La strategia terapeutica del carcinoma del colon metastatico
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- Cleopatra Dalton
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1 Dalla Capecitabina al TAS-102 Milano, 29 settembre 2016 La strategia terapeutica del carcinoma del colon metastatico Gianluca Masi U.O. di Oncologia Medica Universitaria Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori
2 MCRC: KEY POINTS FOR A WINNING STRATEGY 1. MULTI-DISCIPLINARY ASSESSMENT Opportunity & timing for resect primary T Opportunity & timing for resect sites of M 2. CHOICE OF FIRST-LINE TREATMENT Set chemo-intensity (mono, doublet, triplet) Pick the best biological partner (anti-vegf vs anti-egfr) 3. ASSURE THE BEST CONTINUUM OF CARE Maintenance, Re-inducion, Re-challenge Second-line, Third-line,
3 Examples of treatment strategies in MCRC TREAT UNTILL PD AND SWITHC («old fashioned») Treatment 1 PD Treatment 2 PD Treatment 3 CHEMO HOLIDAYS AND SWITHC AT PD Treatment 1 PD Treatment 2 PD Treatment 3 SWITHC AT PD AND RECHALLENGE Treatment 1 PD Treatment 2 PD Treatment 1 CHEMO HOLIDAYS AND REINTRODUCTION AT PD Treatment 1 PD Treatment 1 PD Treatment 2 MAINTENANCE AND REINTRODUCTION AT PD Treatment 1 Maintenance PD Treatment 1 PD Tr 2
4 MCRC: CHOOSE THE FIRST-LINE THERAPY RESECATBILITY of MTS Easy, Border-line, Potentially CLINICAL PRESENTATION Sites of Mts & Burden Symptoms Side of Primary T (!?) MOLECULAR PROFILE RAS, RAF MSI (?), HER2 (?), THE PATIENT Comorbidities Expectations,
5 Upfront treatment is still a crucial step to Achieve disease control Allow further interventions (surgery and other systemic treatments)
6 The funnel effect PATIENTS 1st line 2nd line 3rd line 4th line 5th line
7 The funnel effect in the case of disease control/response 1st line 2nd line 3rd line 4th line 5th line PATIENTS
8 The funnel effect in the case of initial PD 1st line 2nd line 3rd line PATIENTS PD, progressive disease
9 What are our best evidenced-based options in first-line? Less intense Fluoropyrimidine + BV Doublets (FOLFOX, XELOX or FOLFIRI) + BV Doublets (FOLFOX or FOLFIRI) + anti-egfr More intense Triplet (FOLFOXIRI) + BV
10 What are our best evidenced-based options in first-line? Less intense Fluoropyrimidine + BV Doublets (FOLFOX, XELOX or FOLFIRI) + BV More intense Triplet (FOLFOXIRI) + BV
11 The AVEX study Capecitabine + BV 280 mcrc pts 1st line mcrc AGE >70 yrs R Stratification factors: ECOG PS (0 1 vs 2) Geographic region Capecitabine Key inclusion criteria ECOG PS 0 2 Prior adjuvant chemotherapy allowed if completed >6 month before inclusion Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin Cunningham D. et al, Lancet Oncol 13
12 AVEX - Progression Free Survival Cunningham D. et al, Lancet Oncol 13
13 . The TASCO 1 trial
14 The TASCO 1 trial TAS-102 Twice a day 35 mg/m² orally BEVACIZUMAB 5 mg/kg IV 28-day cycle OR CAPECITABINE Twice a day 1250mg/m² orally BEVACIZUMAB 7.5 mg/kg IV 21-day cycle
15 What are our best evidenced-based options in first-line? Less intense Fluoropyrimidine + BV Doublets (FOLFOX, XELOX or FOLFIRI) + BV More intense Triplet (FOLFOXIRI) + BV
16 TRIBE Study Design FOLFIRI + bev (up to 12 cycles) 5-FU/LV + bev 508 mcrc pts 1st line unresectable stratified by center PS 0/1-2 adjuvant CT R FOLFOXIRI + bev (up to 12 cycles) 5-FU/LV + bev PD INDUCTION MAINTENANCE Primary Endpoint: PFS Loupakis et al., NEJM 2014
17 Primary endpoint: PFS FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos HR: 0.75 [ ] p=0.003 Loupakis et al., NEJM 2014
18 TRIBE: FOLFOXIRI + bev improves RECIST response, ETS and DoR RECIST Response: 53% vs 65 % p=0.006 Tumour shrinkage 20% at 8 wks Depth of response FOLFIRI + bevacizumab FOLFOXIRI + bevacizumab 80 FOLFIRI + bevacizumab (37.8%) 60 FOLFOXIRI + bevacizumab 40 (43.4%) % 62.7% P =.003 P =.025 Loupakis F, et al. N Engl J Med. 2014;23;371(17): Cremolini C, et al. Ann Oncol. 2015;26(6):
19 TRIBE: Updated OS results Median follow-up: 48.1 mos FOLFIRI + bev, median OS: 25.8 mos FOLFOXIRI + bev, median OS: 29.8 mos HR: 0.80 [ ] P = year OS rate 24.9% vs 12.4% Cremolini C, et al. Lancet Oncol 2015
20 TRIBE in molecular subgroups - OS RAS and BRAF wild-type arm A RAS mutant arm A BRAF mutant arm A RAS and BRAF wild-type arm B RAS mutant arm B BRAF mutant arm B Median OS 41.7 months 33.5 months 27.3 months 23.9 months 19.0 months 10.7 months Cremolini et al, Lancet Oncol 15
21 Decision drivers for FOLFOXIRI FOLFOXIRI plus bev appropriateness
22 What are our best evidenced-based options in first-line? Less intense Fluoropyrimidine + BV Doublets (FOLFOX, XELOX or FOLFIRI) + BV Doublets (FOLFOX or FOLFIRI) + anti-egfr More intense Triplet (FOLFOXIRI) + BV
23 Capecitabine + Oxaliplatin vs 5FU + Oxaliplatin N RR PFS OS German AIO CapOx % FUFOX % Spanish TTD Xelox % FUOX % NO16966 Xelox 350 n.a FOLFOX 351 n.a
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25 6 randomized trials (N=3494) Decreased RR (OR= 0.85, p=0.02) Equivalent PFS (HR= 1.04, p=0.17) Equivalent OS (HR= 1.04, p=0.41)
26 NO16966 study design Recruitment June 2003 May 2004 Recruitment Feb 2004 Feb 2005 XELOX N=317 FOLFOX4 N=317 XELOX + placebo N=350 FOLFOX4 + placebo N=351 XELOX + bevacizumab N=350 FOLFOX4 + bevacizumab N=350 Initial 2-arm open-label study (N=634) Protocol amended to 2x2 placebocontrolled design after bevacizumab phase III data 1 became available (N=1401) Saltz et al, JCO 2009
27 PFS estimate PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups Months Months XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events XELOX subgroup HR = 0.77 [97.5% CI ] (ITT) p = FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events FOLFOX subgroup HR = 0.89 [97.5% CI ] (ITT) p = Saltz et al, JCO 2009
28 Maughan et al, ESMO 2009
29 Maughan et al, ESMO 2009
30 Capecitabine + Irinotecan vs 5FU + Irinotecan EORTC CAPIRI vs FOLFIRI: suspended due to occurrence of 6 treatment related deaths in the CAPIRI arm BICC-C CAPIRI vs FOLFIRI: efficacy safety CAIRO-1 CAPIRI: is safe Oral chemotherapy needs ACTIVE management!!!
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33 WHICH BIOLOGIC IN FIRST-LINE? Direct comparisons anti-egfrs vs bev FIRE-3 CALGB C80405 PEAK
34 Phase III study design FOLFIRI + Cetuximab mcrc 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v min q 2w Key inclusion criteria Patients 18 years with histologically confirmed diagnosis of mcrc ECOG PS 0-2 prior adjuvant chemotherapy allowed if completed >6 month before inclusion Amendment in October 2008 to include only KRAS wildtype patients 150 active centers in Germany and Austria FOLFIRI: 5-FU: 400 mg/m 2 (i.v. bolus); folinic acid: 400mg/m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m 2 (i.v. 46h)
35 Probability of survival Progression-free survival Events n/n (%) FOLFIRI + Cetuximab 250/297 (84.2%) FOLFIRI + Bevacizumab 242/295 (82.0%) Median (months) 95% CI HR 1.06 (95% CI ) Log-rank p= numbers at risk months since start of treatment
36 Probability of survival Overall survival Events n/n (%) FOLFIRI + Cetuximab 158/297 (53.2%) FOLFIRI + Bevacizumab 185/295 (62.7%) Median (months) 95% CI HR 0.77 (95% CI: ) Log-rank p= numbers at risk months since start of treatment
37 Probability of survival Overall survival RAS* wild-type * KRAS and NRAS exon 2, 3 and 4 wild-type Events n/n (%) FOLFIRI + Cetuximab 91/171 (53.2%) FOLFIRI + Bevacizumab 110/171 (64.3%) Median (months) 95% CI HR 0.70 (95% CI: ) p (log-rank)= No. at risk months since start of treatment Adapted from Heinemann V, et al. ECCO-ESMO 2013
38 CALGB/SWOG 80405: FINAL DESIGN mcrc 1st-line KRAS wild type (codons 12,13) FOLFIRI or FOLFOX MD choice Chemo + Cetuximab Chemo + Bevacizumab N = Endpoint: Overall Survival
39 CALGB/SWOG 80405: Overall Survival Arm Chemo + Cetux N (Events) OS (m) Median 95% CI 578 (375) Chemo + Bev 559 (371) P=0.34 HR ( ) Presented by: Venook A
40 CALGB 80405: Overall Survival By Arm (All RAS Wild Type Patients) Arm Chemo + Bev Chemo + Cetux N (Events) 256 (178) 270 (177) Median (95% CI) 31.2 ( ) 32.0 ( ) HR (95% CI) 0.9 ( ) p 0.40 Lenz HJ et al, ESMO 2014
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43 OS
44 PFS
45 RR
46 Main troubles with H-H comparison trials PEAK Phase II random Primary EP (PFS): negative FIRE-3 Primary EP (RR): negative Data interpretation CALGB/SWOG N. pts analyzed Data quality
47 FIRE-3: possible explanations for OS Choice and duration of 2nd line therapy Change in tumor biology during 1st line therapy OS Depth of response
48 Early Tumor Shrinkage & Deepness of Response Lethal tumor load OS Baseline tumor load ETS ETS ETS predicts sensitivity ETS predicts the potential DpR DpR predicts OS DpR (smallest tumor size) Time under treatment ETS: early tumor shrinkage 1,2 DpR: depth of response 3 At least 20% decrease (shrinkage) in the sum of the longest diameter compared with baseline at week 8 Percentage of tumor shrinkage observed at the smallest tumor size compared with baseline adapted from Mansmann et al, ASCO GI 2013 abstract #427
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51 Courtesy :Andrea Sartore Bianchi AIOM 2015
52 PFS 2nd = First-line FOLFIRI+CET = First-line FOLFIRI+BEV OS 2nd
53 COMETS: Study design Study conducted in 11 centres in Italy PFS BEV + FOLFIRI (n=110) PD Randomise 1:1 Irinotecan/ CETUXIMAB FOLFOX FOLFOX Irinotecan/ CETUXIMAB 101 events were required to achieve a power of 80% of detecting a HR of 0.57 in favour of one of the two sequences, translating in an increase of median overall PFS from 4 to 7 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the log-rank test. 110 assessable patients were needed to reach the target number of events. Primary endpoint Secondary endpoints Progression-free survival (PFS) Overall survival (OS) from randomisation; PFS 2 and 3 line; Overall response rate Safety Clinicaltrials.gov: NCT Research Funding Source: AIFA (Agenzia Italiana del Farmaco) Code FARM 6XB38F Cascinu S., Labianca R. et al. ECC 2015
54 Efficacy data according to arm Arma A CETUX/CPT (55 patients) Arm B FOLFOX (55 patients) Hazard ratio (95% CI) Response rate (%) 19/52 (37%) 30/53 (57%) p= 0.05 Fisher exact test Overall median PFS (months) HR 0.83 ( ); p= 0.37 Overall median survival (months) HR 0.79 ( ); p= 0.26 Arm A: Cetuximab/irinotecan followed by FOLFOX Arm B: FOLFOX followed by Cetuximab/irinotecan Adapted: Cascinu S., Labianca R. et al. ECC 2015
55 X Colon?? RIGHT LEFT
56 Metastatic Colorectal Cancer: Does Side Matter? PUBLICATION (Study) Patients N Molecular Selection Treatment OUTCOME RIGHT LEFT O Dwyer JCO, 2001 (E2290) Brule, Eur J Can, 2015 (CO.17) Loupakis, JNCI, 2015 N = 1120 NONE 5FU VARIATIONS OS (MOS) N =399 KRAS wt BSC v. BSC + CET N = 2053 NONE FOLFIRI/BEV FUOX/BEV IFL/BEV PFS (MOS) OS (MOS)
57 80405: Overall Survival by Sidedness Side N (Events) Left 732 (550) Right 293 (242) Median HR (95% CI) (95% CI) 33.3 ( ) ( ) ( ) p < Left Right Presented by:
58 Right versus Left and Bevacizumab AVF2017g : p for interaction OS=0.38; PFS=0.59 NO16966 : p for interaction OS=0.29; PFS=0.62
59 Right versus Left and anti-egfr: OS in FIRE-3 FOLFIRI+cetuximab FOLFIRI+bevacizumab Heinemann et al., ASCO 14
60 Impact of primary tumor location on Overall Survival and Progression Free Survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG (Alliance) A Venook, D Niedzwiecki, F Innocenti, B Fruth, C Greene, BH O Neil, J Shaw, J Atkins, LE Horvath, B Polite, JA Meyerhardt, EM O Reilly, R Goldberg, HS Hochster, CD Blanke, R Schilsky, RJ Mayer, M Bertagnolli, HJ Lenz for SWOG and the ALLIANCE
61 Patient Characteristics by Tumor Side, (KRAS wt) RIGHT-SIDED (N = 293) LEFT-SIDED (N = 732) TOTAL* (N = 1137) P Age (mean) < Gender (M %) 54.9% 65.0 % 62.1% Synchronous Stage IV 86.9% 76.0% 79.3% Prior Adjuvant 10.6% 15.7% 14.2% 0.03 FOLFOX / FOLFIRI 74.4 / / / Primary in place 19.2% 29.6% 26.6% Pattern mets: liver only liver mets extra-hepatic 27.5% 40.5% 32.0 % 32.1% 43.2% 24.7% 30.9% 42.8% 28.5% *Transverse colon 66 (excluded from analysis); unknown - 46 **Test of any liver metastases versus extrahepatic 0.02**
62 80405: OS by Sidedness (Bevacizumab) Median Side N (Events) HR(95% CI) p (95% CI) 31.4 Left 356 (280) 1.32 ( ) 0.01 ( ) 24.2 Right 150 (121) ( ) Right Left Presented by:
63 80405: OS by Sidedness (Cetuximab) Median HR Side N (Events) p (95% CI) (95% CI) 36.0 Left 376 (270) 1.87 ( ) < ( ) 16.7 Right 143 (121) ( ) Right Left Presented by:
64 80405: Overall Survival by Sidedness and Biologic 31.4 ( ) 36.0 ( ) 24.2 ( ) 16.7 ( ) Presented by:
65 MIDGUT Bettington, et al. Histopathology HINDGUT Bettington, et al Histopathology, 2013
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69 Which is the best strategy in mcrc? RAS WT (and BRAF WT) pts have a MAJOR benefit from anti-egfr moabs Maintenance & Treatment Beyond PD maximize the benefit of BEVA WHAT IS THE NEED OF A RAPID & DEEP RESPONSE??? WHAT IS THE CHANCE TO RECEIVE A THIRD-LINE THERAPY???
70 Which variables to consider in the choice of second-line? Patient clinical characteristics Patient preferences Performance status Age Comorbidities Prior adjuvant treatment Expectations Toxicity profile First-line related factors Which chemo Which biologic Which response Tolerance Residual toxicities Drug free-interval Tumour Molecular characteristics Tumour clinical characteristics RAS BRAF Tumour burden Resectability Related symptoms Aggressiveness
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73 Targeted agents in second line MCRC COMBINATION STUDY RR PFS OS Bevacizumab + IRI or LOHP-based CT (E3200) TML BEPYP NO YES YES Aflibercept + FOLFIRI VELOUR YES YES YES Ramucirumab + FOLFIRI RAISE NO YES YES Cetuximab + IRI EPIC Panitumumab + IRI PICCOLO Panitumumab + FOLFIRI 181 YES YES NO
74 Anti-angiogenic agents in 2nd line Bevacizumab Aflibercept Ramucirumab FDA and EMA approved VEGF-A PlGF VEGF-B VEGF-A VEGFR-2
75 Bevacizumab beyond progression: TML trial 2 nd line chemo 820 mcrc pts progressed to a 1st line chemo plus Beva* R Primary Endpoint: Overall survival 2 nd line chemo + BEV * progressed up to 3 months after discontinuing 1st-line bevacizumab switched chemo Bennouna et al, Lancet Oncol 2013
76 Bevacizumab Beyond Progression: TML trial - OS Bennouna, Lancet Oncol 2013
77 Anti-angiogenic agents in 2nd line Bevacizumab Aflibercept Ramucirumab FDA and EMA approved VEGF-A PlGF VEGF-B VEGF-A VEGFR-2
78 Aflibercept: VELOUR trial 1226 mcrc pts progressed to a 1st line oxaliplatin-based therapy* Primary Endpoint: Overall survival R 2 nd line FOLFIRI 2 nd line FOLFIRI+afl * 1 st -line bev allowed and administered in 30% of pts Van Cutsem et al, J Clin Oncol 2012
79 VELOUR trial: Primary endpoint met (OS) Van Cutsem et al, J Clin Oncol 12
80 VELOUR trial: PFS & Response Rate
81 Anti-angiogenic agents in 2nd line Bevacizumab Aflibercept Ramucirumab VEGF-A PlGF VEGF-B VEGF-A VEGFR-2
82 Ramucirumab: RAISE trial 1072 mcrc pts progressed to a 1st line therapy with oxaliplatin, fluoropyrimidine and BEV R 2 nd line FOLFIRI 2 nd line FOLFIRI+ram Primary Endpoint: Overall survival Tabernero et al, Lancet Oncol 2015
83 RAISE trial: OS results Tabernero et al, Lancet Oncol 2015
84 Angiogenesis inhibition in second line Bevacizumab Aflibercept Ramucirumab Study TML E3200 VELOUR RAISE mos HR 0.81* 0.75* 0.82* 0.84* mpfs HR 0.68* 0.61* 0.76* 0.79* RR (%) * * * p< % prior Beva NO prior Beva 30% prior Beva 100% prior Beva Bennouna Lancet Oncol Giantonio JCO Van Cutsem JCO 2012 Tabernero Lancet Oncol 2015
85 Can toxicity profile help us? G3/4 adverse events, % Chemo + bevacizumab TML FOLFIRI + aflibercept VELOUR FOLFIRI + ramucirumab RAISE Diarrhea 10% 19% 19% 11% Stomatitis 3% 14% 11% 4% Neutropenia 16% 37% 20% 38% Hypertension 2% 19% 16% 11% Venous thromboembolism 5% 8% 7% 3% Arterial thromboembolism 2% 2% 2% <1% ITT Prior Bev 100% prior Bev 100% prior Bev population subgroup Adapted from: Bennouna et al, Lancet Oncol 2012; Tabernero et al, Eur J Cancer 2014; Van Cutsem et al, J Clin Oncol 2012; Tabernero et al, Lancet Oncol 2015
86 Bevacizumab Beyond PD: alternatives??? Anti EGFR EPIC, J Clin Oncol 2008 PICCOLO, Lancet Oncol 2013 Pmab 181, Ann Oncol 2014 No Formal Evidence of Survival Benefit Cross over (activity in third-line) Re-think on the basis of extended molecular selection
87 Panitumumab in 2nd line: 181 trial 1186 mcrc pts progressed to a 1st line fluoropyrimidine-based therapy R 2 nd line FOLFIRI 2 nd line FOLFIRI+Pan Primary Endpoints: Overall survival and Progression-free Survival, by KRAS status Peeters et al, JCO 2010
88 181 trial: OS and PFS results in RAS wt population OVERALL SURVIVAL PROGRESSION-FREE SURVIVAL 34% of patients assigned to FOLFIRI eventually received anti-egfr Peeters et al, Clin Cancer Res 2015
89 In the Event that Tumor Shrinkage Is Needed Study: ORR and Depth of response Peeters et al, Clin Cancer Res 2015
90 Anti-EGFR moabs in second line Cetuximab Panitumumab Study EPIC PICCOLO mos HR (p=0.08) 0.92 mpfs NA NA HR 0.69* 0.70* 0.68* RR (%) 16.4* * * 12.3 * p<0.05 No molecular selection RAS wt all-wt (RAS, BRAF, PIK3CA) Sobrero JCO 2008 Peeters Clin Cancer Res Seymour Lancet Oncol
91 Which Biologic After CT+Bev? Bevacizumab both after Oxa-based and CPT-based 1 st line and with FOLFIRI or FOLFOX or XELOX Aflibercept only after oxa-based 1 st -line and only with FOLFIRI Ramucirumab only after oxa-based+beva 1 st -line and only with FOLFIRI Anti-EGFRs only RAS WT; only with CPT-based CT; mainly if shrinkage is needed
92 Third and further-line treatments
93 Well established «salvage» options Anti-EGFR (pani, cet +/- irinotecan) In RAS wt pts not previously treated with anti-egfr Chemo Rechallenge No prospective evidences Carefully consider previous benefit and toxicity REGORAFENIB TAS-102
94 Regorafenib: indication and approval mcrc pts, pretreated or not considered candidates for available tx 27 September August August 2015
95 CORRECT trial Study design mcrc pts treated with all standard tx PD during or 3 months after last tx R 1:2 N= 760 Placebo + BSC N= 255 Regorafenib + BSC Stratification by Prior BV Time from diagnosis of mets Geographical region N= 505 Primary end-point: OS Grothey et al, Lancet 2013
96 CORRECT trial: Patients characteristics Grothey et al, Lancet 2013
97 CORRECT trial Primary end-point MET Regorafenib mos = 6.4 mos Placebo mos = 5.0 mos HR=0.77 (95%CI ) p= Grothey et al, Lancet 2013
98 CONCUR trial Outcome Results Regorafenib mos = 8.8 mos Placebo mos = 6.3 mos HR=0.55 (95%CI ) p= Regorafenib mpfs = 3.2 mos Placebo mpfs = 1.7 mos HR= % CI p< HR=0.31 (95%CI ) p< Li et al, Lancet Oncol 2015
99 Regorafenib: safety profile G 3 Adverse event % Rego (n=505) CORRECT CONCUR CONSIGN Placebo (n=255) Rego (n=136) Placebo (n=68) Rego (2872) HFS 17 < Fatigue Hypertension Diarrhea Rash <5 Bilirubin increase Grothey et al, Lancet 2013 Li et al, Lancet Oncol 2015 Van Cutsem et al, WCGIC 2015
100 AEs and dose modifications: CORRECT and CONCUR Rego (n=505) CORRECT Placebo (n=255) Rego (n=136) CONCUR Placebo (n=68) G 3 AE Treatment modification* *interruption, delay, dose reduction Grothey et al, Lancet 2013 Li et al, Lancet Oncol 2015
101 TAS-102: indication and approval mcrc pts, pretreated or not considered candidates for available tx 22 September April 2016 Pending
102 TAS-102: mechanism of action TPase FTY (inactive form) TPI TAS-102 FTD + TPI Molar ratio = 1:0.5 FTD:Trifluorothymidine TPI:Tipiracil-HCl FTD F 3 TMP F 3 TDP F 3 TTP Inhibition of tumor growth DNA dysfunction FTD incorporation into DNA 15mg tablet 20mg tablet
103 RECOURSE trial Study design mcrc pts treated with 2 tx lines refractory to all standard tx* R 1 : 2 N= 800 Placebo + BSC N= 266 TAS 102+ BSC N= 534 About 20% rego-pretreated Primary end-point: OS *PD during or 3 months after all active drugs Mayer et al, NEJM 2015
104 Recourse trial Primary end-point OS MET TAS-102 mos = 7.1 mos Placebo mos = 5.3 mos HR=0.68 (95%CI ) p<0.001 Mayer et al, NEJM 2015
105 Survival distribution function Recourse trial updated OS Trifluridine/tipiracil (N=534) Placebo (N=266) Median OS (months) Stratified log-rank test: p< HR: 0.69, 95% CI [0.59, 0.81] Alive at 12 months, % No. at Risk: Months from randomization Trifluridine/tipiracil Placebo Carried out at 89% of events (138 additional events) Cut off October 8th, 2014: 712 events Mayer R, et al. ASCO GI 2016 Abstract 634
106 Recourse trial subgroup analysis OS Subgroup Favours trifluridine/tipiracil Favours placebo Events / N HR (95% CI) All patients 574 / ( ) KRAS status Wild type Mutant Time since diagnosis of first metastasis <18 months 18 months Geographic region Japan US, Europe & Australia Age <65 years 65 years Gender Male Female ECOG performance status 0 1 Primary tumor site Colon Rectum Number of prior regimens Prior use of regorafenib Yes No 280 / / / / / / / / / / / / / / / / / / / ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Refractory to fluoropyrimidine part of last prior regimen 329 / ( ) Hazard ratio: Trifluridine/tipiracil vs. placebo (95% CI) Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:
107 Recourse trial RR & DCR Disease control rate Response rate 60% 50% 40% 30% 20% 10% 0% 44% p< % Trifluridine/tipiracil Placebo Trifluridine/tipiracil (N=112) % Placebo (N=57) % CR 0 0 PR SD ORR (%) Mayer RJ, Van Cutsem E, et al. N Engl J Med. 2015;372:
108 REGO vs TAS Efficacy CORRECT RECOURSE Rego (n=500) Placebo (n=253) TAS-102 (534) Placebo (266) mpfs HR mos HR
109 RECOURSE trial Safety profile Lab abnormalities, % TAS-102 (n=533) Placebo (n=265) All Gr Gr 3 All Gr Gr 3 Leukopenia Anemia Neutropenia <1 0 Thrombocytopenia <1 TAS-102 (n=533) Placebo (n=265) Adverse events, % All Gr Gr 3 All Gr Gr 3 Febrile neutropenia Adapted from Mayer et al, NEJM 2015
110 REGO vs TAS: how can we choose? Toxicity profile Previous treatments toxicities Previous treatments efficacy Biomarkers??? COST!!!
111 Recourse trial: Subgroup analysis for OS Mayer et al, NEJM 2015
112 Mayer et al, N Eng J Med 2015 Clinical selection in advanced lines is essential CORRECT Grothey et al, Lancet 2013 RECOURSE TAS-102 mpfs = 2.0 mos Placebo mpfs = 1.7 mos HR= 0.48 (95%CI ) p<0.001
113 How can I optimize the tx of my MCRC pt? Use a comprehensive & carefull approach (clinical & molecular) Plan a strategy Modulate therapy Assess & re-think the strategy DON T BE DOGMATIC, BUT RATHER PRAGMATIC!
114 Grazie per l attenzione! alfredo.falcone@med.unipi.it
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