aiom post-asco 2018media.aiom.it/userfiles/files/doc/aiom-servizi/slide/...colorectal cancer:...

Colorectal Cancer: Critical review

AIOM POST-ASCO 2018

Updates and Review from Chicago

Milano, June 15-16, 2018

Alfredo Falcone, MD Department of Oncology and Translational Medicine

University of Pisa and Azienda Ospedaliero Universitaria Pisana

PISA- ITALY

OUTLINE

MALATTIA LOCALIZZATA

Colon

Retto

MALATTIA METASTATICA

Mantenimento dopo I linea anti-EGFR

Rechallange anti-EGFR e biopsia liquida

HIPEC

FOLFOXIRI+anti-EGFR

Sequenza Regorafenib/anti-EGFR

Immunoterapia nei MSS

As an Oncologist: What am I going to do?

Presented By Weijing Sun at 2018 ASCO Annual Meeting

Colon adiuvante: 3 vs 6 mesi

Educational Session

Jeanne Tie et al. abst. #3516 (poster discussion)

Circulating tumor DNA as a prognostic marker

in stage III colon cancer: DFS

4-10 wks after surgery After adjuvant CT

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



Historic Oxaliplatin-based XRT studies

Presented By Cathy Eng at 2018 ASCO Annual Meeting

Oxaliplatin-based RT in Rectal Cancer

Presented By Hans-Joachim Schmoll at 2018 ASCO Annual Meeting

PETACC-6

Overall survival (ITT)

Presented By Hans-Joachim Schmoll at 2018 ASCO Annual Meeting

PETACC-6

Disease Free Survival

Presented By Yanhong Deng at 2018 ASCO Annual Meeting

FOWARC

Overall survival

Presented By Yanhong Deng at 2018 ASCO Annual Meeting

FOWARC

Study design and Rationale

Presented By Yong Sang Hong at 2018 ASCO Annual Meeting

ADORE

Disease-free survival, ITT population


ADORE


ADORE

TAKE HOME MESSAGES: MALATTIA LOCALIZZATA

Nel colon III stadio 3 mesi di CAPOX adiuvante “si può fare” se basso rischio, ma più strategico definire più accuratamente il rischio!

Nel retto II-III stadio l’aggiunta dell’oxali alla RT + fluoropirimidina neoadiuvante non migliora DFS e OS

Nel retto II-III stadio patologico dopo CT+RT considerare FOLFOX adiuvante x 8 cicli (o XELOX)

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



Presented By Filippo Pietrantonio at 2018 ASCO Annual Meeting

600

RAS and BRAF

wt

mCRC pts

R 1:1

FOLFIRI +

cetuximab

x 8 cycles

FOLFIRI +

cetuximab until

PD

cetuximab until

PD

FOLFIRI +

cetuximab

x 8 cycles

Anti-EGFR maintenance – trials ongoing

ERMES

Phase III trial

Primary endpoint:

• PFS for non-inferiority

280 pts

SD or better

after 3 mos of

FOLFOX +

panitumumab in

RAS wt mCRC

R 1:1

FUFA +

panitumumab

FUFA

FOLFOX +

panitumuma

b until PD or

unacceptabl

e toxicity

PD

PANAMA

Phase II trial

Primary endpoint:

• PFS

Anti-EGFR maintenance – trials ongoing

USC trial

Phase III trial

Primary endpoint:

• PFS

450

RAS wt

mCRC pts

R 1:1

FUFA +

panitumumab

Capecitabine

FOLFOX +

panitumumab x 6

cycles

FOLFOX +

panitumumab x 6

cycles

Sponsor: AIO Cooperative Group

Sponsor: Amgen

PD

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



mCRC pts

RAS and BRAF wt

FOLFIRI/

FOLFOXIRI

+ Cetuximab

FOLFOX/XELOX

/

FOLFOXIRI

+ Bevacizumab

Irinotecan

+ Cetuximab

Target accrual: 27 pts

Study Design

PD PD

Phase II, non comparative, study

• At least a RECIST 1.1 partial response

• 1st-line PFS ≥6 months • PD to 1st-line cetuximab

within 4 weeks after the last cetuximab administration

• Time between the end of 1st-line therapy and the start of 3rd-line ≥4 months

Study treatment: Irinotecan 180 mg/sqm iv Cetuximab 500 mg/sqm iv

Patients RAS status on

ctDNA

Objective

Response

#1 Wild-type Confirmed PR

#2 KRAS G12D PD


#4 Wild-type PD

#5 Wild-type SD

#6 KRAS G12D PD

#7 Wild-type SD


#10 Wild-type Unconfirmed

PR

#11 Wild-type PD

#12 KRAS G12D PD

#13 KRAS G12V PD

#15 NRAS Q61L SD

Patients RAS status

on ctDNA

Objective

Response

#16 Wild-type SD

#17 KRAS G12V/

Q61H

PD

#18 KRAS G12V PD

#19 Wild-type Confirmed

PR

#21 KRAS G12D SD

#22 KRAS G12V SD

#23 KRAS G12V PD

#24 KRAS G12D Unconfirme

d PR

#25 KRAS G12D SD

#26 Wild-type SD

#27 Wild-type PD

#28 Wild-type SD

Predictive Role of ctDNA

No RAS mutations were detected in samples from patients who achieved a confirmed PR

• RAS mutations were found in liquid biopsies collected at the rechallenge baseline in 12 (48%) out of 25 evaluable patients

• No BRAF or PI3KCA mutations were found

How do RAS and EGFR mut alleles decay?

Parseghian et al, ASCO Ann Meeting 2018; abst #3511

Discovery Set

N=135 pts

RAS/BRAF/EGFRwt

treated with anti-EGFRs

Validation Set

N=267 pts

RAS/BRAF/EGFRwt

treated with anti-EGFRs

Exponential decay:

median estimated

t/2: 4-5 months

RAS and EGFR mutations testing on ctDNA [Guardant360®]

Liquid biopsy: potential applications

Use of liquid biopsy for treatment strategy in various stages of cancer

REFRACTORY DISEASE

Monitoring response and

tracking resistance;

Identification of mechanisms

of acquired resistance.

METASTATIC DISEASE

Molecular profiling and

replacement of tumor

tissue analyses;

Prognostication.

LOCALIZED DISEASE

Prognostication;

Detection of residual disease

and treatment

personalization in

macroscopically resected

patients.

EARLY DETECTION

Diagnosis of cancer

or pre-cancer earlier

through screening.

adapted from Wan et al, Nature Rev 2017;

adapted from Heitzer et al, Precision Oncology 2017

Presented By Giulia Siravegna at 2018 ASCO Annual Meeting

Plasma HER-2 copy number to predict response in HERACLES

ctDNA NGS assay GUARDANT360

Presented By Katherine Clifton at 2018 ASCO Annual Meeting

Detection of gene fusions in plasma

ctDNA NGS assay GUARDANT360

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



Unicancer Prodige 7 trial design

Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting

265 pts with isolated perioteneal mets and Peritoneal Cancer Index (PCI) < 25

Overall survival (ITT)


Primary Enpoint: OS

Overall survival and PCI


Overall Survival in PCI 11-15 subgroup

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



mFOLFOXIRI+pan N=63

FOLFOXIRI N=33

OR p

Response Rate 87.3% 60.6% 4.47 0.004

Left-sided tumors N=53 N=25

4.52 0.02 90.6% 68.0%

Right-sided tumors N=10 N=8

3.89 0.34 70.0% 37.5%

RAS/BRAF wt N=43 N=17

3.36 0.08 86.0% 64.7%

BRAF mut N=7 N=9

21.0 0.04 85.7% 22.2%

mFOLFOXIRI+Pani in VOLFI trial: RECIST RR

Geissler et al, ASCO Ann Meeting 2018; abstr #3508

To improve tumor shrinkage: TRIPLETE study by G.O.N.O.

R

RAS and BRAF wt

mCRC pts

1st line

unresectable

mFOLFOX6+pani (up to max 12 cycles)

mFOLFOXIRI+pani (up to max 12 cycles)

5-FU/LV +Pani

5-FU/LV +Pani

PD

INDUCTION MAINTENANCE

Phase III random

Stratification factors: • PS 0-1 vs 2; • primary tumor location (right vs left or rectum); • previous adjuvant chemotherapy; • liver-only metastases.

Primary endpoint: Response Rate

Target accrual: 432 pts

OUTLINE


Colon

Retto




HIPEC

FOLFOXIRI+anti-EGFR



TAKE HOME MESSAGES: MALATTIA METASTATICA

Considerare dopo induzione con comboCT+anti-EGFR mantenimento con anti-EGFR+5FU/LV (in attesa di nuovi dati)

Rechallange con anti-EGFR da considerare nella pratica clinica in alcuni casi, ma previa rivalutazione di RAS

La biopsia liquida sarà uno strumento importante nel management dal carcinoma del colon-retto

Chirugia su mets peritoneali SI, ma HIPEC?

FOLFOXIRI+anti-EGFR, sequenza Rego/anti-EGFR ed immunotx nei MSS: aspettiamo i risultati di nuovi studi

[email protected]

Grazie per l’attenzione!

aiom post-asco 2018media.aiom.it/userfiles/files/doc/aiom-servizi/slide/...colorectal cancer:...

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