What to do after 1st-line failure in mcrc?

Transcription

1 What to do after 1st-line failure in mcrc? Werner Scheithauer Univ.Klinik für Innere Med. I & CCC, Med.Uni.Wien-AKH

2 mcrc front-line treatment strategy today

3 Updated results of head-to-head trials in mcrc, RAS wt: Doublet + Bev vs. Anti-EGFR

4 Current principles of mcrc management Exposure to multiple chemotherapy agents is associated with prolonged OS Integration of biologicals has resulted in additional OS benefit Rechallenge with a previous effective treatment-line should be kept in mind

5 Accumulating evidence that limited treatment duration with oxaliplatin & re-induction results in improved therapeutic outcome Tournigand C et al, J Clin Oncol 24: , 2006 OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer-a GERCOR study. In arm B oxaliplatin was reintroduced in only 40.1% of the patients, but in 69.4% of them responses or stabilizations were achieved. DeGramont A et al, J Clin Oncol 25:3224-9, 2007 Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced. Hochster HS et al, Ann Oncol 25:1172-8, 2014 Improved time to treatment failure with an intermittent oxaliplatin (IO) strategy: results of CONcePT. The IO schedule was superior to CO (HR = 0.581, P = ) for both TTF and time-totumor progression (TTP) (HR = 0.533, P = 0.047).

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8 2 nd line with anti-vegf-therapies E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + (n=612) Plac + (n=614) Ramu + (n=536) Bev before? none all 30% all mos, months mpfs, months ORR, % Plac + (n=536) HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p= HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= Plac = placebo p< ns p= ns Giantonio, 1. Langer, et al. J ESMO Clin Oncol 2008; 22007;. Peeters, Benounna, et al. JCO 2010; Arnold 3. Van et al, Cutsem, Lancet et Oncol al. WCGC 2012; 2011 Van Cutsem, et al. J Clin 4. Giantonio, Oncol 2012 et al. ; J Tabernero Clin Oncol 2007; et al., 5. Roche ASCO data GI 2015 on file

9 2 nd line with anti-vegf-therapies E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + (n=612) Plac + (n=614) Ramu + (n=536) Bev before? none all 30% all mos, months mpfs, months ORR, % Plac + (n=536) HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p= HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= Plac = placebo p< ns p= ns Giantonio, 1. Langer, et al. J ESMO Clin Oncol 2008; 22007;. Peeters, Benounna, et al. JCO 2010; Arnold 3. Van et al, Cutsem, Lancet et Oncol al. WCGC 2012; 2011 Van Cutsem, et al. J Clin 4. Giantonio, Oncol 2012 et al. ; J Tabernero Clin Oncol 2007; et al., 5. Roche ASCO data GI 2015 on file

10 2 nd line with anti-vegf-therapies E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + (n=612) Plac + (n=614) Ramu + (n=536) Bev before? none all 30% all mos, months mpfs, months ORR, % Plac + (n=536) HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p= HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= Plac = placebo p< ns p= ns Giantonio, 1. Langer, et al. J ESMO Clin Oncol 2008; 22007;. Peeters, Benounna, et al. JCO 2010; Arnold 3. Van et al, Cutsem, Lancet et Oncol al. WCGC 2012; 2011 Van Cutsem, et al. J Clin 4. Giantonio, Oncol 2012 et al. ; J Tabernero Clin Oncol 2007; et al., 5. Roche ASCO data GI 2015 on file

11 2 nd line with anti-vegf-therapies E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + (n=612) Plac + (n=614) Ramu + (n=536) Bev before? none all 30% all mos, months mpfs, months ORR, % Plac + (n=536) HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p= HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= Plac = placebo p< ns p= ns Giantonio, 1. Langer, et al. J ESMO Clin Oncol 2008; 22007;. Peeters, Benounna, et al. JCO 2010; Arnold 3. Van et al, Cutsem, Lancet et Oncol al. WCGC 2012; 2011 Van Cutsem, et al. J Clin 4. Giantonio, Oncol 2012 et al. ; J Tabernero Clin Oncol 2007; et al., 5. Roche ASCO data GI 2015 on file

12 2 ND LINE: +/- PANITUMUMAB OS-Wahrscheinlichkeit 1,0 0,75 0,50 0, Primäre Analyse (K-RAS-WT, Exon 2) Panitumumab + 12,5 14,5 Ereignisse n/n (%) 200/303 (66) 207/294 (70) HR (95% CI) Log-rank p-wert Median, Monate (95% Cl) 14,5 (13,0; 16,0) 12,5 (11,2; 14,2) 0,85 (0,70;1,04) 0, Zeit (Monate) OS-Wahrscheinlichkeit 1,0 0,75 0,50 0, Erweiterter RAS-WT-Status Panitumumab + 13,9 16,2 HR (95% CI) Log-rank p-wert Ereignisse n/n (%) 130/208 (63) 143/213 (67) 13,9 (11,9; 16,0) 0,81 (0,63; 1,03) 0, Zeit (Monate) Median, Monate (95% Cl) 16,2 (14,5; 19,7) Peeters, et al. ASCO Abstract 3568

13 2ND LINE: SEQUENCE AFTER /BEV Cascinu et al., ECC 2015

14 2ND LINE: SEQUENCE AFTER /BEV PFS OS Cascinu et al., ECC 2015

15 KRAS wild-type; N=182 2ND LINE, NACH FOLFOX/BEV: /P MAB VS. /BEV Hecht et al., Clin Colorectal Cancer 2015

16 SEQUENTIAL STUDIES: STRATEGIC-1 Phase III, GERCOR PI: Benoist Chibaudel

17 SEQUENTIAL STUDIES: STACCATO Continued cfdna analysis (q 6-8 weeks) Int l Phase III (TTD et al.) PI: Alfredo Carrato & Jean-Yves

18 SEQUENTIAL STUDIES: FIRE-4 Phase III, AIO PI: Volker Heinemann

19 IS THERE AN OPTIMAL SEQUENCE OF COMBINATION CT IN MCRC: WHAT, WHEN & HOW LONG? There does not exist an optimal sequence along treatment lines 2nd-line therapies have different anticancer activities, which depend on previous treatment lines Sequencing anti-vegf! anti-vegf is the best established option Treatment decisions should be individualized, dependent on multiple factors Continuum of Care is important and: Does not implicate Chemo forever, but should utilze all available treatment lines Utilize de-eskalation/maintenance or ablative therapies Utilize re-induktion

20 SALVAGE THERAPY OPTIONS & EFFICACY CO.17 1 (KRAS WT) Study (KRAS WT) CORRECT 3 (ITT) Cet + BSC (n=110) BSC (n=105) Pan + BSC (n=124) BSC (n=119) Reg + BSC (n=505) Placebo + BSC (n=255) mos, months * HR=0.55 p<0.001 HR=NR p=nr HR=0.77 p= mpfs, months HR=0.4 p<0.001 HR=0.45 p< HR=0.49 p< *90 patients (76%) crossed over to receive panitumumab following progression of disease 1. Karapetis, et al. NEJM Amado, et al. JCO Grothey, et al. ASCO GI 2012

21 SALVAGE THERAPY OPTIONS & SAFETY Grade 3/4 AE, % CO.17 1 (ITT) Cet + BSC (n=288) BSC (n=274) Study (ITT) Pan + BSC (n=229) BSC (n=234) Reg + BSC (n=500) CORRECT 3 (ITT) Plac + BSC (n=253) Any Grade 3/ Diarrhoea <1 Nausea <1 <1 0 Hypertension 7 <1 Bleeding <1 0 Oedema <1 Fatigue Anorexia Constipation Fever/pyrexia 0 2 <1 0 Abdominal pain Hand-foot syndrome 17 <1 Skin rash 12 < Jonker, et al. NEJM 2007; 2. Van Cutsem, et al. JCO 2007; 3. Grothey, et al. ASCO GI 2012

22 ADDITIONAL IMMINENT MCRC SALVAGE THERAPY OPTIONS Nintedanib: A new angiokinase-inhibitor, which blocks 3 different classes of receptor tyrosinekinases: VEGFR 1-3, FGFR 1-3 & PDGFR alpha and beta. Placebo-controlled Lume-Colon 1 Phase III Trial (n=764) Ruxolitinib: An oral JAK pathway inhibitor that has shown promising activity in chemorefractory metastatic pancreatic cancer. Double-blind study of R or placebo in combination with regorafenib (n=346) TAS-102: A novel combination chemotherapy agent consisting of cytotoxin (trifluridin), which inhibits cell growth & a thymidine phosphorylase inhibitor (tipiracil), which protects trifluridine from breakdown. Placebo-controlled 2:1 RECOURSE Phase III Trial (n=800)

23 ADDITIONAL IMMINENT MCRC SALVAGE THERAPY OPTIONS Nintedanib: A new angiokinase-inhibitor, which blocks 3 different classes of receptor tyrosinekinases: VEGFR 1-3, FGFR 1-3 & PDGFR alpha and beta. Placebo-controlled Lume-Colon 1 Phase III Trial (n=764) Ruxolitinib: An oral JAK pathway inhibitor that has shown promising activity in chemorefractory metastatic pancreatic cancer. Double-blind study of R or placebo in combination with regorafenib (n=346) TAS-102: A novel combination chemotherapy agent consisting of cytotoxin (trifluridin), which inhibits cell growth & a thymidine phosphorylase inhibitor (tipiracil), which protects trifluridine from breakdown. Placebo-controlled 2:1 RECOURSE Phase III Trial (n=800)

24 mcrc front-line treatment strategy today

25 Herzlichen Dank