ESMO SUMMIT LATIN AMERICA 2019

Paulo M. Hoff, MD, PhD, FACP, FASCO

Current Standards of Care of Colorectal Cancer

CONFLICT OF INTEREST DISCLOSURE

Institutional clinical research:CNPq, FAPESP, Roche, Astra-Zeneca, Sanofi-Aventis, Novartis

Paid honoraria I do not receive any honoraria or personal payment from pharmaceutical industries

CRC incidence around the world

GLOBOCAN 2018

Colon cancer in brazil

Males Females

http://www.inca.gov.br/2018

5-Fluorouracil60 years and still going strong!

1920 - 1983

Metastastatic CRC treatment 1997

5 – Fluorouracil

Bolus

Mayo

Roswell-Park

AIO

Infusional

Lockich

LV5FU2

Maximal median survival around 11 months with any combination or sequence

Growing complexity of mCRCtreatment

5-FU Capecitabine

Irinotecan Oxaliplatin

Relationship between drug use and median survival

Grothey A. ASCO GI 2006. General Session.Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442.

Patients with 3 drugs (%)

0

Media

n OS

(mon

ths)

10 20 30 40 50 60 70 80

13141516171819202122

12

Maximal median survival around 23 months with any combination or sequence

Liver metastasis resection

Kopetz S et al. JCO 2009;27:3677-3683

Hanahan & Weinberg. Cell 2011.

Growing complexity of mCRCtreatment

5-FU Capecitabine

Irinotecan Oxaliplatin

Bevacizumab Aflibercept Ramucirumab Regorafenib

Targeting angiogenesis

EARLY EFFECTS CONTINUED EFFECTS

Normalisation of remaining tumour vasculature

1

2

Regression of existing tumourmicrovasculature

Inhibition of new tumour vasculature3

Anti-VEGF agents may act against tumours in several ways regression of existing microvasculature normalisation of mature vasculature inhibition of vasculature (re)growth

Anti-VEGF in CRC

Bevacizumab has been tested extensivelly in first line

Benefit is significant with 5-FU, Capecitabine or IFL

Modest benefit with FOLFIRI or FOLFOX

All anti-VEGF tend to have similar activity in second line

Aflibercept can be used for patients who progressed early to combinations

with bevacizumab

Modest gains as a rescue option

Only regorafenib has prooven activity as a single agent

Growing complexity of mCRCtreatment

5-FU Capecitabine

Irinotecan Oxaliplatin

Bevacizumab Aflibercept Ramucirumab Regorafenib

Cetuximab Panitumumab

Impact of RAS status

Adapted from Roberts Der. Oncogene 2007

B-RAF mutation:• CRC (10%)• Melanoma (70%)• Papillary thyroid cancer (50%)

K-RAS mutation:• CRC (30–50%)• Pancreatic cancer (90%)• Papillary thyroid cancer (60%)• NSCLC (30%)

EGFR mutation:• NSCLC (10%)• Glioblastoma (20%)

MAPK

MEK

B-Raf *

K-Ras *

TGF-α

Grb2

Sos

* Mutated in human cancersNSCLC = non-small cell lung cancerTGF = transforming growth factor

EGFR*

EGFR overexpression:• CRC (27–77%)• Pancreatic cancer (30–50%)• Lung cancer (40–80%)• NSCLC (14–91%)

J Clin Oncol 34, 2016 (suppl; abstr 3504)

36 vs 16.7 months!

Anti-EGFR mAb in CRC

Activity restricted by mutations in K-RAS, N-RAS and B-RAF

Less than 40% of patients are candidates

Poor results when used against right sided tumors

Activity as a single-agent, as well as in combination with

chemotherapy

Different agents seem to have similar activity in second and further

lines. Rechallenge?

Similar types of toxicity, with small differences in intensity

Journal of Clinical Oncology 37, no. 4_suppl (February 1 2019) 585-585

CRC overall survival

Evolution of CRC biology knowledge

19th century 1980s 2000

Histology

21st century

DNA arraysSNP analysisMultiplex PCR

Multi-gene predictorsSingle gene predictors

Molecular subtypes of CRC

Nat Med. 2015 Nov; 21(11): 1350–1356.

Molecular subtypes of CRC

Nat Med. 2015 Nov; 21(11): 1350–1356.

OS following recurrence

CMS1 vs. CMS2 HR=2.3 (1.4 – 3.8)P=0.001*CMS4 vs. CMS2 HR=1.5 (1.1 – 2.1)P=0.008*

Overall log-rank p=0.0004

*Adjusted for stage, MSI, BRAFmut, adjuvant CT

- MSI Immune- Canonical- Metabolic- Mesenchymal

Growing complexity of mCRCtreatment

5-FU Capecitabine

Irinotecan Oxaliplatin

Bevacizumab Aflibercept Ramucirumab Regorafenib

Cetuximab Panitumumab

Immunotherapy

Microsatellite instability in CRC• Phase II trial• 41 pts with metastatic carcinoma with or without MMR deficiency• Pembrolizumab 10mg/Kg q2w, max. 24 months

N Eng J Med 2015;372:2509-20

dMMR predicts response to PD1 blockade

Le DT et al. Science. 2017

MSI CRC + MSI Non CRC

Phase II12 different tumor typesMetastatic disease, progression after ≥ 1 line of therapyPembrolizumab 10mg/Kg IV q14d

Cohort A e C expansion

dMMR predicts response to PD1 blockade

Le DT et al. Science. 2017

ORR 53%Complete response 21%Partial response 32%

Disease control rate 77%Objective response 53%Stable disease 24%

Radiographic responses at 20 weeks

*No significant difference between CRC x non-CRC and Lynch x non-Lynch

dMMR predicts response to PD1 blockade

Le DT et al. Science. 2017

mPFS and mOS not reached after a median F/U of 12.5 months

Immune checkpoint inhibitors in dMMR CRC

CheckMate-142 trial - ESMO 2018

First line therapy – CheckMate 142

Metastatic / recurrent CRC MSI-H / dMMR N = 45 Median FU: 13.8 months

Nivo 3 q2w

Nivo 3 q2w + Ipi 1 q3w (4 doses and then Nivo 3 q2w)

Nivo 3 q2w + Ipi 1 q6w

Previously treated

1st Line

Immune checkpoint inhibitors in dMMR CRC

ESMO 2018

First line therapy – CheckMate 142

mPFS: NR12-mo PFS rate: 77%

mOS: NR12-mo OS rate: 83%

Nivo 3 (q2w) + Ipi1 (q6w)N = 45

ORR, n (%) 27 (60)Best overall response, n (%)

CRPRSD PD Not determined

3 (7)24 (53)11 (24)6 (13)1 (2)

Disease control rate n (%) 38 (84)

Growing complexity of mCRCtreatment

5-FU Capecitabine

Irinotecan Oxaliplatin

Bevacizumab Aflibercept Ramucirumab Regorafenib

Cetuximab Panitumumab

Immunotherapy

HER-2? B-RAF? Combinations?

The next big step

Different molecular CRC subtypes have been identified

Growing understanding of the molecular background of all subtypes

will lead to personalized treatment with greater efficacy and less

toxicity

Immunotherapy and MSI CRC is a great example of how the field will

advance in the future

Strategic decisions in CRC

In most countries, cost is a major issue in the decision of incorporating newer treatments

Tumor biology and behavior

Patient characteristics

and wishesTreatment

characteristics

Possible treatment proposal for mCRC 2019

Resectable mets Potentially resectable Agressive, unresectable Indolent, unresectable

FOLFOX (Peri or post-op)

FOLFOXIRI +/- Bev or FOLFOX or FOLFIRI +/-- Anti-EGFR: Left + RAS and

RAF WT- Anti-VEGF: Right or mutated

FOLFIRI or FOLFOX +/-- Anti-EGFR: Left + RAS and

RAF WT- Anti-VEGF

5-FU/LV orcapecitabine +/-Bevacizumab

• Several other options are reasonable• Second, third, and subsequent lines depend molecular subtyping and first line choice• Capecitabine can be used instead of infusional 5-FU in most regimens• Immunotherapy likely to be moved to first line soon for MSI patients

Metastatic CRCConclusions

Treatment for metastatic CRC has improved greatly over the last 2 decades

More patients are able to have surgery for mets

Personalized treatment to the patient and the tumor is likely to continue growing in importance and success

The cost of incorporating new diagnostic tests, as well as novel treatments is a major challenge for developing countries