Adjuvant therapy in patients with pancreatic cancer & EGA Per Pfeiffer, MD, PhD Professor in Clinical Oncology Dept of Oncology, OUH, Denmark Institute of Clinical Research, USD, Denmark
Pancreatic cancer Stage and therapy Resectable LAPC Metastatic Resection + Adjuvant Gem CT or CRT CT 5year OS: 20% 6 mo -> 12 mo & Symptom relief 3 mo -> 6 mo & Symptom relief
CT in non-resectable PC Gem vs other mpc vs LAPC R A N D O M I S A T I O N Gemcitabine Numerous phase III - no benefit of combo Gemcitabine + other
CT in mpc Gem vs Gem-Capecitabine 533 patients LAPC or mpc PS 0-2 R A N D O M I S A T I O N Gem Gem Cap Cunningham et al, JCO 2009
CT in mpc Gem vs Gem-Capecitabine Median survival 12-month (months, 95%CI) survival GEM 6.0 (5.4, 7.1) 19% GEM-CAP 7.4 (6.5, 8.5) 26% Hazard Ratio: 0.80 (95% CI: 0.65, 0.98) Log rank p=0.026; χ 2 LR=4.93 Cunningham et al, ECCO 2005
CT in mpc Gem vs Gem-Capecitabine Cunningham; JCO 2009; n = 533 Gem Gem-Cap No of pts 266 267 Response rate invest 12% 19%* Median PFS invest (months) 3.8 5.3* Median survival (months) 6.2 7.1 PFS OS Cunningham et al, JCO 2009 Months Months
CT in mpc Gem vs Gem-Capecitabine Cunningham; JCO 2009; n = 533 Gem Gem-Cap No of pts 266 267 Response rate invest 12% 19%* Median PFS invest (months) 3.8 5.3* Median survival (months) 6.2 7.1 Cunningham et al., JCO 2009 & Hermann et al, JCO 2007 & Scheithauer et al, Ann Oncol 2003
CT in mpc Gem vs FOLFIRINOX Prodige 4 ACCORD11 2005-9 342 patients mpc PS 0-1 R A N D O M I S A T I O N Gem FOLFIRINOX FU + Iri + Ox Conroy et al., NEJM 2011; 364: 1817-25
CT in mpc Gem vs FOLFIRINOX Conroy; NEJM 2011; n = 342 Gem FOLFIRINOX No of pts 171 171 Response rate 9% 32%* Median PFS (months) 3.3 6.4* Median survival (months) 6.8 11.1* Conroy et al., NEJM 2011; 364: 1817-25
CT in mpc Gem vs Gem-Abraxane MPACT 2009-12 861 patients mpc PS 0-1 R A N D O M I S A T I O N Gem Gem Abraxane Von Hoff et al., NEJM 2013
CT in mpc Gem vs Gem-Abraxane Von Hoff; NEJM 2013; n = 861 Gem Gem-Abraxane No of pts 430 431 Response rate invest 8% 29%* Median PFS invest (months) 3.7 5.5* Median survival (months) 6.7 8.5* Von Hoff et al., NEJM 2013
Double chemotherapy in non-resectable PC OUH, 2012-14 1.0 Kaplan-Meier estimate of overall survival 0.8 0.6 0.4 0.2 12 0.0 0 6 12 18 24 30 Months from first series containing S1 Bjerregaard. Pfeiffer. WCGIC 2015
Phase III in non-resectabel PC Burris 1997 PRODIGE Conroy, 2011 MPACT Hoff, 2013 GemS1 OUH Variable Gem n = 63 5-FU n = 63 FOLFIRINOX n = 171 Gem n = 171 nab-p +Gem n = 431 Gem n = 430 GemS1 N=64 Age Median 62 61 61 61 62 63 68 0 0 0 37 39 58 62 25 PS, % 1 30 32 62 61 42 38 46 2 70 68 0 0 0 0 29 M1, % 72 76 all all 61 RR, % 5 0 31 9 29 7 30 PFS, mo 2.2 1 6.4 3.3 5.5 3.7 9.0 OS, mo 5.7 4.4 11.1 6.8 8.5 6.7 11.7
Danish guidelines Adjuvant therapy with 1 or 2 or 3 drugs?
Adjuvant CT in PC Single or combination RO or R1 R A N D O M I S A T I O N BSC Gem
Resectable PC Adjuvant chemotherapy ESPAC 1 Surgery S + CT No of pts 142 147 2 year survival, % 30 40* 5 year survival, % 8 21* Neoptolemos et al, NEJM 2004
Survival by Treatment: Adjuvant CT in PC ESPAC4 Single or combination
Adjuvant CT in PC Single or combination No Surgery 5 year OS ESPAC 1 143 8% 147 5FU 21% CONKO1 175 10% 179 Gem 21% ESPAC 3 551 5FU 16% 539 Gem 18% ESPAC 4 366 Gem 16% 364 GemCap 29%
Adjuvant CT in PC Single or combination ESPAC4 5YS 29 16 5YS JASPAC 44 24 Neoptolemos et al, ASCO 2016 Uesake et al, Lancet 2016
Adjuvant CT in PC Single or combination No Surgery 5 year OS ESPAC 1 143 8% 147 5FU 21% CONKO1 175 10% 179 Gem 21% ESPAC 3 551 5FU 16% 539 Gem 18% ESPAC 4 366 Gem 16% 364 GemCap 29% JASPAC 193 Gem 24% 192 S1 44%
Adjuvant therapy Adjuvant Surgery Gemcitabine Gem vs GemCap (ESPAC 4) Positive Gem vs S1 (JASPAC) Positive Gem vs GemAbraxane (APACT)? Gem vs FOLFIRINOX (ACCORD)?
Esophago-gastric adenocarcinoma (EGA) E EGJ G
Kirurgi alene er ikke godt nok ved EGA Supplerende behandling virker Asien Kirurgi US Kirurgi ACTS-GT (Japan) RT 5-FU S1 CLASSIC (Korea) Cap Ox INT-0116 & ARTIST Epirubicin Cisplatin FU CVI RT Carboplatin Paclitaxel EU Kirurgi Kirurgi MAGIC & FFCD CROSS Epirubicin Cisplatin FU CVI Sakuramoto et al. NEJM 2007 & Sasako et al, JCO 2011; Bang et al, Lancet 2012 MacDonald NEJM 2001; 345: 725-30; Cunningham NEJM 2006; 355: 11-20; Ychou et al, JCO 2011
Facts about additional therapy in resectable EGA Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM 2006 100% 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO 2011 100% 224 E / EGJ / G Peri CT > Surgery +14%
Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM 2006 100% 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO 2011 100% 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM 2007 100% 1059 G Post S1 > Surgery +11% CLASSIC Lancet 2012 100% 1035 G Post CapOx>Surgery +9%
Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM 2006 100% 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO 2011 100% 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM 2007 100% 1059 G Post S1 > Surgery +11% CLASSIC Lancet 2012 100% 1035 G Post CapOx>Surgery +9% Post-operative CRT ~ US INT 0116 NEJM 2001 100% 559 EGJ / G Post CRT > Surgery +15% ARTIST JCO 2015 100% 415 G Post CRT = Post CT -
Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM 2006 100% 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO 2011 100% 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM 2007 100% 1059 G Post S1 > Surgery +11% CLASSIC Lancet 2012 100% 1035 G Post CapOx>Surgery +9% Post-operative CRT ~ US INT 0116 NEJM 2001 100% 559 EGJ / G Post CRT > Surgery +15% ARTIST JCO 2015 100% 415 G Post CRT = Post CT - CRITICS ASCO 2016 100% 788 EGJ / G Peri CT = Peri CRT - Pre-operative CRT CROSS NEJM 2012 75% 366 E / EGJ Pre CRT > Surgery +13% POET JCO 2009 100% 119 EGJ Pre CRT > Pre CT +10% ICORG? 100% 366 E / EGJ MAGIC vs CROSS 15%
East vs West CRITICS ARTIST 75% 40% NL, S, DK N = 788 EGJ / G South Korea N = 458 G Verheij et al, ASCO 2016 Park et al, JCO 2015
Perioperativ EU strategi udfordres Epirubicin Cisplatin FU CVI MAGIC Kirurgi Epirubicin Cisplatin FU CVI CROSS 1.0 0.8 0.6 Overall survival 44% 34% 0.4 0.2 36% 23% RT Carboplatin Paclitaxel Kirurgi 0.0 0 1 2 3 4 5 Van Hagen et al, NEJM 2012 Cunningham et al, NEJM 2006
Perioperativ EU strategi udfordres Epirubicin Cisplatin FU CVI MAGIC Kirurgi Epirubicin Cisplatin FU CVI Neo-AEGIS or ICORG 10-14 N = 366 E / EGJ RT Carboplatin Paclitaxel CROSS Kirurgi Van Hagen et al, NEJM 2012 Cunningham et al, NEJM 2006
pcr OS FLOT x 4 16%- ECX x 3 6% - EGJ Al-Batran et al, ESMO 2015
FUTURE of EGA treatment? Pre-op CRT CROSS Pre-op therapy Selected by biology Pre-op triple CT FLOT DOS
Is IMAB362 (anti CLDN18.2 antibody) promising in EGA? Reference Name Age Line No Regimen MET Iveson et al Lancet Onc 2014 RR PFS OS HR % months months RILOMET 60 1 st 17 ECX 12 4.4 0.46 5.7 0.46 MET+ 61 41 ECX+Ril 50* 6.8* 10.6 HR Cunningham et al RILOMET-1 59 1 st 305 ECX 39* 5.7* 1.27 11.5* 1.36 ASCO 2015 MET+ 61 304 ECX + Ril 30 5.7 1.03-1.58 9.6 1.05-1.75 Shah et al MetGastric 58 1 st 283 FOLFOX+Pl 41 6.8 0.90 11.3 0.82 ASCO 2015 MET+ 59 279 FOLFOX + Ona 46 6.7 11.0 10.6 mo (+Ril) 11.5 mo (ECX) 5.7 mo (ECX) 9.6 mo (+Ril)
Thank you for your attention??
Slide 16
CALGB 80802: Overall Survival by Treatment
Immunotherapy KeyNote studies phase1/2 181 and 180 180: 3 line 181: 2. line P vs Tax 061 2. line P vs Tax 012 phase 1* 059 Cohort 1: 180 pts; PD-L1?, 3. line Pembro Cohort 2: 20+20 pts, PD-L?, 1. line Pembro + CF Cohort 3: 50 pts, 1. line, PD-L+ Pembro Muro et al, Lancet Oncol 2016, May e-pub Esophagus 180, 181 EGJ: 061 EGJ: 061 Gastric: 061 CheckMate 032 phase1/2 59 pts, ASCO GI 2016 RR 14%, mos ~ 6 mo, 12 mo 36%
Overall survival (%) Overall survival (%) OS comparison: ITT vs MET HIGH population 100 80 ITT population Rilotumumab + ECX (n = 82) Placebo + ECX (n = 39) 100 80 MET HIGH population Rilotumumab + ECX, MET HIGH (n = 27) Placebo + ECX, MET HIGH (n = 11) 60 60 40 40 20 20 0 0 0 1 2 3 4 5 6 7 8 9 101112131415161718 192021 222324252627 Months 0 1 2 3 4 5 6 7 8 9 1011 1213 1415 161718 192021222324 2526 Months Median months (80% CI) Rilotumumab + ECX 10.6 (9.5 12.0) Placebo + ECX 8.9 (5.7 10.6) HR = 0.70 (95% CI, 0.45 1.09) Median months (80% CI) Rilotumumab + ECX 11.5 (9.2 12.1) Placebo + ECX 5.7 (4.5 10.4) HR = 0.34 (95% CI, 0.15 0.78) Iveson et al, Lancet Onc 2014
Completed phase III trials in agea with biological agents Reference Name Age Line No Regimen MET Iveson et al Lancet Onc 2014 RR PFS OS HR % months months RILOMET 60 1 st 17 ECX 12 4.4 0.46 5.7 0.46 MET+ 61 41 ECX+Ril 50* 6.8* 10.6 HR Cunningham et al RILOMET-1 59 1 st 305 ECX 39* 5.7* 1.27 11.5* 1.36 ASCO 2015 MET+ 61 304 ECX + Ril 30 5.7 1.03-1.58 9.6 1.05-1.75 Shah et al MetGastric 58 1 st 283 FOLFOX+Pl 41 6.8 0.90 11.3 0.82 ASCO 2015 MET+ 59 279 FOLFOX + Ona 46 6.7 11.0 10.6 mo (+Ril) 11.5 mo (ECX) 5.7 mo (ECX) 9.6 mo (+Ril)
Overall Survival Presented By David Cunningham at 2015 ASCO Annual Meeting
Discontinuation of first-line chemotherapy (CT) after 6 weeks of CT in patients with metastatic squamous-cell esophageal cancer: A randomized phase II trial. Adenis et al. Presented By Peter Enzinger at 2016 ASCO Annual Meeting
Conclusion. 2 Presented By Peter Enzinger at 2016 ASCO Annual Meeting
Can these studies succeed when the others have failed? Presented By Peter Enzinger at 2016 ASCO Annual Meeting
Progression-Free Survival Presented By Jonathan Strosberg at 2016 ASCO Annual Meeting
Slide 16 Presented By Stephen Chan at 2016 ASCO Annual Meeting
CALGB 80802: Overall Survival by Treatment Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting