Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde Incorporalos?

Transcription

1 Nuevos Agentes en el Manejo de Cáncer Colorectal: Dónde Incorporalos? Prof. Dr. Paulo M. Hoff Instituto do Câncer do Estado de São Paulo - ICESP Faculdade de Medicina Universidade de São Paulo (USP)

2 Conflicts of interest Scientific consultant: Roche, Astra-Zeneca Research support: Roche, Astra-Zeneca, Novartis, Sanofi- Aventis, Pfizer, CNPq All honoraria received by me from pharmaceutical companies is donated to filantropic institutions

3 Treatment options for advanced colorectal cancer in 2012 Six different classes/ 13 drugs available: Fluoropyrimidines 5-FU, FUDR, Capecitabine, UFT, S-1 Platins Oxaliplatin Topoisomerase I inhibitors Irinotecan Direct TS inhibitors Raltitrexed Anti-VEGF Bevacizumab, regorafenib, aflibercept Anti-EGFR Cetuximab, Panitumumab

4 Disponibilidade de todos os agentes citotóxicos relacionados com a sobrevida SG Mediana (meses) Pacientes com 3 drogas (%) Grothey A. ASCO GI General Session. Grothey A and Sargent D. J Clin Oncol. 2005;23:

5 New concepts in CRC Maintenance therapy vs treatment breaks Sequential therapy Molecular targeted treatments Individualization of therapy Neo-adjuvant therapy Conversion therapy Continuum of care Strategic planning

6 Molecular events and cancer Signal Transduction Deregulation of growth factors and receptors Autocrine growth factor secretion Angiogenesis Matrix metalloproteinase secretion Changes in oncogenes and tumor suppressor genes

7 VEGF Pathway as a Target

8 Impact of Bevacizumab Increased PFS with all tested regimens Increased RR and OS with fluoropirimidines alone and with irinotecan based regimens Did not increase RR nor OS with oxaliplatin based regimens in first line (only second) May be benefitial even after first PD

9 ML18147 study design (phase III) BEV + standard firstline CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomise 1:1 CT switch: Oxaliplatin Irinotecan Irinotecan Oxaliplatin Standard second-line CT (oxaliplatin or irinotecan-based) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD Primary endpoint Secondary endpoints included Stratification factors Overall survival (OS) from randomisation Progression-free survival (PFS) Best overall response rate Safety First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS ( 9 months, >9 months) Time from last BEV dose ( 42 days, >42 days) ECOG PS at baseline (0/1, 2) Study conducted in 220 centres in Europe and Saudi Arabia Arnold ASCO 2012

10 PFS: ITT population 1.0 CT (n=410) BEV + CT (n=409) 0.8 PFS estimate Unstratifieda HR: 0.68 (95% CI: ( ) p< (log-rank test) Stratifiedb HR: 0.67 (95% CI: ) p< (log-rank test) mo 5.7 mo Time (months) No. at risk CT BEV + CT aprimary analysis method; bstratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS ( 9 months, >9 months), time from last dose of BEV ( 42 days, >42 days), ECOG performance status at baseline (0, 1) Arnold ASCO 2012

11 1.0 OS: ITT population CT (n=410) BEV + CT (n=409) OS estimate Unstratifieda HR: 0.81 (95% CI: ) p= (log-rank test) Stratifiedb HR: 0.83 (95% CI: ) p= (log-rank test) mo 11.2 mo No. at risk Time (months) CT BEV + CT Median follow-up: CT, 9.6 months (range ); BEV + CT, 11.1 months (range ) aprimary analysis method; bstratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS ( 9 months, >9 months), time from last dose of BEV ( 42 days, >42 days), ECOG performance status at baseline (0, 1) Arnold ASCO 2012

12 Aflibercept Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹ Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)² High affinity binds VEGF-A and PlGF more tightly than native receptors 1. Holash J et al. Proc Natl Acad Sci USA. 2002;99: Tew WP et al. Clin Cancer Res. 2010;16:

13 VELOUR Study Design Metastatic Colorectal Cancer R A N D O M IZ 600 1:1 Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks Disease Progression Death Stratification factors: ECOG PS (0 vs 1 vs 2) Prior bevacizumab (Y/N) E 600 Placebo IV, day 1 + FOLFIRI q2 weeks Primary endpoint: overall survival Sample size: HR=0.8, 90% power, 2-sided type I error 0.05 Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of (α spending function) Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

14 VELOUR Study OS PFS Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

15 Overall Survival: Stratified by Prior Bevacizumab ITT Population Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.

16 Safety: Adverse Events Prior Bevacizumab No Prior Bevacizumab Safety Population, % of Patients Placebo/ FOLFIRI (n=172) Aflibercept/ FOLFIRI (n=171) Placebo/ FOLFIRI (n=433) Aflibercept/ FOLFIRI (n=440) Serious AEs Any AE leading to death Grade 3/4 AEs in >10% of patients in any treatment group Neutropenia Diarrhea Asthenic conditions Infections and infestations Stomatitis

17 CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy 2:1 Evaluation with CT scan of abdomen and chest every 8 weeks Multicenter, randomized, double-blind, placebo-controlled, phase III Stratification: prior anti-vegf therapy, time from diagnosis of metastatic disease, geographical region Global trial: 16 countries, 114 centers Recruitment: May 2010 to March 2011 Van Cutsem ASCO 2012

18 Progression-free survival (secondary endpoint) Regorafenib significantly improves PFS compared to placebo Van Cutsem ASCO 2012

19 Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis) Van Cutsem ASCO 2012

20 Overall response and disease control rates (secondary endpoints) Regorafenib significantly improves DCR compared to placebo Best response, % Regorafenib N=505 Placebo N=255 Complete response 0 0 PR SD Progressive disease DCR* *DCR = PR + SD ( 6 weeks after randomization); p< Van Cutsem ASCO 2012

21 Drug-related treatment-emergent adverse events occurring in 10% of patients Adverse event, % All grades Regorafenib N=500 Grade 3 Grade 4 Grade 5* All grades Placebo N=253 Grade 3 Grade 4 Grade 5* Hand-foot skin reaction Fatigue Hypertension Diarrhea Rash / desquamation Anorexia Mucositis, oral Thrombocytopenia Fever Nausea Bleeding Voice changes Weight loss * Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm

22 EGFR Pathway as a Target

23 Targeting the EGFR pathway: K-Ras mutations TGF-α EGFR overexpression: CRC (27 77%) Pancreatic cancer (30 50%) Lung cancer (40 80%) NSCLC (14 91%) EGFR* Grb2 Sos K-Ras* B-Raf* K-Ras mutation: CRC (30 50%) Pancreatic cancer (90%) Papillary thyroid cancer (60%) NSCLC (30%) EGFR mutation: NSCLC (10%) Glioblastoma (20%) MEK MAPK *Mutated in human cancers NSCLC = non-small cell lung cancer TGF = transforming growth factor Adapted from Roberts Der. Oncogene 2007

24 Cetuximab and Panitumumab Similar activity but different epitopes in EGFR Only active against wild-type K-Ras, with question remaining in G13D mutation Increase RR with almost all regimens tested Questions remaining regarding OS, particularly when combined with oxaliplatin

25 CAIRO 2: Chemotherapy + Bevacizumab and Cetuximab Previously Untreated CRC Pts R N=736 Capecitabina (2 g/m2, D1-14) Oxaliplatina (130 mg/m2, D1) Bevacizumabe (7,5 mg/kg, D1) Capecitabina, Oxaliplatina Bevacizumabe e Cetuximabe (400 mg/m2 na semana 1 e 250 mg/m2 semanal) Punt, et al. N Engl J Med Feb 5;360(6):563-72

26 CAIRO2: PFS Progression free survival probability Bevacizumab + XELOX: 10.7 months ( ) Bevacizumab + XELOX + cetuximab: 9.6 months (8.5 Hazard ratio for progression: 1.21 p value Months from randomization Punt, et al. N Engl J Med Feb 5;360(6):563-72

27 How to choose the First-Line?

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29 Treatment Goals: " Cure " Extend Survival " Extend Progression Free Survival " Relieve symptoms " Improve quality-of-life

30 Tumor Characteristics: " Extent and Number of Metastatic Sites " Resectability " Symptomatic? " Treatening Vital Organs? " Need for a Quick Response " Histology

31 Patient Characteristics: " Performance Status Baseline Tumor related " Chronological and Physiological Age " Comorbidities " Patient wishes!

32 $

33 Treatment Options for mcrc Resectable Disease Poten/aly Resectable Agressive Unresectable Disease Indolent Unresectable Disease mfolfox (Peri or post surgery) * Wild-Type K-Ras FOLFOXIRI or FOLFOX/ FOLFIRI +/- cetuximab* or panitumumab* Depend on first- line FOLFIRI/FOLFOX +/- Bevacizumab FOLFOX +/- Bevacizumab or FOLFIRI +/- aflibercept Irinotecan + cetuximab* or panitumumab* 5- FU/LV or capecitabine +/- Bevacizumab mfolfox ou XELOX +/- Bevacizumab Irinotecan or FOLFIRI +/- aflibercept Regorafenib Irinotecan + cetuximab* or panitumumab* Regorafenib

34 Seculo XXI Seculo XIX 1980s 2000 DNA arrays SNP analysis Multiplex PCR Proteomics Histology Single gene predictors Multi-gene predictors (?)

35 What Did We Learn? Plan for a sequence of regimens Continuing antiangiogenics likely a good thing Not all patients nor colorectal cancers are equal. Not from the start and they may change as they are treated. Plan accordingly Biomarker studies are an essential component in large randomized trials