CANCER METRONOMIC THERAPY GASTROINTESTINAL CANCERS

Transcription

1 AIOM Meeting Milan, 26 February 2016 CANCER METRONOMIC THERAPY GASTROINTESTINAL CANCERS Lisa Salvatore Polo Oncologico Azienda Ospedaliero-Universitaria Pisana Università di Pisa

2 My Agenda The metronomic story: The Asian studies The European (Italian) studies Maintenance studies Open issues and possible future perspectives

3 A premise My focus will be on mcrc

4 The Asian Production

5 The Asian Production Study Lin, 2007 Ogata, 2007 Ogata, 2013 Phase Regimen FOLFOX >metrouft metrocpt DFUR metrocpt-11+s-1 Setting 5FU-resistant mcrc I-II line mcrc I line mcrc N Pts RR 35.7% 35.6% 48.9% PFS OS Tox G3/4 <5% 2% <10%

6 The Asian Production Study Lin, 2007 Ogata, 2007 Ogata, 2013 Phase Regimen FOLFOX >metrouft metrocpt DFUR metrocpt-11+s-1 Setting 5FU-resistant mcrc I-II line mcrc I line mcrc N Pts RR 35.7% 35.6% 48.9% PFS OS Tox G3/4 <5% 2% <10%

7 The Asian Production Study Lin, 2007 Ogata, 2007 Ogata, 2013 Phase Regimen FOLFOX >metrouft metrocpt DFUR metrocpt-11+s-1 Setting 5FU-resistant mcrc I-II line mcrc I line mcrc N Pts RR 35.7% 35.6% 48.9% PFS OS Tox G3/4 <5% 2% <10%

8 The Asian Production Study Lin, 2007 Ogata, 2007 Ogata, 2013 Phase Regimen FOLFOX >metrouft metrocpt DFUR metrocpt-11+s-1 Setting 5FU-resistant mcrc I-II line mcrc I line mcrc N Pts RR 35.7% 35.6% 48.9% PFS OS Tox G3/4 <5% 2% <10%

9 The Asian Production Study Lin, 2007 Ogata, 2007 Ogata, 2013 Phase Regimen FOLFOX >metrouft metrocpt DFUR metrocpt-11+s-1 Setting 5FU-resistant mcrc I-II line mcrc I line mcrc N Pts RR 35.7% 35.6% 48.9% PFS OS Tox G3/4 <5% 2% <10%

10 The European Production

11 The Italian Production Study Allegrini, 2008 Allegrini, 2012 Marmorino, 2013 Phase NA Regimen metrocpt-11 metrouft+ctx+cxb metro cape+ctx Setting advanced line mcrc advanced line GIC advanced line mcrc N Pts RR 0% 0% NA PFS OS Tox G3/4 0% 0% 0%

12 The Italian Production Study Allegrini, 2008 Allegrini, 2012 Marmorino, 2013 Phase NA Regimen metrocpt-11 metrouft+ctx+cxb metro cape+ctx Setting advanced line mcrc advanced line GIC advanced line mcrc N Pts RR 0% 0% NA PFS OS Tox G3/4 0% 0% 0%

13 The Italian Production Study Allegrini, 2008 Allegrini, 2012 Marmorino, 2013 Phase NA Regimen metrocpt-11 metrouft+ctx+cxb metro cape+ctx Setting advanced line mcrc advanced line GIC advanced line mcrc N Pts RR 0% 0% NA PFS OS Tox G3/4 0% 0% 0%

14 Asia vs Italy Study Lin, 2007 Allegrini, 2012 Marmorino, 2013 Phase Regimen FOLFOX >metrouft metrouft+ctx+cxb metro cape+ctx Setting 5FU-resistant mcrc advanced line GIC advanced line mcrc N Pts RR 35.7% 0% NA PFS OS Tox G3/4 <5% 0% 0%

15 Asia vs Italy Study Lin, 2007 Allegrini, 2012 Marmorino, 2013 Phase Regimen FOLFOX >metrouft metrouft+ctx+cxb metro cape+ctx Setting 5FU-resistant mcrc advanced line GIC advanced line mcrc N Pts RR 35.7% 0% NA PFS OS Tox G3/4 <5% 0% 0%

16 Asia vs Italy Study Lin, 2007 Allegrini, 2012 Marmorino, 2013 Phase Regimen FOLFOX >metrouft metrouft+ctx+cxb metro cape+ctx Setting 5FU-resistant mcrc advanced line GIC advanced line mcrc N Pts RR 35.7% 0% NA PFS OS Tox G3/4 <5% 0% 0%

17 Asia vs Italy: why such difference? Different ethnicity Different drugs and different schedules Different setting

18 Is metro really left out?

19 CAIRO-3: metro as maintenance tx Maintenance cape 625 mg/sqm/bid continuously Simkens et al, Lancet 2015

20 CAIRO-3: PFS Median PFS2 Observation 8.5 m Maintenance 11.7 m Stratified HR 0.67 [95%CI: ] p value < Median PFS1 Observation 4.1 m Maintenance 8.5 m Stratified HR 0.43 [95%CI: ] p value < Simkens et al, Lancet 2015

21 CAIRO-3: Tox G3/4 adverse events, Observation Maintenance p % patients N=279 N=278 Any G3/4 AEs < Hypertension HFS reaction 0 23 < Hyperbilirubinaemia < Adapted from Simkens et al, Lancet 2015

22 CAIRO-3: Tox G3/4 adverse events, Observation Maintenance p % patients N=279 N=278 Any G3/4 AEs < Hypertension HFS reaction 0 23 < Hyperbilirubinaemia < Adapted from Simkens et al, Lancet 2015

23 CAIRO-3: Tox G3/4 adverse events, Observation Maintenance p % patients N=279 N=278 Any G3/4 AEs < Hypertension HFS reaction 0 23 < Hyperbilirubinaemia < Adapted from Simkens et al, Lancet 2015

24 Nordic ACT2: metro as maintenance tx N=71 N=67 Maintenance cape 500 mg twice daily continuously Hagman et al, Ann Oncol 2016

25 Nordic ACT2: metro cape as maintenance tx KRAS mut Bev (N=34) Metro Cape (N=33) 3mos PFR PFS OS 75% 66.7% p= HR=1.19; p= HR=1.57; p=0.128 G3/4 AEs 20.6% 15.2% Adapted from Hagman et al, Ann Oncol 2016

26 Can maintenance metro cape have a future? Hagman et al, Ann Oncol 2016

27 A Made in Italy study was born: the MOMA trial Started on May partecipating centers Sponsored by 3

28 MOMA Study: maintenance metro CT + Bev Randomized phase II study 1st line Unresectable mcrc pts R 1:1 N=232 Arm A Arm B FOLFOXIRI + bevacizumab x 8 cycles FOLFOXIRI + bevacizumab x 8 cycles Bevacizumab until PD Bevacizumab + metro CT* until PD Primary endpoint: PFS *Cape 500 mg/tid continuously CTX 50 mg/die continuously

29 Open Issues Defining the optimal drug Defining the optimal dose Defining the optimal schedule Defining the optimal combination Better understanding the metro mechanism of action

30 Possible future perspectives Metro + Immunotp Metro + Bev Metro + CT Pasquier et al, Nature Rev 2010

31 Take home messages No role of metro in advanced line mcrc Maybe a role of metro as maintenance tx (waiting for MOMA) Open issues (drug, dose, schedule, combination) Several targets and several actions: antiangiogenic, cytotoxic and immunotp

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