Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde...

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Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde Incorporalos? Prof. Dr. Paulo M. Hoff Instituto do Câncer do Estado de São Paulo - ICESP Faculdade de Medicina Universidade de São Paulo (USP)

Transcript of Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde...

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Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde

Incorporalos?

Prof. Dr. Paulo M. Hoff Instituto do Câncer do Estado de São

Paulo - ICESP Faculdade de Medicina

Universidade de São Paulo (USP)

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Conflicts of interest

•  Scientific consultant:

–  Roche, Astra-Zeneca

•  Research support:

–  Roche, Astra-Zeneca, Novartis, Sanofi-

Aventis, Pfizer, CNPq

•  All honoraria received by me from

pharmaceutical companies is donated to

filantropic institutions

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Treatment options for advanced colorectal cancer in 2012

•  Six different classes/ 13 drugs available: –  Fluoropyrimidines •  5-FU, FUDR, Capecitabine, UFT, S-1

–  Platins •  Oxaliplatin

–  Topoisomerase I inhibitors •  Irinotecan

–  Direct TS inhibitors •  Raltitrexed

–  Anti-VEGF •  Bevacizumab, regorafenib, aflibercept

–  Anti-EGFR •  Cetuximab, Panitumumab

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Disponibilidade de todos os agentes citotóxicos relacionados com a sobrevida

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

Pacientes com 3 drogas (%)

0

SG M

ed

iana

(m

ese

s)

10 20 30 40 50 60 70 80

13 14 15

16

17 18 19

20 21 22

12

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New concepts in CRC

•  Maintenance therapy vs treatment breaks

•  Sequential therapy

•  Molecular targeted treatments

•  Individualization of therapy

•  Neo-adjuvant therapy

•  Conversion therapy

•  “Continuum of care” – Strategic planning

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Molecular events and cancer

Signal Transduction

Autocrine growth factor secretion

Matrix metalloproteinase secretion

Changes in oncogenes and tumor suppressor genes

Angiogenesis

Deregulation of growth factors and receptors

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VEGF Pathway as a Target

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Impact of Bevacizumab

•  Increased PFS with all tested regimens

•  Increased RR and OS with fluoropirimidines

alone and with irinotecan based regimens

•  Did not increase RR nor OS with oxaliplatin

based regimens in first line (only second)

•  May be benefitial even after first PD

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BEV + standard first-line CT (either oxaliplatin or

irinotecan-based) (n=820)

Randomise 1:1

Standard second-line CT (oxaliplatin or irinotecan-based)

until PD

BEV (2.5 mg/kg/wk) + standard second-line CT

(oxaliplatin or irinotecan-based) until PD

PD

ML18147 study design (phase III)

CT switch: Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

Study conducted in 220 centres in Europe and Saudi Arabia

Primary endpoint •  Overall survival (OS) from randomisation

Secondary endpoints included

•  Progression-free survival (PFS) •  Best overall response rate •  Safety

Stratification factors •  First-line CT (oxaliplatin-based, irinotecan-based) •  First-line PFS (≤9 months, >9 months) •  Time from last BEV dose (≤42 days, >42 days) •  ECOG PS at baseline (0/1, 2)

Arnold ASCO 2012

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PFS: ITT population P

FS e

stim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42

No. at risk CT 410 119 20 6 4 0 0 0 BEV + CT 409 189 45 12 5 2 2 0

CT (n=410) BEV + CT (n=409)

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test)

aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

Arnold ASCO 2012

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OS: ITT population O

S e

stim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48

No. at risk CT 410 293 162 51 24 7 3 2 0 BEV + CT 409 328 188 64 29 13 4 1 0

CT (n=410) BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test)

aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

Arnold ASCO 2012

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Aflibercept

  Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹

  Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)²

  High affinity – binds VEGF-A and PlGF more tightly than native receptors

1.  Holash J et al. Proc Natl Acad Sci USA. 2002;99:11393-11398.

2.  Tew WP et al. Clin Cancer Res. 2010;16:358-366.

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VELOUR Study Design

Primary endpoint: overall survival Sample size: HR=0.8, 90% power, 2-sided type I error 0.05 Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of 0.0466 (α spending function)

Metastatic Colorectal Cancer

R A N D O M I Z E

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks

Placebo IV, day 1 + FOLFIRI q2 weeks

1:1 Disease Progression Death

600

600 Stratification factors: •  ECOG PS (0 vs 1 vs 2) •  Prior bevacizumab (Y/N)

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

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VELOUR Study

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

OS PFS

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Overall Survival: Stratified by Prior Bevacizumab –

ITT Population

Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

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Safety: Adverse Events

Prior Bevacizumab No Prior Bevacizumab

Safety Population, % of Patients

Placebo/ FOLFIRI (n=172)

Aflibercept/ FOLFIRI (n=171)

Placebo/ FOLFIRI (n=433)

Aflibercept/ FOLFIRI (n=440)

Serious AEs 32 52 33 47

Any AE leading to death 6 6 4 6

Grade 3/4 AEs in >10% of patients in any treatment group

Neutropenia 13 20 25 27

Diarrhea 9 19 7 20

Asthenic conditions 9 16 11 17

Infections and infestations 8 14 7 12

Stomatitis 4 11 5 14

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CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after

failure of standard therapy

•  Multicenter, randomized, double-blind, placebo-controlled, phase III –  Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region

•  Global trial: 16 countries, 114 centers •  Recruitment: May 2010 to March 2011

2:1

Evaluation with CT scan of abdomen and chest every 8 weeks

Van Cutsem ASCO 2012

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Regorafenib significantly improves PFS compared to placebo

Progression-free survival (secondary endpoint)

Van Cutsem ASCO 2012

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Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis

(1-sided p<0.009279 at approximately 74% of events required for final analysis)

Van Cutsem ASCO 2012

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Overall response and disease control rates (secondary endpoints)

Best response, % Regorafenib N=505

Placebo N=255

Complete response 0 0

PR 1.0 0.4

SD 42.8 14.5

Progressive disease 49.5 80.0

DCR* 41.0 14.9

*DCR = PR + SD (≥6 weeks after randomization); p<0.000001

Regorafenib significantly improves DCR compared to placebo

Van Cutsem ASCO 2012

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Drug-related treatment-emergent adverse events occurring in ≥10% of patients

Adverse event, %

Regorafenib N=500

Placebo N=253

All grades

Grade 3 Grade 4 Grade 5* All grades

Grade 3 Grade 4 Grade 5*

Hand-foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0

Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0

Hypertension 27.8 7.2 0 0 5.9 0.8 0 0

Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0

Rash / desquamation 26.0 5.8 0 0 4.0 0 0 0

Anorexia 30.4 3.2 0 0 15.4 2.8 0 0

Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0

Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0

Fever 10.4 0.8 0 0 2.8 0 0 0

Nausea 14.4 0.4 0 0 11.1 0 0 0

Bleeding 11.4 0.4 0 0.4 2.8 0 0 0

Voice changes 29.4 0.2 0 0 5.5 0 0 0

Weight loss 13.8 0 0 0 2.4 0 0 0 * Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm

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EGFR Pathway as a Target

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Targeting the EGFR pathway: K-Ras mutations

Adapted from Roberts Der. Oncogene 2007

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

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

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

MAPK

MEK

B-Raf*

K-Ras*

TGF-α

Grb2

Sos

*Mutated in human cancers NSCLC = non-small cell lung cancer TGF = transforming growth factor

EGFR*

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Cetuximab and Panitumumab

•  Similar activity but different epitopes in EGFR

•  Only active against wild-type K-Ras, with

question remaining in G13D mutation

•  Increase RR with almost all regimens tested

•  Questions remaining regarding OS, particularly

when combined with oxaliplatin

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R

CAIRO 2: Chemotherapy + Bevacizumab and Cetuximab

Capecitabina (2 g/m2, D1-14) Oxaliplatina (130 mg/m2, D1)

Bevacizumabe (7,5 mg/kg, D1)

Capecitabina, Oxaliplatina Bevacizumabe e Cetuximabe (400 mg/m2 na semana 1 e

250 mg/m2 semanal)

Punt, et al. N Engl J Med. 2009 Feb 5;360(6):563-72

Previously Untreated CRC Pts

N=736

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CAIRO2: PFS

Punt, et al. N Engl J Med. 2009 Feb 5;360(6):563-72

Bevacizumab + XELOX: 10.7 months (9.7-12.5) Bevacizumab + XELOX + cetuximab: 9.6 months (8.5-10.7)

Hazard ratio for progression: 1.21 p value 0.018

0 6 12 18 24 30 Months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n f

ree

surv

ival

pro

bab

ilit

y

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How to choose the First-Line?

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" Cure

" Extend Survival

" Extend Progression Free Survival

" Relieve symptoms

" Improve quality-of-life

Treatment Goals:

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" Extent and Number of Metastatic Sites

" Resectability

" Symptomatic?

" Treatening Vital Organs?

" Need for a Quick Response

" Histology

Tumor Characteristics:

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" Performance Status

–  Baseline

–  Tumor related

" Chronological and Physiological Age

" Comorbidities

" Patient wishes!

Patient Characteristics:

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$

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Treatment Options for mCRC Resectable  Disease   Poten/aly  Resectable   “Agressive”  

Unresectable  Disease  “Indolent”  Unresectable  Disease  

mFOLFOX  (Peri  or  post  surgery)    

FOLFOXIRI  or  FOLFOX/FOLFIRI  +/-­‐  cetuximab*  or  panitumumab*    

FOLFIRI/FOLFOX  +/-­‐  Bevacizumab    

5-­‐FU/LV  or  capecitabine  +/-­‐  Bevacizumab  

Depend  on  first-­‐line   FOLFOX  +/-­‐  Bevacizumab  or  FOLFIRI  +/-­‐  aflibercept  

mFOLFOX  ou  XELOX  +/-­‐  Bevacizumab  

Irinotecan  +  cetuximab*  or  panitumumab*  

Irinotecan  or  FOLFIRI  +/-­‐  aflibercept  

Regorafenib   Irinotecan  +  cetuximab*  or  panitumumab*  

Regorafenib  

* Wild-Type K-Ras

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Seculo XIX 1980s 2000

Histology Single gene predictors Multi-gene predictors (?)

Seculo XXI

DNA arrays SNP analysis Multiplex PCR

Proteomics

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What Did We Learn?

•  Plan for a sequence of regimens

•  Continuing antiangiogenics likely a good thing

•  Not all patients nor colorectal cancers are equal.

–  Not from the start and they may change as they are treated.

Plan accordingly

•  Biomarker studies are an essential component in large

randomized trials