Metastatic CRC: recent therapeutic developments

Dott. Carlo Garufi

Oncologia Medica AIstituto Regina Elena, Roma

• 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

Diferent Stage IV Disease in Different Patients

• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable

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

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

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

FOCUS TRIAL

Koopman M et al. Lancet vol 370:135-142, 2007

CAIRO TRIAL

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

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)

Kabbinavar F et al: JCO 23:3706-3712, 2005

Saltz L. et al: IFL NEJM 2004

Sobrero A et al: FOLFIRI Oncology 2009

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

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

EGF down-stream signaling

courtesy by Vincenzi B.

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

Campanella C et al. 2010

Campanella C et al. 2010

Tossicità cutanea ed Abs Anti-EGFR

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

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

Months

Pro

po

rtio

nA

live

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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

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

*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

Diferent Stage IV Disease in Different Patients

• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable

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

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

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.

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)

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*

* **

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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

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*KRAS wt, **ITTLLD=liver-limited disease

ERBITUX improves resections

60

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

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

Grazie per l’Attenzione