dott.ssa alessandra santomaggio u.o.c. oncologia medica dipartimento di oncologia direttore: dott....
TRANSCRIPT
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.
KRAS Status in Response to Cetuximab
• 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
Bokemeyer C, et al. J Clin Oncol 2009; 27:663-71
KRAS Status in Response to Cetuximab
• 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
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”