Terapia di I linea Il Carcinoma del Colon-Retto Metastatico 07 Aprile 2011 Il Carcinoma del Colon-Retto Metastatico TAVOLA ROTONDA Terapia di I linea Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott. Amedeo Pancotti Ospedale Mazzini – Teramo

2010 NCCN Guidelines: Advanced/mCRC Patient 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 → 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 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 1. NCCN. Clinical practice guidelines in oncology: colon cancer. 2011.

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.

FOLFIRI vs FOLFOX: no difference in first-line efficacy Arm A FOLFIRI  FOLFOX6 Arm B FOLFOX6  FOLFIRI FOLFIRI vs FOLFOX: no difference in first-line efficacy n 109 81 111 69 RR 56% 15% 54% 4% Median PFS (months) 8.5 4.2 8.0 2.5 Median PFS (months) 14.2 10.9 for sequence Median overall survival 21.5 20.6 (months) Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

Three Drugs combinations RR, 41% v 66%; P .0002 RR 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 a three-drug exposure in a sequential strategy Falcone A, et al. J Clin Oncol 2007; 25:1670-1676

Targeting VEGF(R) Recombinant humanized monoclonal IgG1 moAb Recognizes VEGF-A and blocks VEGF function

IRINOTECAN-based regimen and BEVACIZUMAB Hurwitz H, et al. N Engl J Med 2004;350:2335–42

BICC-C Trial, 1st line MCRC Irinotecan-based Chemotherapy + Beva First-line mCRC (n=430) FOLFIRI n=144 CapeIri n=145 mIFL n=141 First-line mCRC (n=115) FOLFIRI + Bevacizumab n=56 CapeIri + Bevacizumab mIFL + Bevacizumab n=59 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 Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

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

OXALIPLATIN-based regimen and BEVACIZUMAB N016966: Study Design Randomized 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.

XELOX is not inferior to FOLFOX-4 in First Line Colorectal Cancer PFS significantly increased with addition of bevacizumab to chemotherapy XELOX is not inferior to FOLFOX-4 in First Line Colorectal Cancer Saltz LB, et al. J Clin Oncol. 2008;26:2013-9

ARIES: Study Design FOLFOX + Bev (n = 739) First-line mCRC (N = 1550 enrolled) PFS OS FOLFIRI + Bev (n = 191) Community-based prospective observation cohort study 244 sites, 43 states in US 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. 23

Targeting EGFR Expression of EGF Receptors Ligands Bind EGF Receptor Dimerization TGF-  EGF Extracellular Binding Domain Transmembrane Lipophilic Segment Intracellular Protein Tyrosine Kinase Domain Activation of Signal Transduction Antibody Binds Receptor Internalized chimeric human/murine immunoglobulin G1 (IgG1) MAB targeting the EGFR

CRYSTAL trial: Study design 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 EGFR-expressing metastatic CRC R FOLFIRI irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Stratification factors: Regions ECOG PS Populations Randomized patients n=1217 Safety population n=1202 ITT population: n=1198 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 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, % 59.3‡ 36.2 43.2 40.2 *P = .017; †P = .75; ‡P = .0025 1. Van Cutsem E, et al. ASCO 2008. Abstract 2.

Kaplan–Meier Estimates of PFS and OS in the Wild-Type–KRAS Population mPFS 9.9 vs 8.7 mOS 24.9 vs 21.0 Van Cutsem E, et al. N Engl J Med 2009; 360:1408-17

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 Inhibits Ligand Binding to EGFR and Dimerization 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

PRIME Study: KRAS Status in Response to Panitumumab Randomized, global, open-label, phase III trial Stratified by ECOG PS (0-1 vs 2) and geographic region (Western Europe, Canada, and Australia vs all other locations) Panitumumab 6.0 mg/kg q2w + FOLFOX4 q2w (n = 593) Patients with previously untreated mCRC (N = 1183) FOLFOX4 q2w (n = 590) Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.

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-VEGF Rallenta la crescita tumorale Aumenta la PFS Profilo di tossicità ± favorevole Possibilità di utilizzo fino a progressione Possibilità di mantenimento Non attivo in monoCT No 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-EGFR Attivo anche come agente singolo Aumenta il tasso di risposta Efficace in tutte le linee di trattamento Biomarcatore 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 Braun MS, et al. J Clin Oncol. 2009;27:5519-5528. Patients with previously untreated CRC (N = 2135) Molecular substudy (n = 1188)* Fluorouracil + Irinotecan (n = 175) Fluorouracil + Oxaliplatin (n = 172) Irinotecan (n = 184) (n = 95) (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.

FOCUS: Polymorphisms Potentially Predictive of Toxicity and/or Efficacy Marker/Function Variant At Risk GT Drug Effected Hypothesized Impact Activity Toxicity Other ABCB1/cellular efflux 3435 C to T TT Irinotecan ↓ ↑ ↓ clearance DPYD/detoxification IVS14 + 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 ↓ detoxification MLH1/DNA repair -93 G to A Fluorouracil Irinotecan Oxaliplatin MTHFR/folate pool, modifies FU response 667 C to T -- TYMS/target for FU metabolite 1494: 6 bp insertion +/+ ↓ expression ER: VNTR 28 bp 2R/2R UGT1A1/detoxification VNTR: 6 or 7 TA repeats (*28) 7/7 XRCC1/DNA repair 23,885 G to A Irinotecan Oxaliplatin Braun MS, et al. J Clin Oncol. 2009;27:5519-5528.

Toward Personalized Therapy of CRC: Who Will Benefit From Targeted Therapy? EGFR antibodies KRAS mutational status BRAF mutational status VEGF antibody efficacy Combining EGFR and VEGF antibodies

KRAS and BRAF Mutational Status and EGFR Inhibitors Subgroup PR, % P Value Mutant KRAS (n = 34) 6 .011 Wild-type KRAS (n = 79) 28 .029 Mutant BRAF (n = 11) Wild-type BRAF (n = 68) 32 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. 42

KRAS and BRAF Mutational Status and EGFR Inhibitors (Cont’d) 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 Di Nicolantonio F, et al. J Clin Oncol, 2008;26:5705-5712. 43

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

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

CALGB/SWOG 80405 Study Design Open-Label Phase III Study Bevacizumab followed by FOLFOX or FOLFIRI q2w Register Patient Send tumor tissue block to SWOG PCO Randomize patients with Wild-type KRAS tumor Untreated advanced or mCRC (N = 1500) Screen for eligibility Cetuximab followed by FOLFOX or FOLFIRI q2w One cycle = 8 wks ClinicalTrials.gov. NCT00265850.

PACCE Trial: Chemotherapy + Bevacizumab ± Panitumumab Oxaliplatin-CT + Bevacizumab (n = 410) Patients with metastatic colorectal cancer and ECOG ≤ 1 (N = 1053) Oxaliplatin-CT + Bevacizumab + Panitumumab (n = 413) Irinotecan-CT + Bevacizumab (n = 115) Irinotecan-CT + Bevacizumab + Panitumumab (n = 115) Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

PACCE: PFS and OS for Ox-CT and Iri-CT 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) 10.1 11.7 1.19 (0.79-1.79) 20.7 20.5 1.42 (0.77-2.62) 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 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

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

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 “A NEW ERA: INDIVIDUALIZED THERAPY” Obiettivi terapeutici Continuum of care Terapia di conversione Polimorfismi genetici Nuovi fattori predittivi e prognostici Gene expression profile “A NEW ERA: INDIVIDUALIZED THERAPY”