Post on 15-Dec-2018
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)
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
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
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
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
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
VEGF Pathway as a Target
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
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
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
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
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.
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.
VELOUR Study
Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.
OS PFS
Overall Survival: Stratified by Prior Bevacizumab –
ITT Population
Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.
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
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
Regorafenib significantly improves PFS compared to placebo
Progression-free survival (secondary endpoint)
Van Cutsem ASCO 2012
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
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
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
EGFR Pathway as a Target
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*
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
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
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
How to choose the First-Line?
" Cure
" Extend Survival
" Extend Progression Free Survival
" Relieve symptoms
" Improve quality-of-life
Treatment Goals:
" Extent and Number of Metastatic Sites
" Resectability
" Symptomatic?
" Treatening Vital Organs?
" Need for a Quick Response
" Histology
Tumor Characteristics:
" Performance Status
– Baseline
– Tumor related
" Chronological and Physiological Age
" Comorbidities
" Patient wishes!
Patient Characteristics:
$
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
Seculo XIX 1980s 2000
Histology Single gene predictors Multi-gene predictors (?)
Seculo XXI
DNA arrays SNP analysis Multiplex PCR
Proteomics
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