Patienten mit Lebermetastasen

Universitätsklinikum Carl Gustav Carus Universitätskrebszentrum / Medizinische Klinik I Dresden Patienten mit Lebermetastasen Welche perioperativen Therapiestrategien? Welche Konversionstherapie? Gunnar Folprecht

Offenlegung potentieller Interessenkonflikte 1. Anstellungsverhältnis oder Führungsposition Universitätsklinikum Carl Gustav Carus, Dresden 2. Beratungstätigkeit Merck, Roche, Lilly, Sanofi-Aventis, Bayer, Ipsen 3. Aktienbesitz keiner 4. Honorare Merck, Amgen, Sanofi-Aventis 5. Finanzierung wissenschaftlicher Untersuchungen Merck, 6. Gutachtertätigkeit keine 7. Andere finanzielle Beziehungen keine

ja Resektabel? nein

Überhaupt? Welche? Wann? ja Resektabel? nein

EORTC 40983: Liver met. +/- periop. FOLFOX Progression free survival Overall survival p=0.068 p=0.34 Nordlinger Lancet Oncol 2013

EORTC 40983: Liver surg. +/- FOLFOX HR 95% CI p interaction NO NEOADJUV CEA 0.0680 5 1.09 0.67-1.75 0.7317 5.1 30 0.58 0.37-0.91 0.0180 >30 0.51 0.32-0.84 0.0075 NO NEOADJUV Performance status 0.0367 0 0.60 0.45-0.82 0.0012 1 1.21 0.67-2.17 0.5239 Body mass index 0.0152 <30 0.55 0.40-0.75 0.0001 30 1.25 0.69-2.30 0.4597 Sorbye Ann Surg 2012

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? Wann? ja Resektabel? nein

New EPOC : FOLFOX +/- Cetuximab Progression free survival Overall survival p=0.03 p=0.16 Primrose Lancet Oncol 2014

Resections and Margins in New EPOC 100% 90% Not operated: other 100% 90% 80% 70% 60% Not operated: PD Not resected 80% 70% 60% Missing or not applicable (CR) Margin 1cm 50% Ablation 50% Margin <1cm 40% 30% 20% Resection: Wedge/1 segment Resection: > 1 segment 40% 30% 20% Positive margin 10% 0% + Cetux Resection: multiple resect. 10% 0% + Cetux Data: Primrose et al, Lancet Oncol 2014

New EPOC discussion

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Resektabel?

Resectable metastases wt R FOLFOX/Cet OP FOLFOX/Cet OP FOLFOX/Cet wt R FOLFOXIRI/Bev OP FOLFOXIRI/Bev OP FOLFOX

Resected metastases CapOX HEPATICA OP R closed, 79 pts CapOX/Beva BLP-25 LICC OP R control

Resectable metastases EORTC BOS2 wt FOLFOX OP FOLFOX R FOLFOX/Beva OP FOLFOX/Beva FOLFOX/Pani OP FOLFOX/Pani FOLFOX/Pani PARLIM OP R planned 111 pts FOLFOX

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein Welche?

Response and resection rates within the trials Trials with neoadjuvant focus Trials in met. CRC Jones, Folprecht Eur J Cancer 2014

EGFR vs. VEGF plus chemo RAS wt n RR PFS OS FOLFIRI/Cetux 171 65% 10.4 33.1 FOLFIRI/Beva 171 60% 10.2 25.6 Heinemann, Lancet Oncol 2014 HR 0.93 HR 0.70 p=0.017 FOLFOX/Pani 88 64% 13.0 41.3 FOLFOX/Beva 82 61% 9.5 28.9 Schwartzberg, JCO 2014 HR 0.65 HR 0.63 p=0.058 /Cetux 270 69% 11.4 32.0 /Beva 256 54% 11.3 31.2 Lenz, ESMO 2014 p<0.01 HR 1.1 HR 0.9

Pooling the data (RAS wild type) Response rate Overall survival favors anti-vegf favors anti-egfr favors anti-egfr favors anti-vegf Khattak et al, Clinical Colorectal Cancer 2015

EGFR vs. VEGF plus chemo KRAS exon 2 wt n RR PFS OS FOLFIRI/Cetux 295 62% 10.0 28.7 FOLFIRI/Beva 297 58% 10.3 25.0 Heinemann, Lancet Oncol 2014 p=0.18 HR 1.06 HR 0.77 p=0.017 FOLFOX/Pani 142 58% 10.9 34.2 FOLFOX/Beva 143 54% 10.1 24.3 Schwartzberg, JCO 2014 HR 0.84 HR 0.62 p=0.009 /Cetux 578 66% resected: 82 pts (14.2%) /Beva 559 57% resected: 50 pts (8.9%) Venook, ASCO/WCGIC/ESMO 2014 p<0.02 p<0.01

FOLFOXIRI combinations in first line therapy n RR PFS OS FOLFOXIRI/Bev 252 65% 12.1 31.0 FOLFIRI/Bev 256 53% 9.7 25.8 Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 FOLFOXIRI 122 60% 9.8 22.6 FOLFIRI 122 34% 6.9 16.7 Falcone, JCO 2007 p<0.0001 HR 0.63; p<0.01 HR 0.80;p=0.032 FOLFOXIRI/Bev 41 81% 18.6 FOLFOX/Bev 39 62% 11.5 Gruenberger, Ann Oncol 2015 Δ19[-2-40]% HR 0.43 [0.26-0.72]

CELIM 2 CELIM2 study (random. phase II) Non-resectable liver metastases RAS Status RAS wt RAS mut BRAF mut Cet./FOLFOXIRI Cet./FOLFIRI Beva./FOLFOXIRI FOLFOXIRI Resection Non-resectable liver metastases: technically non-resectable (< 30%) >= 5 metastases local MDT decision for other reasons PS 0-1 No severe comorbidity 138+118 pts planned to be randomized Response rate Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months Gunnar.Folprecht@uniklinikum-dresden.de

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein Welche? - EGFR-AK + X - FOLFOXIRI ± X

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? nein RFA? Welche? - EGFR-AK + X - FOLFOXIRI ± X

CLOCC R RFA + FOLFOX(/Bev) FOLFOX(/Bev) Ruers, ASCO 2015 #3502 Progression free survival Overall survival p=0.025 Ruers, Ann Oncol 2012

CLOCC: Progression free survival 100 90 80 70 60 50 40 30 HR = 0.57 95% CI (0.38-0.85) P = 0.005 (Log-rank test) Median (95% CI) (Months) 9.92 ( 9.07, 12.85) CT 16.82 (11.01, 21.88) RF+CT 5-year PFS: 5.9% CT 24.2% RF+CT 8-year PFS: 2.0% CT 22.3% RF+CT 20 10 0 0 2 4 6 8 10 12 (years) O N Number of patients at risk : Treatment 57 59 12 5 3 1 1 CT 45 60 20 14 12 11 4 RF+\-resection+CT Ruers et al, ASCO 2015

CLOCC: Long term Overall Survival 100 90 80 70 60 50 HR = 0.58 95% CI (0.38-0.88) P = 0.010 (Log-rank test) Median (95% CI) (Months) 40.54 (27.50, 47.67) CT 45.60 (30.32, 67.75) RF+CT 5-year OS: 30.3% CT 43.1% RF+CT 8-year OS: 8.9% CT 35.9% RF+CT 40 30 20 10 0 0 2 4 6 8 10 12 (years) O N Number of patients at risk : Treatment 53 59 43 21 11 4 2 CT 39 60 44 28 21 19 9 RF+\-resection+CT Ruers et al, ASCO 2015

CLOCC vs. EPOC: Long term Overall Survival 100 90 80 70 60 EPOC-trial 50 40 CLOCC-trial 30 20 10 0 0 2 4 6 8 10 12 (years) O N Number of patients at risk : Treatment 53 59 43 21 11 4 2 CT 39 60 44 28 21 19 9 RF+\-resection+CT Ruers et al, ASCO 2015 / Nordlinger Lancet Oncol 2013

Radiofrequency RF + (N=57) Treatment by RF 30 (52.6%) RF + resection* 27 (47.4%) RF procedure laparotomy 51 (89.5%) Type of resection (N=27) laparoscopically 1 (1.8%) percutaneously 4 (7.0%) unknown 1 (1.8%) atypical resection or wedge 16 (59..3%) 2 or more segments 11 (40.7%) Mean time in hospital *1 patient with resection only 4.8 days

Radiofrequency RF + (N=57) Treatment by RF 30 (52.6%) RF + resection* 27 (47.4%) RF procedure laparotomy 51 (89.5%) Type of resection (N=27) laparoscopically 1 (1.8%) percutaneously 4 (7.0%) unknown 1 (1.8%) atypical resection or wedge 16 (59.3%) 2 or more segments 11 (40.7%) Mean time in hospital *1 patient with resection only 4.8 days

CLOCC N RR PFS OS R RFA + FOLFOX(/Bev) FOLFOX(/Bev) 60-16.8 46 mo 59-9.9 41 mo HR 0.57 HR 0.58 p=0.005 p=0.01 Progression free survival Overall survival Ruers, ASCO 2015 #3502

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Was ist das? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

Technical Resectability Remaining functional liver tissue Invaded structures/segments

Prognostic factors - Disease free interval - Number / size of metastases - Tumor markers - Nodal status Technical Resectability Remaining functional liver tissue Invaded structures/segments

Prognostic factors Conversion chemotherapy ( adjuvant ) Staged resections Portal vein embolisation Combination with ablation Conversion chemotherapy (tumour shrinkage) Technical Resectability Mobidity Risk of complications No of resections

FP+Oxal + Beva 24 weeks SD/PR/CR R FP/ Beva Beva Observ. 1 st progression FP+Oxal + Beva 2 nd progression AIO0207 Arnold #3503 CAIRO3 Koopman #3504 PFS1 B vs A: HR=1.21 [0.95-1.56]; p=0.13 C vs A: HR=2.06 [1.60-2.66]; p<0.001 C vs B: HR=1.57 [1.24-1.99]; lp<0.001

6 Monate Leber 1 Leber 2 Lunge Conversion chemotherapy ( adjuvant ) B vs A: HR=1.21 [0.95-1.56]; p=0.13 C vs A: HR=2.06 [1.60-2.66]; p<0.001 C vs B: HR=1.57 [1.24-1.99]; lp<0.001

Screening MDT discussion Overall survival Study design CELIM3 Resection (± ablation) progressive disease therapy* Patients with mcrc - technically resectable - poor prognostic factors* - therapy ( 4 months) R 1:1 therapy** i.e. further response Resection/ablation Quality of life 0 6 12 18 24 mo. * > 10 metastases, DFS after the last resection <6 months and > 3 metastases, Basingstoke score 20 ** therapy is given as investigators choice

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X + SIRT?

Study Design Design: Prospective open-label RCT Primary endpoint: Progression-Free Survival Eligible Patients Non-resectable liveronly or liver-dominant mcrc No prior chemo for advanced disease WHO performance status 0 1 Stratified by Presence of extrahepatic metastases Degree of liver involvement Intended use of bevacizumab Institution Randomized 1:1 SIRT n = 530 n = 263 enrolled mfolfox6 (+ bevacizumab) (1) n = 267 enrolled mfolfox6 (+ bevacizumab) (1) SIRT ANZ: 280 (53%) EME: 191 (36%) US: 59 (11%) 1. Bevacizumab allowed at investigator s discretion, per institutional practice ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; US: United States Gibbs et al, ASCO 2015

Proportion Not Progressing Progression-Free Survival at Any Site 1.00 0.75 n Events Median PFS FOLFOX (+ bev) 263 225 10.2 months FOLFOX (+ bev) + SIRT 267 217 10.7 months HR: 0.93 (95% CI: 0.77 1.12), p=0.43 0.50 0.25 0.00 0 12 24 36 48 60 Time from Randomization (months) Number at risk FOLFOX 263 96 29 9 5 2 FOLFOX + SIRT 267 106 33 11 5 2 Gibbs et al, ASCO 2015

Tumor Response Rate Hepatic Resection Rate Objective Response Rate (ORR) ORR at Any Site ORR in the Liver Hepatic Resection CR + PR: 68.1% 76.4% p=0.113 68.8% 78.7% p=0.042 80% 80% 70% 70% 60% 60% 50% 40% PR: PR: PR: PR: 66,5% 71,9% 66,9% 72,7% 50% 40% 30% 30% 20% 10% CR: CR: CR: CR: p=0.054 1,5% 4,5% 1,9% 6,0% p=0.020 20% 10% 13.7% 14.2% p=0.857 0% FOLFOX (n = 263) FOLFOX + SIRT (n = 267) FOLFOX (n = 263) FOLFOX + SIRT (n = 267) 0% FOLFOX (n = 263) FOLFOX + SIRT (n = 267) CR: Complete Response; PR: Partial Response. Gibbs et al, ASCO 2015 118-EUA-0615

Gibbs et al, ASCO 2015

HAI vs iv Disease free survival Overall survival 3y 5y HAI 75% 54% IV 62% 52% >= 4 liver mets Goere et al, Ann Surg 2013

HAI vs. systemic chemo Progression free survival Overall survival Kerr et al, Lancet2003

HAI vs. systemic chemo Hepatic progression free survival Overall survival Kemeny et al, JCO 2006

Bisher negativ. OS abwarten. Gibbs et al, ASCO 2015

Begrenzter Effekt bei gutem Risiko eingeschränktem PS Welche? - FOLFOX Wann? ja Resektabel? Überlebensvorteil für RFA + (bis 10 Metastasen) nein + RFA Welche? - EGFR-AK + X - FOLFOXIRI ± X + SIRT? Bisher negativ. OS abwarten.