with recurrent/metastatic breast, gastrointestinal cancer (excluding colon-rectal cancer), lung cancer or other neoplasia, excluding in first line patients with well-established actionable targets for which approved and marketed targeted drugs are available (i.e. lung cancer with EGFR mutation, or ALK translocation, B-RAF mutant melanoma, GIST with KIT mutations or breast cancer with HER2 amplification)
• ECOG performance status of 0 or 2
• Biopsiable disease (tumor biopsy mandatory for tumor profiling). The biopsy must be performed when patients completed the conventional therapy for their recurrent/metastatic cancer.
• Measurable disease, progressing to standard treatment. Patients must have measurable or evaluable disease defined, per RECIST 1.1, as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral computed tomography (CT) scan, Magnetic Resonance Imaging (MRI), or a subcutaneous or superficial lesion that can be measured with calipers by clinical exam. For lymph nodes, the short axis must be ≥15 mm. Patients who have assessable
disease by physical or radiographic examination but do not meet these definitions of measurable disease are eligible and will be considered to have evaluable disease. Patient's whose disease cannot be objectively measured by physical or radiographic
examination (e.g., elevated serum tumor marker nly) are NOT eligible. PET scan could be performed, if clinically indicated. For PET response evaluation PERCIST criteria will be applied.
• Adequate renal function defined by a serum creatinine <1.5xUNL (upper normal limit).
• Adequate liver function test defined by SGOT & SGPT <3xUNL (5xUNL in case of liver metastases), and bilirubin level <1.5xUNL
• Adequate bone marrow function defined by platelets >100,000/mm3, hemoglobin >10 g/dL, and neutrophils >1,000/mm3
• For female of child-bearing potential: a negative pregnancy test <72 hours before starting study treatment is required. If sexually active, female of childbearing potential must use "highly effective" methods of contraception for the study duration and for 3 months following the last treatment
• For male of reproductive potential: any sexually active male patient must use a condom while on study treatment and for 3 months following the last treatment
EXCLUSION CRITERIA
• Patients who have only bone and/or brain metastases
• Patients treated with more than 2 line for gastro-intestinal non colorectal cancer, lung cancer and other cancer and with more than 3 line for breast cancer.
• Patients whose brain metastases have not been controlled for >2 months
• Patient participating in another clinical trial with an experimental drug
• Patients who are candidate to receive a molecularly targeted agent that is approved for their disease
• Anticoagulation with anti-vitamin K (Low Molecular Weight Heparin [LMWH] is allowed)
• Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, including uncontrolled diabetes, cardiac disease, uncontrolled hypertension,
congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, active gastrointestinal tract ulceration, severely impaired lung
function
• Pregnant and/or breastfeeding women
• Individually deprived of liberty or placed under the authority of a tutor
• Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• HIV, HBV, or HCV infection as per specific test performed at the screening visit or known as per Medical
History
The problems in polypharmacy today
Personalised Medicine (PM) has yet to be accepted because of
The complexity of
Pharmacogenomics (PGx) and their connections with drug interactions;
The lack of an adequate support system that integrates scientific
evidence in an efficient decision making process;
The lack of a systematic PM application for extensively treated patients;
The difficulty of evaluating long-term clinical and economic benefits due to the points above.
Thousands potential complications resulting from polypharmacy
Pharmaceutical drug side effects are discovered essentially by accident 40% of elderly patients take 5 or more medicines per day
Adverse drug reactions (ADRs) have a significant impact on patient health Despite progress in understanding the factors that condition drug
effectiveness...conventional clinical prescriptions still do not consider drug interactions, let alone the metabolism, case history and genetics of the patient.
Opportunity: Reduction of non-necessary care and ADRs could reduce hospitalisations by more than 5%, prevent 197,000 deaths per year in the EU and reduce public spending by €79 Billion.
The Solution: DRUG-PIN
Through a multidimensional approach and a complex algorithm that has been developed by university researchers over the last decade that draws on multiple updated, medical databases, each drug query on patient’s profile will produce a score where penalties indicate potentially severe interactions and adverse side effects to be avoided.
By considering a patient’s unique characteristics including:
Medical
History DNA Behaviour Metabolism Diet
Efficiency of each drug for patient
Interactions between drugs
La Medicina di Precisione nel Rome trial
• Non è solo questione di geni...
• Trascrittomica
• Proteomica
• Metabolomica (funzionale)
• Epigenomica
• …
• ...e non sono nemmeno tutti nostri...
• Microbioma
• per non trattare delle interazioni tra i sistemi...
• Influenze delle modificazioni del microbiota sulla risposta immunitaria, differenze di genere, interazioni tra farmaci…
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