Per Pfeiffer, MD, PhD

Transcription

1 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

2 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

3 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

4 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

5 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

6 CT in mpc Gem vs Gem-Capecitabine Cunningham; JCO 2009; n = 533 Gem Gem-Cap No of pts Response rate invest 12% 19%* Median PFS invest (months) * Median survival (months) PFS OS Cunningham et al, JCO 2009 Months Months

7 CT in mpc Gem vs Gem-Capecitabine Cunningham; JCO 2009; n = 533 Gem Gem-Cap No of pts Response rate invest 12% 19%* Median PFS invest (months) * Median survival (months) Cunningham et al., JCO 2009 & Hermann et al, JCO 2007 & Scheithauer et al, Ann Oncol 2003

8 CT in mpc Gem vs FOLFIRINOX Prodige 4 ACCORD 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:

9 CT in mpc Gem vs FOLFIRINOX Conroy; NEJM 2011; n = 342 Gem FOLFIRINOX No of pts Response rate 9% 32%* Median PFS (months) * Median survival (months) * Conroy et al., NEJM 2011; 364:

10 CT in mpc Gem vs Gem-Abraxane MPACT 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

11 CT in mpc Gem vs Gem-Abraxane Von Hoff; NEJM 2013; n = 861 Gem Gem-Abraxane No of pts Response rate invest 8% 29%* Median PFS invest (months) * Median survival (months) * Von Hoff et al., NEJM 2013

12 Double chemotherapy in non-resectable PC OUH, Kaplan-Meier estimate of overall survival Months from first series containing S1 Bjerregaard. Pfeiffer. WCGIC 2015

13 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 PS, % M1, % all all 61 RR, % PFS, mo OS, mo

14 Danish guidelines Adjuvant therapy with 1 or 2 or 3 drugs?

15 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

16 Resectable PC Adjuvant chemotherapy ESPAC 1 Surgery S + CT No of pts year survival, % 30 40* 5 year survival, % 8 21* Neoptolemos et al, NEJM 2004

17 Survival by Treatment: Adjuvant CT in PC ESPAC4 Single or combination

18 Adjuvant CT in PC Single or combination No Surgery 5 year OS ESPAC % 147 5FU 21% CONKO % 179 Gem 21% ESPAC FU 16% 539 Gem 18% ESPAC Gem 16% 364 GemCap 29%

19 Adjuvant CT in PC Single or combination ESPAC4 5YS YS JASPAC Neoptolemos et al, ASCO 2016 Uesake et al, Lancet 2016

20 Adjuvant CT in PC Single or combination No Surgery 5 year OS ESPAC % 147 5FU 21% CONKO % 179 Gem 21% ESPAC FU 16% 539 Gem 18% ESPAC Gem 16% 364 GemCap 29% JASPAC 193 Gem 24% 192 S1 44%

21 Adjuvant therapy Adjuvant Surgery Gemcitabine Gem vs GemCap (ESPAC 4) Positive Gem vs S1 (JASPAC) Positive Gem vs GemAbraxane (APACT)? Gem vs FOLFIRINOX (ACCORD)?

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23 Esophago-gastric adenocarcinoma (EGA) E EGJ G

24 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: ; Cunningham NEJM 2006; 355: 11-20; Ychou et al, JCO 2011

25 Facts about additional therapy in resectable EGA Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM % 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO % 224 E / EGJ / G Peri CT > Surgery +14%

26 Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM % 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO % 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM % 1059 G Post S1 > Surgery +11% CLASSIC Lancet % 1035 G Post CapOx>Surgery +9%

27 Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM % 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO % 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM % 1059 G Post S1 > Surgery +11% CLASSIC Lancet % 1035 G Post CapOx>Surgery +9% Post-operative CRT ~ US INT 0116 NEJM % 559 EGJ / G Post CRT > Surgery +15% ARTIST JCO % 415 G Post CRT = Post CT -

28 Facts about additional therapy in resectable EG AdC Study Year AdC No Site Conclusion Δ 5YS Peri-operative CT ~ EU MAGIC NEJM % 503 E / EGJ / G Peri CT > Surgery +13% FFCD JCO % 224 E / EGJ / G Peri CT > Surgery +14% Post-operative CT ~ Asian ACTS-GC NEJM % 1059 G Post S1 > Surgery +11% CLASSIC Lancet % 1035 G Post CapOx>Surgery +9% Post-operative CRT ~ US INT 0116 NEJM % 559 EGJ / G Post CRT > Surgery +15% ARTIST JCO % 415 G Post CRT = Post CT - CRITICS ASCO % 788 EGJ / G Peri CT = Peri CRT - Pre-operative CRT CROSS NEJM % 366 E / EGJ Pre CRT > Surgery +13% POET JCO % 119 EGJ Pre CRT > Pre CT +10% ICORG? 100% 366 E / EGJ MAGIC vs CROSS 15%

29 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

30 Perioperativ EU strategi udfordres Epirubicin Cisplatin FU CVI MAGIC Kirurgi Epirubicin Cisplatin FU CVI CROSS Overall survival 44% 34% % 23% RT Carboplatin Paclitaxel Kirurgi Van Hagen et al, NEJM 2012 Cunningham et al, NEJM 2006

31 Perioperativ EU strategi udfordres Epirubicin Cisplatin FU CVI MAGIC Kirurgi Epirubicin Cisplatin FU CVI Neo-AEGIS or ICORG N = 366 E / EGJ RT Carboplatin Paclitaxel CROSS Kirurgi Van Hagen et al, NEJM 2012 Cunningham et al, NEJM 2006

32 pcr OS FLOT x 4 16%- ECX x 3 6% - EGJ Al-Batran et al, ESMO 2015

33 FUTURE of EGA treatment? Pre-op CRT CROSS Pre-op therapy Selected by biology Pre-op triple CT FLOT DOS

34 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 MET ECX+Ril 50* 6.8* 10.6 HR Cunningham et al RILOMET st 305 ECX 39* 5.7* * 1.36 ASCO 2015 MET ECX + Ril Shah et al MetGastric 58 1 st 283 FOLFOX+Pl ASCO 2015 MET FOLFOX + Ona mo (+Ril) 11.5 mo (ECX) 5.7 mo (ECX) 9.6 mo (+Ril)

35 Thank you for your attention??

36 Slide 16

37 CALGB 80802: Overall Survival by Treatment

38 Immunotherapy KeyNote studies phase1/2 181 and : 3 line 181: 2. line P vs Tax line P vs Tax 012 phase 1* 059 Cohort 1: 180 pts; PD-L1?, 3. line Pembro Cohort 2: 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%

39 Overall survival (%) Overall survival (%) OS comparison: ITT vs MET HIGH population ITT population Rilotumumab + ECX (n = 82) Placebo + ECX (n = 39) MET HIGH population Rilotumumab + ECX, MET HIGH (n = 27) Placebo + ECX, MET HIGH (n = 11) Months Months Median months (80% CI) Rilotumumab + ECX 10.6 ( ) Placebo + ECX 8.9 ( ) HR = 0.70 (95% CI, ) Median months (80% CI) Rilotumumab + ECX 11.5 ( ) Placebo + ECX 5.7 ( ) HR = 0.34 (95% CI, ) Iveson et al, Lancet Onc 2014

40 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 MET ECX+Ril 50* 6.8* 10.6 HR Cunningham et al RILOMET st 305 ECX 39* 5.7* * 1.36 ASCO 2015 MET ECX + Ril Shah et al MetGastric 58 1 st 283 FOLFOX+Pl ASCO 2015 MET FOLFOX + Ona mo (+Ril) 11.5 mo (ECX) 5.7 mo (ECX) 9.6 mo (+Ril)

41 Overall Survival Presented By David Cunningham at 2015 ASCO Annual Meeting

42 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

43 Conclusion. 2 Presented By Peter Enzinger at 2016 ASCO Annual Meeting

44 Can these studies succeed when the others have failed? Presented By Peter Enzinger at 2016 ASCO Annual Meeting

45 Progression-Free Survival Presented By Jonathan Strosberg at 2016 ASCO Annual Meeting

46 Slide 16 Presented By Stephen Chan at 2016 ASCO Annual Meeting

47 CALGB 80802: Overall Survival by Treatment Presented By Ghassan Abou-Alfa at 2016 ASCO Annual Meeting