Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott....

Dott.ssa Alessandra SantomaggioDott.ssa Alessandra Santomaggio

U.O.C. Oncologia MedicaU.O.C. Oncologia Medica

Dipartimento di OncologiaDipartimento di Oncologia

Direttore: Dott. Amedeo PancottiDirettore: Dott. Amedeo Pancotti

Ospedale Mazzini – TeramoOspedale Mazzini – Teramo

07 APRILE 2011

IL CARCINOMA DEL COLON-RETTO METASTATICO

TAVOLA ROTONDA

TERAPIA DI I LINEA

2010 NCCN Guidelines: Advanced/mCRCPatient Can Tolerate Intensive Therapy

First Line Second Line Third Line

FOLFOX ± bevacizumab

FOLFOX ± cetuximab* CapeOx ±

bevacizumab CapeOx ± cetuximab*

FOLFIRI + bevacizumab

FOLFIRI ± cetuximab* 5-FU/leucovorin +

bevacizumab Panitumumab

FOLFOXIRI (2B)

FOLFIRI Irinotecan FOLFIRI +

cetuximab* (2B)Irinotecan + cetuximab*†

FOLFOX CapeOx

Irinotecan + cetuximab*†

FOLFOX CapeOx

Irinotecan → Irinotecan + cetuximab*†

Clinical trial BSC

*Patients with wild-type KRAS only. †In patients who cannot tolerate combination, consider either single-agent cetuximab (wild-type KRAS only) or single-agent panitumumab (wild-type KRAS only); cetuximab and panitumumab should not be used in combination.

NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V2.2010.

Obiettivi della prima linea

• Risposta obiettiva immediata (malattia curabile, potenzialmente resecabile)

• Migliore risposta obiettiva (malattia incurabile aggressiva ->paziente sintomatico)

• Trattamento a lungo termine (malattia incurabile indolente -> paziente asintomatico)

Le caratteristiche del paziente guidano “il processo decisionale”

• Performance status

• Età

• Comorbidità

• Estensione della malattia

• Obiettivi del trattamento: palliative vs potentially curative

• Precedente trattamento adiuvante entro 1 anno

• Funzionalità d’organo: epatica e renale

• Ipertensione non controllata

• Rischio di sanguinamento

• KRAS status

Goals of Treatment: Paziente sintomatico vs asintomatico

CHOICE OF FIRST-LINE MCRC THERAPY BASED ON TREATMENT GOALS FOR THE PATIENT[1]

– Paziente asintomatico, malattia indolente– Considerare età del paziente, comorbidità,

qualità di vita, preferenza del paziente, costi del trattamento

– Paziente sintomatico, malattia aggressiva– Chemioterapia (doppiette o triplette) con

agenti biologici quando possibile per ottenere un rapido “tumor shrinkage” e remissione dei sintomi

1. Adam R, et al. Ann Oncol. 2010;21:1579-1584.

Goals of Treatment: trattamento curativo vs

palliativo• Intento curativo nei pazienti con malattia

metastatica limitata al fegato o al polmone, potenzialmente suscettibili di chirurgia curativa, quindi candidati ad una terapia “neoadiuvante” aggressiva

• Intento palliativo nei pazienti con coinvolgimeto di più organi o di sedi non trattabili chirurgicamente (peritoneo, linfonodi) con l’obiettivo di migliorare la qualità di vita

Ruolo della terapia adiuvante

• Progressione entro 12 mesi dalla terapia adiuvante suggerisce una resistenza del tumore alla terapia

1. NCCN. Clinical practice guidelines in oncology: colon cancer. 2011.

Recommended[1] First-line Treatment Choices for Patients Progressing

< 12 mos after adjuvant FOLFOX > 12 mos after adjuvant FOLFOX, adjuvant 5-FU/LV, or adjuvant capecitabine

FOLFIRI ± bevacizumab FOLFIRI ± cetuximab or panitumumab

(KRAS wild type only)

All active chemotherapy regimens

KRAS Gene Status

• ~ 40% dei tumori del colon-retto presentano mutazione del gene KRAS[1]

– Mutazioni nei codoni 12 e 13 dell’esone 12[2]

– Mutazioni del codone 61 determinano una proteina KRAS costituzionalmente attiva

• Scarsa risposta agli agenti diretti verso EGFR[2]

– L’inibizione EGFR potrebbe essere evitata da attivazione costitutiva KRAS a valle[1]

1. Lièvre A, et al. Oncogene. 2010;29:3033-3043.2. Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49.

Comorbidità: Ipertensione

• Bevacizumab- Associato con una maggiore incidenza (10% to 15%) di ipertensione di grado 3/4- Non dovrebbe essere utilizzato in pazienti con mCRC con ipertensione severa o non controllato dalla terapia- Associato con un maggior rischio di stroke e/o eventi tromboembolici

–Soprattutto in pazienti ≥ 65 anni

Rischio di sanguinamento• Bevacizumab è associato al rischio di

– Sanguinamenti e complicanze

– Ritardata guarigione delle ferite

– Perforazione GI

• Raccomandazioni[1]

– intervallo di almeno 4-6 settimane dall’ultimo trattamento con bevacizumab e la chirurgia

– Intervallo di almeno 6-8 settimane post-intervento prima di somministrare bevacizumab

– Non dovrebbe essere somministrato a pazienti con storia di recentiemorragie o emottisi

1. NCCN. Clinical practice guidelines in oncology: colon cancer. 2011.

Comorbidità• Le comorbidità possono avere un impatto significativo

sulla scelta del trattamento di I linea• Esempi

– L’utilizzo di oxaliplatino potrebbe essere limitato in pazienti con neuropatia diabetica o insufficienza renale in anamnesi

– L’utilizzo di irinotecano potrebbe essere limitato in pazienti con storia di malattie intestinali, che hanno ricevuto precedentemente radioterapia sulla pelvi, con storia di malattie epatiche (epatite virale o cirrosi) con ridotta funzionalità epatica

– Pazienti con malattie cardivascolari potrebbero presentare una cardiotossicità correlata all’utilizzo di fluoropirimidine

Come trattare I pazienti con le seguenti opzioni terapeutiche?

Chemioterapia• FOLFOX• FLOX• FOLFIRI• 5-FU/LV or capecitabine• FOLFOXIRI• CapeOX (XELOX)• CapeIRI (XELIRI)• IROX• Irinotecan

Targeted Therapy• Bevacizumab• Cetuximab• Panitumumab

NCCN. Clinical practice guidelines in oncology: colon cancer. 2011.

n 109 81 111 69

RR 56% 15% 54% 4%

Median PFS (months) 8.5 4.2 8.02.5

Median PFS (months) 14.2 10.9for sequence

Median overall survival 21.5 20.6(months)

Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

Arm AFOLFIRI FOLFOX6

Arm BFOLFOX6 FOLFIRI

FOLFIRI vs FOLFOX: no difference in

first-line efficacy

Falcone A, et al. J Clin Oncol 2007; 25:1670-1676

RR, 41% v 66%; P .0002RR confirmed by an external panel was 34% versus 60% (P .0001).

median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P .0006;

median OS, 16.7 v 22.6 months; HR, 0.70; P .032).

Conclusions of Author:in patients with few chances to achieve athree-drug exposure in a sequential strategy

Three Drugs combinations

Targeting VEGF(R)

• Recombinant humanized monoclonal IgG1 moAb

• Recognizes VEGF-A and blocks VEGF function

• Recombinant humanized monoclonal IgG1 moAb

• Recognizes VEGF-A and blocks VEGF function

IRINOTECAN-based regimenand BEVACIZUMAB

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

BICC-C Trial, 1st line MCRCIrinotecan-based Chemotherapy +

Beva

First-line mCRC (n=115)

FOLFIRI + Bevacizumabn=56

CapeIri + Bevacizumab

mIFL + Bevacizumabn=59

First-line mCRC (n=430)

FOLFIRI

n=144

CapeIri

n=145

mIFL

n=141

Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

BICC-C Study

What is the best 5FU and

Irinotecan-based regimen with Bevacizumab?

FOLFIRI

AVIRI trial

Sobrero, et al. Oncology 2009;77:113-119

• N016966: Study DesignRandomized phase III trial

XELOX + Placebo(n = 350)

Unresectable mCRC with no previous systemic therapy for mCRC and

no previous oxaliplatin or bevacizumab

(N = 1401)

XELOX + Bevacizumab(n = 350)

FOLFOX4 + Placebo(n = 351)

FOLFOX4 + Bevacizumab(n = 350)

1. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.

OXALIPLATIN-based regimenand BEVACIZUMAB

Saltz LB, et al. J Clin Oncol. 2008;26:2013-9

PFS significantly increased with addition of bevacizumab to chemotherapy

XELOX is not inferior to FOLFOX-4 in First Line Colorectal Cancer

ARIES: Study Design

• Community-based prospective observation cohort study• 244 sites, 43 states in US

FOLFIRI + Bev(n = 191)

First-line mCRC(N = 1550 enrolled)

PFSOS

Bendell JC, et al. GI ASCO 2011. Abstract 480.

ARIES Study: Clinical Efficacy

Endpoint, Mos FOLFOX + Bev(n = 72)

FOLFIRI + Bev(n = 73)

PFS 9.9 9.5

OS 24.3 26.3

Bendell JC, et al. GI ASCO 2011. Abstract 480.

Targeting EGFR

Expression ofEGF Receptors

Ligands BindEGF ReceptorDimerization

TGF-

EGF

Extracellular Binding Domain

TransmembraneLipophilic Segment

Intracellular ProteinTyrosine Kinase Domain

Activation of Signal Transduction

• chimeric human/murine immunoglobulin G1 (IgG1) MAB targeting the EGFR

• chimeric human/murine immunoglobulin G1 (IgG1) MAB targeting the EGFR

Antibody Binds

Receptor Internalized

CRYSTAL trial: Study design

Stratification factors: – Regions– ECOG PS

Populations– Randomized patients n=1217– Safety population n=1202– ITT population: n=1198

FOLFIRI

irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly+ irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion)+ FA every 2 weeks

REGFR-expressing metastatic CRC

Van Cutsem E, et al. N Engl J Med 2009; 360:1408-17

KRAS Status in Response to Cetuximab

• CRYSTAL: randomized, multicenter phase III trial[1]

– Significant improvement in PFS with addition of cetuximab to FOLFIRI vs FOLFIRI alone for first-line mCRC treatment

• Retrospective analysis of CRYSTAL[2]

– Included only subset of KRAS-evaluable patients (N = 540)

1. Van Cutsem E, et al. N Engl J Med. 2009;360:1408-1417.2. Van Cutsem E, et al. ASCO 2008. Abstract 2.


• Retrospective analysis of CRYSTAL[1]

– PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS

1. Van Cutsem E, et al. ASCO 2008. Abstract 2.

Outcome Wild-Type KRAS(n = 348)

Mutated KRAS(n = 192)

Median PFS, mos FOLFIRI + cetuximab 9.9 7.6 FOLFIRI 8.7 8.1 HR 0.68* 1.07†

ORR, % FOLFIRI + cetuximab 59.3‡ 36.2 FOLFIRI 43.2 40.2*P = .017; †P = .75; ‡P = .0025

Kaplan–Meier Estimates of PFS and OS in the Wild-Type–KRAS Population

mPFS 9.9 vs 8.7

Van Cutsem E, et al. N Engl J Med 2009; 360:1408-17

mOS 24.9 vs 21.0

Bokemeyer C, et al. J Clin Oncol 2009; 27:663-71


• CRYSTAL and OPUS meta-analysis[1]

– Pooled efficacy analysis of two randomized phase III trials

– CRYSTAL: FOLFIRI + cetuximab vs FOLFIRI alone[2]

– OPUS: FOLFOX + cetuximab vs FOLFOX alone[3]

– After 90% of samples were subjected to KRAS genotype testing, HRs for benefit of addition of cetuximab shown to be highly statistically significant in patients with wild-type KRAS

– PFS—HR: 0.66 (P < .0001)– OS—HR: 0.81 (P = .0062)

1. Bokemeyer C, et al. ASCO 2010. Abstract 3506. 2. Van Cutsem E, et al. N Engl J Med. 2009;360:1408-1417. 3. Bokemeyer C, et al. J Clin Oncol. 2009;27:663-671.

Panitumumab

Inhibition of EGF binding to EGFR

This may lead to: Cell proliferation Cell survival Angiogenesis Metastatic spread

EGF, TGFα or other ligands binding to

EGFR

•A fully human* lgG2 monoclonal antibody to EGFR

•High affinity, KD = 5 x 10-11 M

•Inhibits ligand-induced EGFR tyrosine phosphorylation

Panitumumab Inhibits Ligand Binding Panitumumab Inhibits Ligand Binding to EGFR and Dimerizationto EGFR and Dimerization

PRIME Study: KRAS Status in Response to Panitumumab

• Randomized, global, open-label, phase III trial

Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.

Panitumumab 6.0 mg/kg q2w +FOLFOX4 q2w

(n = 593)

FOLFOX4 q2w(n = 590)

Stratified by ECOG PS (0-1 vs 2) and geographic region (Western Europe, Canada, and Australia vs

all other locations)

Patients with previously untreated

mCRC

(N = 1183)

PRIME Study: Efficacy Results

• PFS significantly improved with FOLFOX4 + panitumumab only in wild-type KRAS patients

• Worse PFS outcome with panitumumab addition in mutated KRAS patients

Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.

PRO E CONTRO DEI FARMACI BIOLOGICI

Anti-VEGFRallenta la crescita tumoraleAumenta la PFSProfilo di tossicità ± favorevolePossibilità di utilizzo fino a

progressionePossibilità di mantenimento

Non attivo in monoCTNo biomarcatori predittivi (VEGF

epithelial and stromal expression; Microvascular density; VEGF and VEGFR SNPs; VEGF plasma levels)

Perde efficacia nelle successive linee di trattamento

Scarso effetto su tasso di risposta

Anti-EGFRAttivo anche come agente

singoloAumenta il tasso di rispostaEfficace in tutte le linee di

trattamentoBiomarcatore predittivo

convalidato

Modesto incremento di PFS e OS

Tossicità cutanea (Interruzione del trattamento, riduzione di dose, compromissione dell’efficacia del trattamento)

Can Genetic Polymorphisms Guide Chemotherapy for Metastatic CRC ?

• FOLFOX– ABCG2 34 G>A: rare transporter gene

• FOLFIRI– UGT1A1 7/7 genotype regimen specific?

• Capecitabine– Differential metabolism not understood

Predicting Oxaliplatin Efficacy

• Genomic DNA from 180/238 patients on C80203 (FOLFOX vs FOLFIRI ± cetuximab)

• Genotype transporter genes involved in irinotecan and oxaliplatin clearance– ABCC2, ABCC4, ABCG2, SLCO1B1, SLC22A1,

SLC22A2• Association of genotype with response and toxicity• Result

– ABCG2 34 G>A associated with response to FOLFOX, resistance to FOLFIRI but not to toxicity

McLeod HL, et al. ASCO 2008. Abstract 3513.

Patients With Reduced UGT1A1 Activity

• Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of irinotecan treatment

• A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele

• Heterozygous patients (carriers of one variant allele and 1 wild-type allele, which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses

Irinotecan [prescribing information].

FOCUS Trial

Patients with

previously untreated

CRC(N = 2135)

Molecular substudy

(n = 1188)*

Fluorouracil + Irinotecan(n = 175)

Fluorouracil + Oxaliplatin(n = 172)

Irinotecan(n = 184)

Fluorouracil + Irinotecan(n = 95)

Fluorouracil + Oxaliplatin(n = 108)

First-line therapy Second-line therapy

*152 patients missing data for primary endpoint.

Fluorouracil(n = 688)

C

B

A

Braun MS, et al. J Clin Oncol. 2009;27:5519-5528.

Marker/Function Variant At Risk GT Drug EffectedHypothesized Impact

Activity Toxicity Other

ABCB1/cellular efflux 3435 C to T TT Irinotecan ↓ ↑ ↓ clearance

DPYD/detoxificationIVS14 + 1G to A

(*2A)Variants Fluorouracil ↓ ↑ ↑ active metabolite

ERCC2/DNA repair 35,931 A to C CC Oxaliplatin ↓ ↑ ↓ DNA repair

GSTP1/detoxification 313 A to G AA Oxaliplatin ↓ ↑ ↓ detoxification

MLH1/DNA repair -93 G to A AAFluorouracilIrinotecan Oxaliplatin

↓ ↑ ↓ DNA repair

MTHFR/folate pool, modifies FU response

667 C to T TT Fluorouracil ↓ ↑ --

TYMS/target for FU metabolite

1494: 6 bp insertion +/+ Fluorouracil -- ↑ ↓ expression

ER: VNTR 28 bp 2R/2R Fluorouracil -- ↑ ↓ expression

UGT1A1/detoxificationVNTR: 6 or 7 TA

repeats (*28)7/7 Irinotecan ↓ ↑ ↓ detoxification

XRCC1/DNA repair 23,885 G to A AAIrinotecan Oxaliplatin

↓ ↑ ↓ DNA repair

FOCUS: Polymorphisms Potentially Predictive of Toxicity and/or

Efficacy

Braun MS, et al. J Clin Oncol. 2009;27:5519-5528.

• EGFR antibodies– KRAS mutational status– BRAF mutational status

• VEGF antibody efficacy

• Combining EGFR and VEGF antibodies

Toward Personalized Therapy of CRC: Who Will Benefit From

Targeted Therapy?

Subgroup PR, % P Value

Mutant KRAS (n = 34) 6 .011

Wild-type KRAS (n = 79) 28 .029

Mutant BRAF (n = 11) 0 .011

Wild-type BRAF (n = 68)

32 .029

KRAS and BRAF Mutational Status and EGFR Inhibitors

• KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGFR

Di Nicolantonio F, et al. J Clin Oncol, 2008;26:5705-5712.

• KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGFR

• Small subset of patients – N = 113 – 22 of 68 patients (32%) with WT KRAS

and WT BRAF responded to treatment with EGFR inhibitor

KRAS and BRAF Mutational Status and EGFR Inhibitors (Cont’d)

Di Nicolantonio F, et al. J Clin Oncol, 2008;26:5705-5712.

Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC): Results of the translational study on

the PETACC 3-EORTC 40993-SAKK 60-00 trial

Roth A, Oral Abstrct Session 2010 ASCO Annual Meeting

Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on

the PETACC 3-EORTC 40993-SAKK 60-00 trial

Sabine Tejpar, Oral Abstract Session 2010 ASCO Annual Meeting

Sabine Tejpar, Oral Abstract Session 2010 ASCO Annual Meeting

Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on the PETACC 3-

EORTC 40993-SAKK 60-00 trial

Untreatedadvancedor mCRC

(N = 1500)

Bevacizumabfollowed by

FOLFOX or FOLFIRIq2w

Cetuximabfollowed by

FOLFOX or FOLFIRIq2w

One cycle = 8 wks

Open-Label Phase III Study

Screenfor

eligibility

Sendtumortissue

block toSWOG

PCO

RegisterPatient

CALGB/SWOG 80405 Study Design

ClinicalTrials.gov. NCT00265850.

Randomizepatients

withWild-type

KRAStumor

Patients with metastatic colorectal

cancer and ECOG ≤ 1

(N = 1053)

Oxaliplatin-CT + Bevacizumab + Panitumumab

(n = 413)

Oxaliplatin-CT + Bevacizumab(n = 410)

Irinotecan-CT + Bevacizumab + Panitumumab

(n = 115)

Irinotecan-CT + Bevacizumab(n = 115)

PACCE Trial: Chemotherapy + Bevacizumab ± Panitumumab

Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

Outcome, mos CT + Bevacizumab

+ Panitumumab

CT + Bevacizumab

HR (95% CI)

Oxaliplatin cohort

(n = 413) (n = 410)

Median PFS 10.0 11.4 1.27 (1.06-1.52)

Median OS 19.4 24.5 1.43 (1.11-1.83)

Irinotecan cohort

(n = 115) (n = 115)

Median PFS 10.1 11.7 1.19 (0.79-1.79)

Median OS 20.7 20.5 1.42 (0.77-2.62)

PACCE: PFS and OS for Ox-CT and Iri-CT

Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

I Proposta: pazienti con buon PS e KRAS mut

In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens

– FOLFOX

– XELOX

– FOLFIRI

– XELIRI

In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens

– FOLFIRI

– XELIRI

Bevacizumab is the biologic agent of choice

IIa Proposta: pazienti con buon PS e KRAS wild-type

• In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens– FOLFOX– XELOX– FOLFIRI– XELIRI

• In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens– FOLFIRI– XELIRI

• Bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab are reasonable biological agents to consider as part of the treatment regimen

• In patients who are potentially surgically resectable, cetuximab may be the optimal biological agent as it yields increased response rates when combined with cytotoxic chemotherapy

IIb Proposta: pazienti con buon PS e KRAS wild-type

III Proposta: pazienti con scarso PS e KRAS mut

• In previously untreated patients, fluoropyrimidine monotherapy is appropriate– 5-FU/LV– Capecitabine

• Bevacizumab is the biologic agent of choice in the absence of contraindications

IV Proposta: pazienti con scarso PS e KRAS wilde type• In previously untreated patients,

fluoropyrimidine monotherapy is appropriate– 5-FU/LV– Capecitabine

• Consider using bevacizumab or the anti-EGFR antibodies cetuximab or panitumumab

CONCLUSIONI• Obiettivi terapeutici• Continuum of care• Terapia di conversione• Polimorfismi genetici• Nuovi fattori predittivi e

prognostici• Gene expression profile

“A NEW ERA: INDIVIDUALIZED THERAPY”

Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott....

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