metastatic crc: recent therapeutic developments dott. carlo garufi oncologia medica a istituto...
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Metastatic CRC: recent therapeutic developments
Dott. Carlo Garufi
Oncologia Medica AIstituto Regina Elena, Roma
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• Colorectal cancer is the fourth most common cancer in men and
the third most common in women worldwide
• About 50% of patients will eventually die of their disease
• At diagnosis:
– the stage of the disease is the most important prognostic
factor: five year survival for stage I: > 85%, stage IV: only 5-
30%
– approximately 25% of patients will present with metastatic
disease
• Around 50% of patients treated with current first-line
chemotherapy regimens will develop progressive disease within
7 - 9 months
CRC Background
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Diferent Stage IV Disease in Different Patients
• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable
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Strategia di Trattamentonelle Neoplasie del Colon-Retto
• Malattia Curabile- Massimo effetto
antitumorale- Tossicità maggiore- Possibilità di
resezione radicale
• Malattia Incurabile- Trattamento a lungo
termine- Tossicità accettabile- Più linee di Terapia
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Malattia IncurabileC’è un chiaro vantaggio in sopravvivenza nell’uso della chemioterapia di combinazione rispetto
• alla monochemioterapia? (± irinotecan; ± oxaliplatino)
• all’uso sequenziale dei farmaci? (FOCUS 2007, CAIRO 2007)
Saltz L, et al: NEJM 343: 905-14,2000, Douillard JY et al: Lancet 355: 1041-47, 2000, Giacchetti S et al: JCO 18:136-47, 2000, De Gramont A et al: JCO 18:2938-47, 2000Seymour MT Lancet 370: 143-52, 2007; Koopman M et al. Lancet 370:135-42, 2007
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Saltz L. et al NEJM, 2000
De Gramont A. et al JCO 2000
Giacchetti S. et al, JCO 2000
Douillard JY. et al The Lancet 2000
Trials di polichemioterapia vs monochemioterapia: Sopravvivenza
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FOCUS TRIAL
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Koopman M et al. Lancet vol 370:135-142, 2007
CAIRO TRIAL
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Monochemioterapia o Terapia di combinazione?
• I risultati degli studi FOCUS e CAIRO possono giustificare l’uso iniziale di una monochemioterapia con Fluoropirimidine nei pazienti nei quali non vi sia indicazione ad un atteggiamento aggressivo
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Cosa Aggiunge Bevacizumab?
• In pazienti “unfit” Beva +5-FU/LV aumenta significativamente RR e PFS ed aumenta la OS da 12.9 a 16.6 mesi (Kabbinavar JCO 23:3697, 2005)
• In pazienti “fit” Beva +5-FU/LV è equivalente ad un regime come IFL in termini di RR, PFS ed OS (Hurwitz JCO 23:3502, 2005)
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Kabbinavar F et al: JCO 23:3706-3712, 2005
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Saltz L. et al: IFL NEJM 2004
Sobrero A et al: FOLFIRI Oncology 2009
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Bevacizumab
• Regimi tipo FOLFIRI + BEVA o 5-FU/FA + BEVA aumentano il PFS e la OS in prima linea
• Efficacia indipendente da biomarkers
• Profilo di sicurezza ben definito
• Migliore utilizzo clinico quando usato fino a progressione
• BEVA può essere usato con sicurezza nei pazienti candidati a resezione di metastasi epatiche
• BEVA non ha attività come agente singolo
• Regimi tipo FOLFOX/XELOX + BEVA aumentano il PFS ma non OS in I linea (aumentano PFS e OS in II linea)
• I dati sull’uso della terapia di mantenimento con BEVA e dopo progressione devono essere confermati
PRO
CONTRO
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Clinical Anti-EGF Receptor Therapies
Inibitori di Tirosin Kinasi“Piccole Molecole”
(Imatinib, Sutinib, Sorafenib, Erlotinib)
Anticorpi Monoclonali(Trastuzumab, Cetuximab,
Panitumumab)
Signal Transduction
R R
Ligand
K K
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EGF down-stream signaling
courtesy by Vincenzi B.
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EGFR GENE COPY NUMBER, FISH/CISH: MAIN STUDIES
Author Method N pts Correl. with Cet Outcome % ICN Notes
Shia et al. CISH 147 NA 11.5% NDR
Sauer et al. FISH 48 NA (15%) Not stated how many ICN
Moroni et al. FISH 30 Positive NA Enrichment strategy
Lievre et al. CISH 30 Positive 10% Amplification for 6 or > signals/nucleusin >50% of cells
Garufi et al. FISH 101 Positive 83% Only 4% amplified; Correlation with RR - PFS
Romagnani et al. FISH 27 Positive??? 89% Not clear definition of ICN
Personeni et al. FISH 70 Negative 92% Multiple centile cut-offs
Sartore-Bianchi A. et al FISH 58 Positive
Increased EGFR copy number associated with disease control
and better PFS
Finocchiaro et al. FISH 85 Positive 48% Multiple criteria Only Moroni’s valid
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Campanella C et al. 2010
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Campanella C et al. 2010
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Tossicità cutanea ed Abs Anti-EGFR
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Phase III CRYSTAL study: Design
Stratification factors: • Region• ECOG performance status
Populations:• Randomized patients (n=1217)• Safety population (n=1202)• ITT population (n=1198)
FOLFIRI
Irinotecan 180 mg/m2 + 5-FU/LV every 2 weeks
ERBITUX + FOLFIRI
ERBITUX IV 400 mg/m2 on day 1,then 250 mg/m2 weekly
+ irinotecan 180 mg/m2 + 5-FU/LV every 2 weeks
REGFR-expressing
mCRC
Van Cutsem E, et al. New Engl J Med 2009;360:1408–1417
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Overall survival in KRAS wt patients
Van Cutsem E, et al. ECCO/ESMO Congress 2009; Abstract No: 6077
Van Cutsem E, et al. ECCO/ESMO Congress 2009; Abstract No: 6077
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Months
Pro
po
rtio
nA
live
0
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
321 321 315 313 310 297 288 278 266 248 226 203 187 165 141 119 102 88 65 47 29 14 9 4 1 1 0331 325 320 311 301 289 281 272 265 243 219 193 177 152 125 110 87 70 52 37 24 15 9 5 2 0 0
Patients at risk:Panitumumab Plus FOLFOXFOLFOX alone
WT KRAS: Overall Survival (Interim Analysis)Eventsn (%)
Median (95% CI) months
Panitumumab + FOLFOX 106 (33) NE (20.3, NE)
FOLFOX 124 (37) 18.8 (17.2, NE)
HR = 0.83 (95% CI: 0.64–1.08) P-value = 0.16
Douillard - PRIME
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COIN: Study design
Arm A: Continuous CT (control)
Continued until progression, cumulative toxicity, or patient choice
2445 randomized
Second-line chemotherapy: After completion of trial therapy, patients will be eligible for treatment with irinotecan or entry into
another clinical trial
Arm B: Continuous CT + ERBITUX
(ERBITUX 400 mg/m2 day 1, then 250 mg/m2 weekly)
Continued until progression, cumulative toxicity, or patient choice
Arm C: Intermittent CT
Treat for 12 weeks then stop CT and monitor. Restart same
CT on progression for a further
12 weeks
Patients with mCRC;no prior CT for advanced disease; fit for combination CT; no prior testing for EGFR status
Maughan T. J Clin Oncol 2007;25(Suppl. 18):Abstract No. 4070
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*Abs. 7LBA
% Erbitux + XELOX/OxMdG
KRAS wt
XELOX/OxMdG
KRAS wt
p
OS months 17 17,9 NS
PFS months 8.6 8.6 NS
ORR 59% 50% 0.015
COIN: first efficacy analysis
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Diferent Stage IV Disease in Different Patients
• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable
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POCHER STUDY
Adjuvant therapy for
4-6 courses (same schedule as pre-
operatively)
Patients with unresectable
liver metastases +/- extrahepatic disease
ERBITUX +
CPT-FFL ~ (n=43)
for 4-6 courses
8 cycles (~4 months)
Technically resectable
Primary endpoint: Response rate
4 further treatment
cycles
RESECTION
Technically unresectable
Garufi C et al ECCO-ESMO, Berlin 2009
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POCHER STUDY
• PreOperative
• Chemotherapy
• Hepatic
• Resection
CPT-11: 130 mg/m2day 1 peak 13:00
Chronomodulated delivery scheme(5d on/16d off or 4d on/10d off)
Time (clock hour)10:00 16:00 22:00 04:00 10:00
Fl o
w r
ate
(a
r b.
Un
its)
5-FU(600-1100 mg/m²/d)
LV(300 mg/m²/d)
L-OHP(25 mg/m²/d)
Cetuximab 400-250 mg/m2 day1
Istituto Regina Elena Roma
Ospedale S Maria degli Angeli Pordenone
Garufi C. et al ECCO/ESMO 2009
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A B C
D E F
Pre-treatment (Fig. A-B-C) and after 6 courses (Fig. D-E-F) spiral TC-scan of SP patient. She was submitted to a two-step hepatectomy and she is free of disease after 36 months of follow-up.
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Figure 3. Kaplan-Meier curves of progression-free survival (PFS) and overall survival. (A) overall survival in the entire population (n = 43);B)PFS in the entire population (n = 43); (C)
PFS in patients with resected liver metastases (n = 26)
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ERBITUX and Liver Metastases
Selected population (liver metastases)
CTCT + ERBITUX Unselected population
Res
pons
e (%
)
POCHER CRYSTAL
39.7
57.3
P<0.0001
OPUS
p=0.0027
57.3
34
CELIM
79*
* **
0
10
20
30
40
50
60
70
80
79
Doublets Triplet
LLD
*
77
Van Cutsem E, et al. ECCOESMO 2009 Abs 6077Van Cutsem E, et al. N Engl J Med 2009;360:1408–1417
Van Cutsem E, et al. Ann Oncol 2008;19(Suppl.8):viii4 [Update to 710]Bokemeyer C, et al. J Clin Oncol 2009;27:663–671
Bechstein WO, et al. J Clin Oncol 2009;27(Suppl. 15): Abstract No. 4091Garufi C, et alECCO/ESMO, Berlin, 2009
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
*KRAS wt, **ITTLLD=liver-limited disease
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ERBITUX improves resections
60
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Chemioterapia + Abs Anti-EGFR
Abs (Cetuximab e Panitumumab) possono essere usati solo nei pazienti k-ras wild-type
B-RAF, P-TEN, PI3-PK sono target in corso di valutazione Abs hanno attività come agenti singoli nei pazienti pretrattati
indipendentemente dalla linea di trattamento Regimi tipo FOLFIRI+ Cetuximab aumentano il PFS e la OS in
prima linea (CRYSTAL) Regimi tipo FOLFOX + Panitumumab aumentano il PFS in prima
linea ma non OS (PRIME) I pazienti con metastasi epatiche sembrano essere quelli che
traggono il maggior beneficio dagli ABs
Regimi con Tripletta (5-FU/FA/CPT-11/OXA) + Cetuximab sembrano essere particolarmente promettenti come regime neoadiuvante nei pazienti candidati a resezione di metastasi epatiche
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Pazienti con cancro del colon-retto avanzato
I linea
MetastasiEpatiche
Malattia Disseminata
K-ras wild type
Tripletta o Doppietta + Cetuximab
K-ras mutatoMalattia Indolente o Malattia Aggressiva?
Tripletta o Doppietta +Bevacizumab
Algoritmo Ideale di Trattamento CRC Avanzato nel 2009
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Grazie per l’Attenzione