Unresectable or boarderline resectable (Groupp 1) chemotherpy +/- targeted agents

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1 ESMO Preceptorship Program March Singapore Unresectable or boarderline resectable (Groupp 1) chemotherpy +/- targeted agents Claus-Henning Köhne Klinik für Onkologie und Hämatologie North West German Cancer Center (NWTZ)

2 ESMO approach: Grouping of patients Liver / Lung limited disease Curative approach resectable unresectable ESMO Group 0 ESMO Group 1 Supported by randomised trials

3 Resectable LLD but high risk of recurrence Age 51y Rectal Adeno-Ca: ct3, N+ Synchroneous LLD, ø 12 cm CEA 568 ng/ml >12cm

4 Resectable LLD but high risk of recurrence Fong Score Primary tumor N + DFI < 12 Monate > 1 Metastasis > 5 cm CEA > 200 ng/ml >12cm Age 51y Rectal Adeno-Ca: ct3, N+ Synchroneous LLD, ø 12 cm CEA 568 ng/ml High Fong Score Estimated 5y < 10%

5 Group 0 Resectable metastases Primary tumor N + DFI < 12 Monate > 1 Metastasis > 5 cm CEA > 200 ng/ml Fong score > 2 Disease specific survival (DSS)

6 Adjuvant systemic chemotherapy of CLM: Overall survival Combined analysis FFCD / EORTC trial 5-FU/FA Overall survival FOLFIRI 1.00 Treatment HR=0.89: 95%CI [ ] Probability year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51% Months Number at risk LV5FUs LV5FUs+IRI LV5FUs adjusted Logrank p=0.43 LV5FUs+IRI Mitri et al. JCO 2008 Ychou et al. ASCO 2008

7 EORTC 40983: PFS irrespective of resection (usual definition), all patients, updated May25, 2009 Group 0 Resectable metastases R FOLFOX -> OP -> FOLFOX OP Overall Logrank test: p=0.026 PFS = DFS? (years) O N Number of patients at risk : Treatment Surgery Pre&Postop C

8 Progression-free survival in eligible patients 100 HR= 0.77; CI: , p= Periop CT +8.1% At 3 years Surgery only 36.2% 28.1% (years) O N Number of patients at risk : Nordlinger et al. Lancet 2008

9 Progression-free survival in eligible patients MOST LIKELY BENEFIT Borderline resectable pts? High proliferative tumors? MOST LIKELY NO BENEFIT Easily resectable? Fong score 0-2? (years) O N Number of patients at risk : Nordlinger et al. Lancet 2008

10 Group 0 Resectable metastases New EPOC study Neoadjuvant FOLFOX +/- Cetuximab in LLD Primrose et al. Lancet Oncol 2014

11 Liver limited diesase: Patient selection EPOC New EPOC Surgery Chemo Chemo Inclusion Definitely resectable Definitely and suboptimal resectable N Lesions Maximum 4 unlimited unresectable 10% 4% 12-19% Köhne JCO accepted for publication

12 Liver limited diesase: Patient selection Clearly resectable Chemotherapy adjuvant to surgery Borderline resectable Definitely NOT resectable Surgery adjuvant to chemotherapy

13 Potential disadvantage of effective neoadjuvant chemotherapy inresectable liver metastases CT/MRI prior chemo CT/MRI after chemo prior surgery Non - visible on CT/MRI, potentially visible during operation Visible on CT/MRI Köhne JCO accepted for publication

14 New EPOC is considered as a national embarrassment (Graeme Poston) The PFS difference in New EPOC is a most likely a nonrelevant and biased artefact. (Köhne JCO 2015 accepted) New EPOC is a failed trial of no relevance to the licensed indication for Erbitux (European Medicine Agency)

15 ESMO approach: Grouping of patients Liver / Lung limited disease Curative approach resectable unresectable ESMO Group 0 ESMO Group 1 Supported by randomised trials

16 Case: Male 44 y, sigmoid adenocarcinoma well until 4 months ago, PS 2 weight loss ~ 5 Kg within last 3 months grossly enlarged palpable liver abdominal US: difuse hypodensic liver leasons CT scans: Synchroneous diffuse liver metastases LDH elevated, WBC /dl Bilirubin normal, LFT < 4x ULN

17 Case: Male 44 y, 05/06 Base line 05/06-11/06 FOLFIRI + Cetux 11/06-03/07 FOLFOX + Cetux PS 2 PS 0 liver mets operable primary tumor pcr + 5 kg mets not operable Patient died 02/15

18 Group 1 Potentially resectable metastase s Secondary liver resection rates and tumour response: 25 prospective studies Folprecht G.Köhne CH et al. Ann Oncol 2005; 16: Jones R et al. Eur J Cancer, 2014 Pre-defined resectability R 2 = 0.62 p = High response rate Patient selection Multidisciplinary team (MDT) Resectability defined Resectability not defined size of square denotes size of population studied 15/04/2015 Rates of secondary liver resection versus response to chemotherapy: Resectability clearly defined Resectability not clearly defined

19 FOLFIRI vs. FOFOXIRI Regimen N RR Author FOLFIRI % Falcone FOLFOXIRI % JCO 2007 FOLFIRI+Bev % Falcone FOLFOXIRI+Bev % NEJM 2015 FOLFOXIRI more effective than FOLFIRI Unproven role of bevacizumab

20 Secondary endpoint: Resection of Metastases The GONO experience FOLFIRI N=122 FOLFIRI + bev Arm A N = 256 FOLFOXIRI N=122 FOLFOXIRI + bev Arm B N = 252 P (comparison of bev arms) Secondary surgery with radical intent 21% 26% R0 secondary surgery 8% 12% 15% 15% Liver-only subgroup N = 46 N = 59 Secondary surgery with radical intent 41% 39% R0 secondary surgery 12% 28% 36% 32% 0.823

21 Randomised trials of EGFR antibodies 1 st line k-ras exon 2 wt only European & Asian experience Trial Therapy ORR CRYSTAL (n=666) FOLFIRI +/- Cetux 40% vs. 57% Infusional Chinese * (n=138) FOLFIRI or FOLFOX+/- Cetux 40% vs. 57% 5FU PRIME (n=656) FOLFOX +/- Pani 48% vs. 57% OPUS (n=197) FOLFOX +/- Cetux 34% vs. 57% Bolus 5FU COIN (n=729) XELOX/FOLFOX +/- Cetux 57% vs. 64% Cape NORDIC (n=194) FLOX +/- Cetux 47 vs. 46% sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only

22 CRYSTAL: Resection rates by country Worked within MDTs No MDT working Country No. Pts Resections Data on file

23 Group 1 Potentially resectable metastases Chinese randomized trial in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab Ye et al. JCO 2013

24 Group 1 Potentially resectable metastases CELIM: R0 Resection as a surgical maintenance therapy in the continuum of care Progression free survival Overall survival R0 resected: %CI: Not R0 res.: %CI: HR 2.10 [ ] p<0.001 R0 resected: %CI: Not R0 res.: %CI: HR 2.25 [ ], p= y-OS: 45.8% few patients without relaps Update CELIM 12/2012, ASCO 2013

25 Group 1 Potentially resectable metastases Randomized trials in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab METHEP Chinese study CELIM OLIVIA FOLFIRI/F OLFOX ~30 FOLFOXIRI N=30 FOLFIRI/FOL FOX N=68 CT + Cet N=70 FOLFIRI/F OLFOX + Cet N=67 FOLFOX + Bev N=39 FOLFOXIRI + Bev N=41 RR ~60 73% 40% 57% 70% 62% 81% R0 resection ~23 30% 7% 26% 33% 31% 54% OS all pts (mo) OS resected pts (mo) ~ NR Ychou Ann Surg Oncol 2013; Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010; Gruenberger Ann Oncol 2015

26 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % Non-Caucasian, % Achieve NED: FOLFOX, %* Prior Radiation, %* / Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

27 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Palliative intent, % curative intent % 13.6% 17.5% curative intent N Resected NED (R0) N Pat Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % Liver metastases only, % *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132

28 CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm Chemo + Bev Chemo + Cetux N (Events) 50(15) 82(30) Median HR (95% CI) (95% CI) 67.4 (50.6-NA) ( ) ( ) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy

29 Chemotherapy : Optimal timing? Clearly resectable Borderline resectable Chemotherapy adjuvant to surgery? Individual discussion Definitely NOT resectable Surgery adjuvant to chemotherapy

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31 CELIM 2 Köhne JCO accepted for publication

32 CRC liver metastases a continuum of clinical presentation Resectable technically resectable unresectable (low risk) but high risk for relaps 2 cm single > 5 mets > 5 cm etc. Surgery peri-operative Ctx conversion CTx Neo/Adjuvant CTx? (CTx+/- Cetux?) (achieve high RR) FOLFOXIRI FOLFIRI+EGFR FOLFOX + EGFR (p)cr a problem? no wait until mets come back

33 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % Non-Caucasian, % Achieve NED: FOLFOX, %* Prior Radiation, %* / Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

34 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Age, years Median (range) 59 (21 85) 59 (20 89) 55 (24 82) 55 (21 79) Male, % Non-Caucasian, % FOLFOX, %* Prior Radiation, %* Prior Adjuvant Chemotherapy, %* Palliative intent, % Primary in place, % Liver metastases only, % *Stratification Factor

35 CALGB/SWOG 80405: Baseline Characteristics Resected Patients Characteristic Kras WT codons 12/13 n=1137 Chemo + Bev n=559 Chemo + Cetux n=578 Chemo + Bev n=75 Resected Pts n=180 Chemo + Cetux n=105 Palliative intent, % curative intent % 13.6% 17.5% curative intent N Resected NED (R0) N Pat Resected NED (R0) % 8.0% 11.4% 60.0% 62.8% Primary in place, % Liver metastases only, % *Stratification Factor Discrepance of numbers: Resected NED =111; Resected achieved NED=132

36 CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm Chemo + Bev Chemo + Cetux N (Events) 50(15) 82(30) Median HR (95% CI) (95% CI) 67.4 (50.6-NA) ( ) ( ) p 0.56 Most pts were resectable upfront, thus surgery is the main driver or survival rather than pre-op chemotherapy

37 Potential impact of type and duration of chemotherapy on surgery Mortality rate not increased Morbidity rate related to the number of cycles of CT Steatohepatitis Sinusoidal distention Karoui Nordlinger et al, Ann.Surg Vauthey et al. JCO 2006

38 Impact of pathological response after chemotherapy on survival 1st line: 66% CPR: 29/738 (4%) FOLFOX: 6% Adam et al, JCO st line: 100% CPR total : 25/271 (9%) FOLFOX : 12% FOLFOX + Bev: 8.6% Blazer et al, JCO 2008

39 Evaluation of ORR Primary analysis FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p ITT population (N= 592) Assessable for response (N= 526) p = Fisher s exact test (one-sided) Heinemann V- et al J Clin Oncol 31, 2013 (suppl; abstr LBA3506)

40 Evaluation of ETS Rate (Early Tumor Shrinkage) Rate of Early Tumor Shrinkage* CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 wt n= ( ) Final RAS wt n= ( ) *ETS: early tumor shrinkage 20% at 6 weeks p = Fisher s exact test (two-sided)

41 Evaluation of Depth of Response (DpR*) FOLFIRI + Cetuximab FOLFIRI + Bevacizumab median DpR % SE % SE p KRAS exon 2 wt n= (±54.6%) (± 44.3%) Final RAS wt n= (±54.8%) % (± 42.3%) < Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test) *DpR: percentage of maximal tumor shrinkage observed at the nadir compared with baseline SE = standard error; p = two-sided Wilcoxon test p

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43 Rate of resection in LLD and no formal MDT prior chemo NO16966 N R0 CTx + bevacizumab % CTx + placebo % CRYSATL (KRAS wt) FOLFIRI+Cetuximab % FOLFIRI % Okines et al. BJC 2009 Köhne etal. WCGIC 2011

44 Colorectales - Ca R0 Resection of Metastases Controversy: Adjuvant Therapy? USA Yes (Kemeny NEJM 1999) Europa No (Lorenz NEJM 200)

45 Liver metastases: adjuvant HAI + i.v. CTX p=0.02 Median overall survival Fong 0-2 Fong 3-5 HAI+systemic 83.3 mo 60.0 mo (10y: 38.7%) systemic 82.8 mo 38.3 mo (10y: 16.3%) p=0.13 Kemeny et al NEJM 1999 and 2005

46 Adjuvant chemotherapy after liver resection Majo clinic regimen vs. Observation (n=171) FFCD ACHBTH AURC 9002 Trial Disease free survival Overall survival Cox multivariat Analysis p=0.028 n.s. Portier et al. JCO 2006

47 - Curative approach in k-ras wt tumors Arguments disfavouring CapeOX or VEGF antibodies : Higher RR for FOLFOX vs.capeox No increase in RR if Beva is added to FOLFOX or CapeOx Investigator report IRC data Chemo+ Chemo placebo + Bev FOLFOX+ FOLFOX placebo + Bev XELOX+ XELOX placebo + Bev 49% 47% 50% 47% 48% 46% p = 0.90 p = 0.88 p = % 38% 36% 38% 39% 37% p = 0.99 p = 0.49 p = 0.48 Potential bleeding and wound healing complications

48 Questions to CALGB in resected patients 1. Liver limited disease pts obviously only 50% of all resected pts. Which metastases were resected in the other half? Primary tumor +/- liver metastases? If so, this is not the usual patient with metastatic disease entering a trial to improve median survival 2. Number of pts with curative intent nearly equal those who were later resectable. Where these pts resectable upfront? And why have they not been resected? 3. How was curative intend defined? By investigator or by multidisciplinary team? 4. Curative intent at baseline higher for Cetuximab arm. 5. Discrepance of numbers: Resected NED =111 but Resected achieved NED=132

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50 Group 1 Potentially resectable metastases Randomized trials in patients with non resectable k-ras exon 2 wt CRC LLD Chemotherapy +/- Cetuximab METHEP Chinese study CELIM OLIVIA FOLFIRI/ FOLFOX ~30 FOLFOXIRI N=30 FOLFIRI/FO LFOX N=68 CT + Cet N=70 FOLFIRI/F OLFOX + Cet N=67 FOLFOX + Bev N=39 FOLFOXI RI+Bev N=41 RR ~60 73% 40% 57% 70% 62% 81% R0 resection ~23 30% 7% 26% 33% 31% 54% OS all pts (mo) OS resected pts (mo) ~ NR OS non resected pts Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010

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52 Response rates = resection rates? CT CT + Erbitux Response (%) p< p= Why? R0 resection (%) p= p= CRYSTAL (KRAS wt) OPUS (KRAS wt) 0 CELIM (KRAS wt) 0 POCHER (ITT)* Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Folprecht G, et al. EMCC 2011 (Abstract 6009); Garufi C, et al. Br J Cancer 2010;103:

53 Comparison of process and liver resection rates in Erbitux trials in liver limited kras WT studies Study CRYSTAL Who recruited? Entry by general oncologist % RR Erbitux arm Treatment with Erbitux RR 70% Who determined liver resectability? Decision on liver resection by general oncologist Liver resection rate Erbitux arm 13% OPUS Entry by general oncologist Treatment with Erbitux RR 75% Decision on liver resection by 16% general oncologist CELIM Entry by MDT with Liver Surgeon Treatment with Erbitux RR 70% Decision on liver resection by MDT 34% with Liver Surgeon POCHER Entry by MDT with Liver Surgeon Treatment with Erbitux RR 78% Decision on liver resection by MDT 60% with Liver Surgeon Liver surgeons MUST work with medical oncologists from the outset if these outcomes are to be reproduced