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Monoclonales En 2ª Línea Tras Progresión a Folfox Ras

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Monoclonales En 2ª Línea Tras Progresión a Folfox Ras ESMO Guidelines 2014/2015 Annals of Oncology 25 (Supplement 3): iii1–iii9, 2014 doi:10.1093/annonc/mdu260 Published online 4 September 2014 Angiogenesis Tumoral Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111. Angiogénesis Anti-angiogenics Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials VEGF is an early and persistent promoter of tumour angiogenesis1–4 VEGF VEGF VEGF VEGF VEGF bFGF bFGF bFGF bFGF TGFβ-1 TGFβ-1 TGFβ-1 TGFβ-1 PLGF PLGF PLGF PD-ECGF PD-ECGF Pleiotrophin Continued VEGF expression3 • Tumours continually require VEGF to recruit new vasculature5 • VEGF continues to be expressed throughout tumour progression, even as secondary pathways emerge2,3,6,7 1. Bergers, Benjamin. Nat Rev Cancer 2003; 2. Kim, et al. Nature 1993; 3. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2005; 4. Ferrara, et al. Nat Med 2003; 5. Inoue, et al. Cancer Cell 2002; 6. Mesiano, et al. Am J Pathol 1998; 8 7. Melnyk, et al. J Urol 1999 Prolonged angiogenesis inhibition with bevacizumab maintains tumour control over time • First-line and continued VEGF inhibition are essential strategies in the treatment of patients with metastatic disease1–6 First-line use of bevacizumab: Continued use of bevacizumab: attaining tumour control maintaining tumour control 1. Mabuchi, et al. Clin Cancer Res 2008; 2. Bagri, et al. Clin Cancer Res 2010; 3. Grothey, et al. JCO 2008; 4. Galizia, et al. Clin Cancer Res 2004; 9 5. Mancuso, et al. J Clin Invest 2006; 6. Vosseler, et al. Cancer Res 2005 Preclinical evidence: prolonged angiogenesis inhibition with bevacizumab maintains tumour control over time1 • Human colorectal cancer (SW620) xenografts were implanted into mice1 • Anti-VEGF antibodies were given twice weekly for 3 weeks, or until the end of the study – anti-VEGF antibodies B20-4.1 and B20- 4.1.1. were used as murine surrogates of bevacizumab Data shown until <50% of mice remain on study. • Anti-VEGF treatment reduced tumour growth relative to control – tumour inhibition was more effective when treatment was continued for a longer period of time EOS=end of study. * Continued for 3 weeks. † Continued until the end of the study. Figure reprinted with permission from Bagri A, et al. Clin Cancer Res 2010;16:3887-900, Figures 2A and B 10 1. Bagri, et al. Clin Cancer Res 2010 Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials Early discontinuation of bevacizumab may compromise clinical effectiveness1,2 • In Study NO16966, a significant increase in median PFS was observed predominantly in the subset of patients who continued to receive bevacizumab until disease progression1,2 12 1. Saltz, et al. ASCO GI 2007 (Abstract); 2. Saltz, et al. JCO 2008 Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials MANTENIMIENTO • Bevacizumab – MACRO, SAKK, AIO • Bevacizumab + FP – CAIRO, AIO • Bevacizumab + Erlotinib* – DREAM – Nordic-ACT *Erlotinib no está aprobado en cáncer colorrectal14 MACRO: XELOX + Beva → XELOX + Beva o Beva monoterapia en mantenimiento • Non-inferiority study • Objectives/endpoints – Primary endpoint: PFS – Secondary end points include: OS, ORR, time to response, duration of response, and safety Patients XELOX-Beva x6 q3w with XELOX-Beva (n=239) Treat previously until untreated PD mCRC XELOX-Beva Single-agent (s/a) (N=480) x6 q3w (n=241) Beva • XELOX-Beva (Xeloda 1000 mg/m2 bid days 1–14 q3w + oxaliplatin 130 mg/m2 + Avastin 7.5 mg/kg day 1 q3w) initially given for 6 cycles Díaz-Rubio E. et al. The Oncologist 2011 MACRO: Supervivencia Libre de Progresión (ITT) Treatment XELOX-Avastin s/a Avastin Follow-up median 21.1 (0–40) 20.4 (0–38) Progression-free probability months (range) 1.00 XELOX-Avastin s/a Avastin  0.75 No. of Patients 239 241 Event 161 (67%) 174 (72%) Censored 78 (33%) 67 (28%) 0.50 Median (95% CI) 10.4 (9.3–11.9) 9.7 (8.5–10.6) HR: 1.11 (0.89, 1.37) 0.25 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Patients Time (months) at risk XELOX-A 239 204 158 108 71 49 27 13 7 4 2 1 0 s/a Avastin 241 199 160 102 58 40 27 17 11 8 6 4 1 16 Díaz-Rubio et al. Oncologist 2012 MACRO: Supervivencia Global (población ITT) Treatment XELOX-Avastin s/a Avastin Follow-up median 21.1 (0–40) 20.4 (0–38) Survival probability months (range) 1.00 0.75 0.50 XELOX-Avastin s/a Avastin  No. of patients 239 241 0.25 Event 131 (55%) 130 (54%) Censored 108 (45%) 111 (46%) Median (95% CI) 23.4 (20.0–26.0) 21.7 (18.3–25.1) HR: 1.04 (0.81–1.32) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients Time (months) at risk XELOX-A 239 227 208 191 170 146 120 85 60 40 23 13 6 2 s/a Avastin 241 226 210 193 159 132 101 77 54 39 26 19 8 0 17 Díaz-Rubio et al. Oncologist 2012 SAKK 41/06: non-inferiority trial of Beva continuation vs no continuation after 1L Beva + CT Continued Beva PD (n=131) Previously Beva + untreated mCRC chemotherapy R (n=262) (4–6 months) No treatment PD (n=131) • Phase III • Primary endpoint: non-inferiority in TTP (from randomisation) • Secondary endpoints: PFS, time to second-line treatment, OS, adverse events related to Beva, treatment costs Koeberle, et al. ASCO 2013; Stein A et al. Clin Colorectal Cancer 2015 SAKK 41/06: TTP (from randomisation) was numerically increased with continued Beva vs no Bevacizumab 1.0 Continued Beva No Beva 0.8 No. of events 124 123 Median (95% CI) 4.1 (3.1–5.4) 2.9 (2.8–3.8) 0.60 HR 95% CI 0.74 (5.7–0.95) Non-inferiority p=0.47 0.40 TTP estimate TTP 0.20 2.9 4.1 0 0 6 12 18 24 30 36 42 48 Time (months) Patients at risk Avastin 131 40 14 8 6 5 3 2 1 No Avastin 131 22 10 7 5 1 1 1 0 Koeberle, et al. ASCO 2013. Koeberle, et al. ASCO 2013; Stein A et al. Clin Colorectal Cancer 2015 AIO 0207: Treatment algorithms Hegewisch S et al. Lancet 2015 AIO 0207 TFS Hegewisch S et al. Lancet 2015 AIO 0207 PFS Hegewisch S et al. Lancet 2015 AIO 0207 OS Hegewisch S et al. Lancet 2015 CAIRO3 study<br />study design Presented By Cornelis Punt at 2015 ASCO Annual Meeting CAIRO3: Maintenance Cape-Beva DREAMS: Bevacizumab vs bevacizumab + erlotinib Johnsson A et al. Ann Oncol 2013 Clin Colorectal Cancer 2015 Slide 32 Presented By Dirk Arnold at 2016 ASCO Annual Meeting Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials Continued bevacizumab may correlate with clinical benefits • In the non-randomised, observational BRiTE study of bevacizumab plus chemotherapy in patients with mCRC, median OS was increased in patients receiving bevacizumab beyond progression vs those stopping bevacizumab at progression (31.8 vs 19.9 months, respectively, HR=0.48, p<0.001)1 PD=progressive disease. • To be confirmed in ongoing prospective phase III trials 31 1. Grothey, et al. JCO 2008; 2. Grothey, et al. ASCO 2007 (Abstract and poster) Survival Outcomes of Beva Beyond Progression: USO and ARIES Cartwrigh T et al. Clinical Colorectal Cancer 2012 Grothey A et al. Farmacoepidemiology and drugs safety 2014 Targeting Sustained Angiogenesis “Mantained VEGF blocking achieves and prolongs tumor regression” • Preclinical studies • Pivotal trials • Maintenance trials • Non randomised observational studies • Randomized phase III trials E3200: Añadir Bevacizumab a FOLFOX en 2ª línea incrementa la eficacia FOLFOX/beva12.9 meses Folfox/beva:7.3 meses FOLOX: 10.8 meses P=0.0011 Folfox: 4.7 meses Beva; 10.2 meses Beva: 2.7 meses P< 0.0001 Giantonio et al. J Clin Oncol 2007; 25(12):1539-44 Bevacizumab: Ensayo ML18147 (TML) Standard second-line CT (oxaliplatin BEV + standard first- or irinotecan-based) until PD line CT (either oxaliplatin or PD Randomise 1:1 irinotecan-based) BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin (n=820) CT switch: or irinotecan-based) until PD Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin Primary endpoint • Overall survival (OS) from randomisation Secondary endpoints • Progression-free survival (PFS) included • Best overall response rate • Safety Stratification factors • 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) Median: BEV + CT 11.2 months, CT 9.8 months Median: BEV + CT 5.7 months, CT 4.1 months Lancet Oncol 2013 Jan;14(1):29-37. TML Study Lancet Oncol 2013 Jan;14(1):29-37. PFS: KRAS population Interaction test by KRAS status is negative (p=0.4436) OS: KRAS population Interaction test by KRAS status is negative (p=0.1266) Conclusions • Study confirms that continuing BEV beyond first progression while modifying CT is beneficial for patients with mCRC and leads to a significant improvement in OS and PFS • This provides a new second-line treatment option for patients who have been treated with BEV + standard CT in first line while maintaining an acceptable safety profile BEBYP trial: Study Design R § I-line CT * + BV A.
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