Biomarcatori nel tumore del colon-retto: passato, presente e futuro

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Biomarcatori nel tumore del colon-retto:

PASSATO, PRESENTE e FUTURO

MONICA NIGER ISTITUTO NAZIONALE DEI TUMORI

MILANO

NOVITA’ IN TEMA DI TUMORI DEL COLON

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AGENDA

 PAST AND PRESENT BIOMARKERS FOR mCRC

 FUTURE BIOMARKERS FOR mCRC RAS

BRAF

CMS

MSI

ALK/ROS/panTRK/ RET HER2

MGMT

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AGENDA

 PAST AND PRESENT BIOMARKERS FOR mCRC

 FUTURE BIOMARKERS FOR mCRC CMS

MSI

ALK/ROS/panTRK/ RET HER2

MGMT

RAS

BRAF

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PAST (and PRESENT)

Extracted from Van Cutsem et al. Ann Oncol 2016

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RAS in short

 KRAS-mut (ex 1- 4) represent 35% of mCRC population and are predictive of anti-EGFR resistance and NRAS-mut (ex 1-4)

Sorich MJ et al 2014

 NRAS-mut (ex 1- 4) represent 20% of mCRC population and are predictive of anti-EGFR resistance

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BRAF in short

 BRAF-mut is a rare (8 - 10%) and aggressive molecular mCRC subtype.

 Anti-EGFRs (w/o chemotherapy) and BRAFi (w/o MEKi) have limited activity

 Preclinical and early phase 1/2 evidences suggested that anti-EGFRs plus BRAFi targeted combinations have encouraging activity and a manageable safety profile.

Addionally, preclinical and early phase 1/2 evidences suggested that the addition of irinotecan to cetuximab-vemurafenib is tolerable and may further increase activity

Data from randomized clinical trials are still lacking

Pietrantonio et al, EJC 2015; Corcoran JCO 2015; Corcoran et al, ESMO 2016;

Yaeger CCR 2015; Hong et al, Cancer Discov ’16; Cremolini, Annal Onc 2015; Jones J.c. et al JCO 2017

 Not all BRAF are the same: non-V600E BRAF mutation (ex codon 594 and 596 mutant) have longer OS when compared to BRAF V600E

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BRAF, BeCool

Multicenter retrospective study 395 BRAFm mCRC pts enrolled!

Loupakis et al. AIOM 2017

OS

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Siravegna et al, Nature Medicine 2015

RECHALLENGE - rationale

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RECHALLENGE - Cricket

Cetuximab Rechallenge in Irinotecan-pretreated mCRC, KRAS, NRAS and BRAF wild-type treated in 1st line with anti-EGFR Therapy.

 mCRC pts

 RAS and BRAF wt

FOLFIRI/

FOLFOXIRI + Cetuximab

FOLFOX/XELOX/

FOLFOXIRI + Bevacizumab

Irinotecan + Cetuximab

PD PD

Rossini et al. ASCO 2018

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A Phase II Trial Of ReCHallenge With Panitumumab DRiven by RAS ClONal-Mediated Dynamic Of ReSistance: The CHRONOS Trial

RATIONALE: expansion of extended-RAS clones is the principal culprit of anti- EGFR acquired resistance, and these clones decay upon anti-EGFR treatment withdrawal, while tumor cells regain sensitivity to anti EGFR treatment.

Individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant RAS. The CRC genome therefore adapts dynamically to intermittent anti-EGFR drug schedules providing a molecular explanation for the efficacy of re-challenge therapies based on EGFR blockade

RECHALLENGE - CHRONOS

time

% mut RAS clones

sensitive resistant

1^stline including anti-EGFR 2^ndline rechallenge

Pre-Screen

1.Documented WT RAS exons 2, 3 and 4 and BRAF V600E;

2.Complete or partial response to frontline chemotherapy including anti-EGFR mAb

Molecular Screening

1. Imaging documented progression while on, or within 6 months from first line therapy including anti-EGFR mAb;

2. A RAS-extended mutational load with >

3% fractional abundance, measured on plasma ctDNA at BML (maximum within 1 week of 1st line progression);

3. A planned 2nd line chemotherapy of any type with the exclusion of further anti EGFRs.

Trial

1.Imaging documented progression at a 2^nd line chemotherapy (regorafenib is allowed);

2.A RAS-extended mutational load measured on plasma ctDNA at RML (maximum within 1 week from 2nd line progression);

3.A > 50% drop in RAS-extended mutational load between BML and RML;

RAS Baseline Mutational Load (BML)

RAS Intermediate Mutational Load (IML)

RAS Rechallenge Mutational Load (RML)

Tumor sensitivity to anti-EGFR

EudraCT n. 2016-0902597-12

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PRESSING PANEL

Cremolini et al, Annals Oncol 2017

• Amplificazione e mutazioni di HER-2,

• Amplificazione di MET,

• Fusioni di TRK/ROS/ALK/RET,

• Mutazioni attivanti dell’asse PIK3CA/PTEN/Akt e MAPKs

vs

* Progrediti entro e non oltre 3 mesi di trattamento contenente un anti-EGFR moAb

Pz PRIMARIAMENTE RESISTENTI a anticorpi anti-EGFR

Pz RESPONSIVI a anticorpi anti-EGFR

** RP/SD confermata in almeno 2 TC durante anti- EGFR in monoterapia o irinotecano+cetuximab in pz chiaramente irinotecano-refrattari

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RESISTANT GROUP SENSITIVE GROUP

Progression Free Survival Overall Survival

PRESSING PANEL

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AGENDA

 PAST AND PRESENT BIOMARKERS FOR mCRC

 FUTURE BIOMARKERS FOR mCRC CMS

MSI

ALK/ROS/panTRK/ RET HER2

MGMT

RAS

BRAF

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Guinney J et al, Nature Med 2015

CONSENSUS MOLECULAR SUBTYPES

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CMS step 2

Mooi et al, ESMO ‘17

Smeby et al, Ann Oncol 2018

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HER 2: A HAPPY ENDING

Sartore Bianchi et al, Lancet Oncology ‘16

Change in target lesion from baseline (%)

SD

Objective Response space ( > 30% shrinkage)

Trastuzumab +

Lapatinib ^PD

Phase II, primary endpoint: ORR (Recist 1.1) 27 HER-2 +, KRAS wt mCRC pts

progressed after fluoropyrimidine, oxaliplatin, irinotecan and

an anti-EGFR moAb

HER2 +

3%

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Drilon et al, Cancer Discov 2017; Sartore-Bianchi et al, JNCI 2015; Amatu et al, BJC 2015

ENTRECTINIB

Entrectinib is a pan-TRK, ROS1 and ALK inhibitor.

Combined analysis of two Phase-1 Trials (ALKA-372-001 and STARTRK-1).

ALK/ROS1/NTRK

0.2%- 2.4%

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Female Older Age

Right colon Lymph nodes mets

RAS&BRAF wt MSI-high

FUSIONS in mCRC

Pietrantonio et al, JNCI 2017

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RET: PROGNOSTIC IMPACT

Pietrantonio et al, Ann Oncol 2018

IHC FISH ^RET+

< 1%

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MMRD predicts response to immunotherapy...

Le et al, N Eng J Med 2015; Le DT et al Science 2017

MSI AND IMMUNOTHERAPY

MSI

15%

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MSI AND IMMUNOTHERAPY

…while there is low benefit for MSS CRC

Topialan et al, N Eng J Med, 2012 Le et al, N Eng J Med 2015 Overman et al, J Clin Oncol 2016 Chung et al, J Clin Oncol, 2016

Author Drug Population ORR

Topialan et al Nivolumab Refractory CRC 0% (n=19)

Le et al Pembrolizumab MSS CRC 0% (n=18)

Overman et al Nivolumab +

Ipilimumab MSS CRC 5% (n=20)

Chung et al Tremelimumab Refractory CRC 2% (n=49)

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MSI AND IMMUNOTHERAPY

Nivolumab and ipilimumab efficacy in MSI-H Thierry Andre et al, ASCO GI 2018

Nivolumab OS in MSI-H

Median OS [95% CI], months 12-month OS rate [95% CI], % 18-months OS rate [95% CI],

NR [19.6, NE]

72 [60.0, 80.9]

67 [54.9, 76.9]

Median OS [95% CI], months 9 -month OS rate [95% CI], % 12-months OS rate [95% CI],

NR [18, NE]

87 [80.0, 92]

85 [77.0, 90.2]

Overman et al, ASCO GI 2018

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ARE WE SURE?

Germano et al, Nature 2017

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Ref. Schedule n(MGM T-m)

RR (MGMT-m)

DCR (MGMT-m)

PFS mo (MGMT-m)

OS mo (MGMT-m) Amatu et al

Clin Cancer R. 2013

DTIC 250 mg/m2 per

day, d 1-4 q21d 68 (26) 3% (8%) 12% (44%) 1.7 (NR) /

Hochauser et al

Mol Can Ther 2013

TMZ 150 mg/m² per

day 7 d on/7 d off 372 (37) 3% (3%) 44% (44%) / /

Pietrantonio et al

Ann Oncol 2014 TMZ 150 mg/m2 per

day d 1-5, q28d 323 (32) 12% (12%) 31% (31%) 1.8 (1.8) 8.4 (8.4)

Target Oncol. 2016

TMZ 75 mg/m² per

day, d 1-21 q28d 214 (21) 24% (24%) 30% (30%) 2.2 (2.2) /

Amatu et al

Ann Oncol 2016

TMZ 200 mg/m²

days 1-5 q28 150 (29) 3.4% (3.4%) 48% (48) 2.6 (2.6) 6.2 (6.2)

Calegari et al

Br J Cancer 2017

TMZ 150-200 mg/m²

d 1-5, q28d 225 (41) 10% (10%) 32% (32%) 1.9 (1.9) 5.1 (5.1)

Morano et al

Ann Oncol 2018

TMZ 150 mg/m²per day, d 1-5

q28d+Irinotecan 100 mg/m² d1, 15 q 28d

25 (25) 24% (24%) 70% (70%) 4.4 (4.4) 13.8 (13.8)

MGMT in mCRC

MGMT

methylation

40 %

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Ref. Schedule n(MGM T-m)

RR (MGMT-m)

DCR (MGMT-m)

PFS mo (MGMT-m)

OS mo (MGMT-m) Amatu et al

Clin Cancer R. 2013

DTIC 250 mg/m2 per

day, d 1-4 q21d 68 (26) 3% (8%) 12% (44%) 1.7 (NR) /

Hochauser et al

Mol Can Ther 2013

TMZ 150 mg/m² per

day 7 d on/7 d off 372 (37) 3% (3%) 44% (44%) / /

Ann Oncol 2014 TMZ 150 mg/m2 per

day d 1-5, q28d 323 (32) 12% (12%) 31% (31%) 1.8 (1.8) 8.4 (8.4)

Target Oncol. 2016

TMZ 75 mg/m² per

day, d 1-21 q28d 214 (21) 24% (24%) 30% (30%) 2.2 (2.2) /

Amatu et al

Ann Oncol 2016

TMZ 200 mg/m²

days 1-5 q28 150 (29) 3.4% (3.4%) 48% (48) 2.6 (2.6) 6.2 (6.2)

Calegari et al

Br J Cancer 2017

TMZ 150-200 mg/m²

d 1-5, q28d 225 (41) 10% (10%) 32% (32%) 1.9 (1.9) 5.1 (5.1)

Morano et al

Ann Oncol 2018

TMZ 150 mg/m²per day, d 1-5

q28d+Irinotecan 100 mg/m² d1, 15 q 28d

25 (25) 24% (24%) 70% (70%) 4.4 (4.4) 13.8 (13.8)

MGMT in mCRC

MGMT

methylation

40 %

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THE TEMIRI STUDY

Morano et al. Ann Oncol 2018

m mOS 13.8 mos N/Events 25/15 mPFS 4.4 mos

N/Events 25/22

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Morano et al. Ann Oncol 2018

THE RELEVANCE OF A BIOMARKER

• ALL MGMT-positive IHC patients were non-responders

• MGMT-negative/low IHC tumors had a longer mPFS

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LOOKING FOR MORE

MULTIPLE MOLECULAR ALTERATIONS

GENE EXPRESSION ANALYSES SINGLE MOLECULAR

ALTERATIONS

multiple molecular alterations

pathways of genomic instability

CONSENSUS MOLECULAR

SUBTYPES

CIMP-H

HYPERMUTATED RAS BRAF

HER2 MSI

ALK/ROS1/NTRK/RET

TRASLATIONAL/CLINICAL PRACTICERESEARCH

MGMT

Courtesy of F. Morano

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RET: PROGNOSTIC IMPACT

Pietrantonio et al, Ann Oncol 2018