Updates and news from the Gastrointestinal Cancers ...

Colon cancer: critical review

AIOM POST-ASCO G.I. 2017 Review

Updates and news from the Gastrointestinal Cancers Symposium in San Francisco, CA,USA

Roma, 10-11 Febbraio 2017

Carmelo Pozzo

Oncologia Medica

Fondazione Policlinico Gemelli

UCSC - Roma

http://www.policlinicogemelli.it/b/?hw=5&b=62

What’s new in colon cancer at ASCO G.I. 2017?

• Colorectal Cancer Heterogeneity

• Role of molecular subtypes, molecular markers and genetic testing in clinical practice

• Immune Checkpoint inhibitors in mCRC

• Nivo +/- ipilimumab

• Sidedness matters

• Molecular subtypes and “surrogate” markers in metastatic and early CRC

• Mature data from some important studies

• IRI+CET +/- vemurafenib in BRAF mut (SWOG S1406)

• Triplet + beva vs FOLFIRI +beva (CHARTA)

• Role of bacteria (microbiota) in colorectal carcinogenesis

• Pro e Contra HIPEC, hyperthermic intraperitoneal chemotherapy


• Colorectal Cancer Heterogeneity

• Role of molecular subtypes, molecular markers and genetic testing in clinical practice

The Role of Molecular Subtypes for Prediction and Prognosis of Colorectal Cancer

Presented By Sabine Tejpar at 2017 Gastrointestinal Cancers Symposium

CMS Groups in CRC


Outcome of the Different Molecular Subgroups


Role of molecular subtypes in CRC

• Numerosi studi per caratterizzare e quantificare l’eterogenietà cellulare nel CRC e proporre dei modelli

• Tumore colorettale: 4 gruppi molecolari o qualcosa di più complesso? Quali i limiti dell’analisi molecolare e del clustering?

• Capacità predittiva ancora in corso di validazione in studi retrospettivi

• “Supervised Pathway Signature” utilizzati nella stratificazione di nuovi trial clinici

• Ancora lontani dall’impiego per una valutazione del rischio e della prognosi (Oncotype DX, Mammaprint etc?)

The Role of Molecular Markers in Clinical Trials

Presented By Sebastian Stintzing at 2017 Gastrointestinal Cancers Symposium

The Tissue is the Issue


When to obtain tissue material


Liquid biopsy


Role of molecular markers in trials (and in clinical practice?)

• Ruolo prognostico ben definito : RAS, BRAF, MSI, meno definito per altri Pi3K, HER-2, CSM and molecular subtypes

• Solo pochi di essi derivano da mutazioni “actionable” o sono “druggable” driver:

• RAS e inibitori EGFR: SI

• MSI e inibitori immunocheckpoint SI

• BRAF e vemurafenib? FORSE

• HER-2 e trastuzumab? FORSE

• Ancora pochissimi gli esempi di “Basket Trial” o “Umbrella Study” nel CRC

Utilization of Genetic Testing in Clinical Practice

Presented By Elena Stoffel at 2017 Gastrointestinal Cancers Symposium

Genetic Evaluation in CRC


Epidemiology of CRC


Screening of CRC Tumors for Mismatch Repair Deficiency (MMRd)*


Screening for Genetic Predisposition


Multigene Panels


Role of genetic testing in clinical practice

• Tutti i tumori colorettali dovrebbere essere testati per MMR deficiency o solo in base al rischio personale (giovane età: < 50 anni) o familiare?

• Il test genetico in presenza di MMRd o mutazione somatica di BRAF deve prevedere anche la ricerca di mutazioni della linea germinale: BRCA 1-2, APC, MUTYH, ATM, NBN, VUS?

• Molte varianti incerte e mutazioni a penetranza variabile “not actionable”

• Potential for anxiety/distress…


• Immune Checkpoint inhibitors in mCRC

• Pembro

• Nivo

• Nivo +/- ipilimumab

• Atezolizumab

• Atezolizumab +/- cometininb

Presented By Luis Diaz at 2017 Gastrointestinal Cancers Symposium

Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142

Presented By Michael Overman at 2017 Gastrointestinal Cancers Symposium

Study Design


Best Reduction in Target Lesion Size <br />in Patients With MSI-H


Investigator-Assessed PFS in Patients With MSI-H<br />Nivolumab ± Ipilimumab in Metastatic CRC


Clinical activity and safety of cobimetinib and atezolizumab in colorectal cancer


Efficacy: Change in Tumor Burden


Efficacy: Change in Tumor Burden Over Time


Single agent anti-PD1


Is immunotherapy in colon cancer holding the promise?

• 15% dei carcinomi colorettali dMMR alla diagnosi, ma solo 4-5% nella malattia metastatica

• Percentuale molto piccola di mCRC (si… ma l’incidenza del CRC è molto elevata!) che presenta mutazioni “actionable” (i.e. dMMR, POLE, POLD)

• PD-L1 non è utlizzabile come biomarker nel CRC

• Con la combinazione risposte più durature (dati ancora preliminari)

• Come incrementare l’immunogenicità o il numero dei tumori CRC immunogenici?

• Cosa fare in seguito a progressione dopo una prolungata risposta a inibitori immunocheckpoint?


• Sidedness matters

• Molecular subtypes in metastatic CRC

• “Surrogate” markers in early CRC

Continuum of molecular alterations from right to left<br />


Molecular Variances Between Rectal <br />and Left-Sided Colon Cancers

Presented By Mohamed Salem at 2017 Gastrointestinal Cancers Symposium

CONSORT Diagram


Multi-platform profiling


Frequency of microsatellite instability in left-sided CRC


Tumor Mutation Load (TML)


Her2/Neu : Overexpression and Amplification


Conclusions


Sidedness matters: right-sided vs left-sided vs rectal

• Migliore conoscenza degli aspetti molecolari: si, ma quale impatto clinico?

• Prognosi peggiore nell’ordine per: colon destro > retto > colon sinistro?

• Le classificazioni molecolari (CMS 1-2-3-4 e TGCA) e alcune mutazioni (RAS, BRAF) o overespressioni (HER2) non sono sufficienti a spiegare la differente prognosi, indipendentemente dalla sede?

• Quanto è “actionable” questa migliore conoscenza biomolecolare del CRC?

• Dati sufficienti per evitare gli inibitori EGFR nel colon destro?

NCCN: si AIOM: no (o ni)

• Reale beneficio del beva nel colon destro o è sufficiente la sola chemioterapia…?

• Reale beneficio di anti EGFR in 2a linea (Pani) o in 3a (Cetux) nel colon destro… ?

• E la tripletta sempre nel colon destro come ‘a vedi..?

Primary Tumor Location and Potential

Treatments

MSI-H

HER2+ BRAF MT

Bevacizumab + CT

Left-sided Right-sided

Anti-EGFRs + CT

Anti-PD1

Bev + Triplet CT HER2-targeted agents

↑KRAS MT ↑KRAS WT

↑AREG/EREG

Bufill JA. Ann Intern Med. 1990;113:779-788; Missiaglia E, et al. ASCO 2013. Abstract 3526; Brule SY, et al. ASCO 2013. Abstract

3528; The Cancer Genome Atlas Network. Nature. 2012490:61-70; Bendardaf R, et al. Anticancer Res. 2008;28:3865-3870.

• Impact of CHARTA (phase 2 !!!) with FOLFOXIRI /BEVA vs FOLFIRI/BEVA:

• None or… finally we know that oxaliplatin is effective but can also be

omitted!

• I am still a little confuse… with regards to the best treatment sequence sin mCRC

and for what patients??

• Chemo mono + bio 1st line

• Chemo doublet 1st line

• Chemo doublet + bio 1st line

• Chemo triplet alone 1st line

• Chemo triplet + bio 1st line

• Chemo + same or other bio 2nd line

• Immunotherapy 2nd or 3rd line

• Bio mono 2nd or 3rd line

• Chemo mono 3rd or 4th or

• De-potentiation

• Maintenance with bio or with chemo mono, etc…

What’s new in CRC at ASCO G.I. 2017? Little steps and many open questions…

• Impact of SWOG S1406 (phase 2 !!) with vemurafenib + Cet + IRI vs Cet + IRI:

• Potentially strong impact… for an off-label use of vemurafenib in BRAF+

• BRAF “druggable” also in CRC or just anti EGFR resistance reversal?

• BRAF blockade to overcome the gap of anti EGFR treatment in right-sided

CRC?

• Is mCRC ready for a “precision medicine” approach?

• Many “not actionable” mutations and “not druggable” drivers

• Few basket and/or umbrella trials ongoing in mCRC

• Strong regulatory issues: i.e. HER-2 iand trastuzumab, BRAF and vemurafenib

MGMT mutation, other potential driver

What’s new in CRC at ASCO G.I. 2017? Little steps and many open questions…

Updates and news from the Gastrointestinal Cancers ...

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