Adjuvant treatment for stage II and III Colon Cancer. Ramon Salazar Catalan Institute of Oncology

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1 Adjuvant treatment for stage II and III Colon Cancer Ramon Salazar Catalan Institute of Oncology

2 Disclosures R. Salazar has served in a consultant or advisory role for Amgen, Merck Serono, Taihoo, MSD, Lylli, BMS, Roche Dx and enjoyed research funding for Roche Dx, Roche Pharma and Merck Serono

3 Outline History (recent ) Key Trials Stage II 3 vs 6 months (Stage III) Elderly

4 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) 1990

5 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) FU/LV better than surgery alone (IMPACT) 1994

6 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) 1990 HDLV = LDLV 5-FU/LV better than 5-FU/Lev 6mo = 12mo Lev unnecessary Weekly = monthly FU/LV better than surgery alone (IMPACT) 1994

7 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) 1990 HDLV = LDLV 5-FU/LV better than 5-FU/Lev 6mo = 12mo Lev unnecessary Weekly = monthly FU/LV better than surgery alone (IMPACT) 1994 LV5FU2 = monthly bolus (André et al) 2002

8 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) 1990 HDLV = LDLV 5-FU/LV better than 5-FU/Lev 6mo = 12mo Lev unnecessary Weekly = monthly 1998 FOLFOX better than LV5FU2 (MOSAIC) FLOX better than 5-FU/LV (NSABP C-07) 2004/ FU/LV better than surgery alone (IMPACT) 1994 LV5FU2 = monthly bolus (André et al) 2002

9 The evolution of treatment of early colon cancer 5-FU/Lev better than surgery alone (Moertel et al) 1990 HDLV = LDLV 5-FU/LV better than 5-FU/Lev 6mo = 12mo Lev unnecessary Weekly = monthly 1998 FOLFOX better than LV5FU2 (MOSAIC) FLOX better than 5-FU/LV (NSABP C-07) 2004/ FU/LV better than surgery alone (IMPACT) FULV2 = monthly bolus (André et al) 2002 Xeloda 5-FU/LV (X-ACT) 2008 XelOx better than 5-FU/LV (NO16968) 2009

10 OS estimate OS estimate Adjuvant therapy increases the chance of survival: evidence in 20,898 CC patients (ACCENT 18 trials 5FU based) Stage II CC Stage III CC p= p< Surgery alone 8-year OS rate (95% CI): 66.8% (63.7% to 70.0%) Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 72.2% (69.3% to 75.2%) Follow-up time (years) CC=colon cancer OS=overall survival Surgery alone 8-year OS rate (95% CI): 42.7% (39.9% to 45.7%) Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 53.0% (50.2% to 55.9%) Follow-up time (years) Sargent, et al. JCO 2009

11 Early DFS predicts long-term survival after adjuvant therapy 2- and 3-year DFS predicts 5- and 6-year overall survival Correlation stronger in patients with stage III disease Correlation coefficient Overall survival (all patients) Overall survival (stage III disease) DFS 5-year 6-year 5-year 6-year 2-year year = perfect correlation Sargent et al. ASCO 2009

12 Key trials in the 21 st century X-ACT Xeloda vs 5FU bolo (Mayo) MOSAIC FOLFOX4 vs LV5FU2 infusion NSABP C-07 FLOX vs 5FULV bolus NO16968 XELOX vs 5FULV bolus (500 mg/m2 weekly x6/8 wk RPark) CALGB 89803, ACCORD 2, PETACC-3 5FU vs FOLFIRI NSABP C-08 mfolfox6 vs mfolfox6 + Bevacizumab AVANT FOLFOX4 vs FOLFOX4 + Avastin vs XELOX + Bevacizumab QUASAR-2 Capecitabine ± bevacizumab PETACC 8 Cetuximab + Folfox vs Folfox NCCTG (North Central Cancer Treatment Group) N0147 trial. Cetuximab + FLOX vs FLOX

13 Phase III Capecitabine vs bolus IV 5-FU/LV in adjuvant colon cancer (randomized) (X-ACT) M66001 Fully resected Stage III colon cancer < 8 weeks prior to study entry R A N D O Capecitabine twice-daily 1250 mg/m 2, D1-14 Q3W Ability to be followed > 5 years after the last patient is randomized M IZ A TI O N Leucovorin 20 mg/m 2 IV, D1-5 Q4W 5-FU 425 mg/m 2 IV bolus, D1-5 Q4W Primary endpoint: Planned sample size: Non-Inferiority in Disease-Free Survival 1956 pts

14 non- inferiority proven & trend to superior DFS with Capecitabine Estimated probability year DFS (%) Xeloda (n=1004) FU/LV (n=983) HR=0.88 (95% CI: ) p= ITT population Absolute difference at 5 years: 4.1% Years Twelves et al. ASCO GI 2008

15 trend to superior OS with Capecitabine Estimated probability year overall survival (%) Xeloda (n=1004) FU/LV (n=983) HR=0.86 (95% CI: ) p= Absolute difference at 5 years: 3.0% Years ITT population Twelves et al. ASCO GI 2008

16 X-ACT: safety Patients (%) Grade 3/4 AEs Xeloda (n=993) 5-FU/LV (n=974) 10 0 * * * * *p<0.001 Scheithauer et al. Ann Oncol 2003

17 Capecitabine is more toxic than infusional LV5FU

18 Seymour et al.

19 3 Adjuvant Trials with 5FU + Oxaliplatin Trial N Pts Treatment Data MOSAIC (NEJM 2004, ASCO 2005, ASCO 2007) Stage II/III 2246 FOLFOX-4 x 6 mos LV5FU2 x 6 mos 5-y DFS 6-y OS NSABP C-07 (JCO 2007) Stage II/III 2407 FLOX x 6 mos Bolus 5FULV w x 6 mos 6-y DFS 6-y OS NO16968 (JCO 2007, ECCO-ESMO 2009) Stage III 1886 XELOX x 6 mos Bolus 5FULV w/q4w x 6 mos 5-y-DFS (DFS 4-y ECCO-ESMO 2009)

20 MOSAIC: Treatment arms FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m² D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2 LV 200 mg/m2 LV 200 mg/m2 5-FU 22h 600 mg/m2 5-FU 22h 600 mg/m2 stage II/III colon cancer R OXA D1 5FU bolus 400 mg/m2 D2 5FU bolus 400 mg/m2 LV5FU2 LV 200 mg/m2 5-FU 22h 600 mg/m2 LV 200 mg/m2 5-FU 22h 600 mg/m2 Cada 2 semanas, 6 meses de tratamiento (12 ciclos)

21 MOSAIC: treatment administration FOLFOX4 LV5FU2 Pacientes aleatorizados Pacientes tratados Número total de ciclos Media/Mediana ciclos 74.7% 86.5% Intensidad de dosis relativa mediana % Oxaliplatino 81 NA 5-FU 85 98

22 PFS (ITT) Probabilidad 1 0,9 3-años FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9% 0,8 0,7 0,6 HR: 0.77 [ ] p < , André et al. NEJM 350;

23 PFS Stage III Probabilidad 1 0,9 3-años FOLFOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5% 0,8 0,7 0,6 0,5 HR: 0.76 [ ] André et al. NEJM 350;

24 MOSAIC and NSABP C-07 Stage II and III (ITT) OS updated results with longer f-up DFS: 61.7 vs 67.5 HR = 0.82 (95% CI, ) DFS: 64.2 vs 69.4 HR = 0.82 (95% CI, ) André et al., JCO 2015; Yothers et al., JCO 2011

25 MOSAIC: safety NCI Gr 3 % FOLFOX4 LV5FU2 (n=1108) (n=1111) Trombocitopenia Neutropenia 41.0 ( Gr 4: 12.2) 4.7 Neutropenia Febril Sepsis Neutropénica Diarrea Estomatitis Vómitos Alergia Alopecia (Gr2) Neurosensory Mortalidad por cualquier causa

26 Adjuvant XELOX vs 5-FU/LV: NO16968 (XELOXA) Phase III trial Chemo/ radiotherapy-naive stage III colon 8 weeks since resection N=1886 R A N D O M I S A T I O N n=944 n=942 XELOX (6 months) capecitabine 1000mg/m 2 bid d1 14 oxaliplatin130mg/m 2 d1 q3w 8 cycles Bolus 5-FU/LV (6 months) Mayo Clinic [n=664] or Roswell Park [n=278] Primary endpoint: superiority of DFS Secondary endpoints: RFS, OS, tolerability Haller et al. ECCO-ESMO 2009

27 5-year DFS: benefit with XELOX maintained and increased over time 3-year DFS 4-year DFS 5-year DFS 1.0 XELOX 5-FU/LV 70.9% 68.4% 66.5% 62.3% 66.1% 59.8% Δ at 3 years: 4.5% HR=0.80 (95% CI: ) p= Δ at 4 years: 6.1% Δ at 5 years: 6.3% Years ITT population

28 Trend to improved OS with XELOX XELOX 5-FU/LV 5-year OS 77.6% 74.2% 0.6 Δ at 5 years: 3.4% HR=0.87 (95% CI: ) p= Years ITT population

29 Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 1.0 NO16968 (XELOXA)* 5-yr OS XELOX (n=944) 77.6% MOSAIC 1 ** FOLFOX4 (n=672) 6-yr OS 72.9% Years *Median observation time: 57.0 months **Median follow-up: 81.9 months ITT population 1. André et al. JCO 2009

30 Safety Grade 3/4 AEs (%) XELOX n=938 5-FU/LV n=926 Febrile neutropenia Neutropenia Diarrhoea Stomatitis Nausea Vomiting HFS Neurosensory Schmoll et al. JCO 2007

31 Cross-trial comparison with MOSAIC Grade 3/4 AEs (%) XELOX n=938 FOLFOX4 (MOSAIC)* n=1108 Febrile neutropenia Neutropenia Diarrhoea Stomatitis Nausea Vomiting HFS Neurosensory Schmoll et al. JCO 2007 *MOSAIC trial: André et al. NEJM 2004

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33 Stage II testing Les meves de ESMO I ESMO GI 2016 Les de la sessio ESMO 2017 del pavo angles

34 QUASAR Gill et al., JCO 2004; Quasar Col Group, Lancet 2007;

35 Introducción Mayor beneficio, pero limitado, en el grupo de pacientes con cáncer de colon estadio II de alto riesgo Factores de mal pronóstico ASCO pt4, alto grado histológico, perforación, ganglios analizados < 13 AJCC ESMO NIH pt4, alto grado histológico, invasión vascular, linfática o perineural, CEA preoperatorio elevado, margen radial afectado pt4, alto grado histológico, obstrucción o perforación, ganglios analizados < 12, invasión vascular, linfática o perineural pt4, alto grado histológico o diferenciación coloide o en anillo de sello, CEA preoperatorio elevado, aneuploidía, delección de 17p o 18q, fase S proliferación elevada Benson et al., JCO 2004; Compton et al., Cancer 2000; Labianca et al.,ann Oncol 2010; JAMA 1990

36 T4MSI Variable HR (95%, CI) T stage (T4 vs T3) 1.73 ( ) No of LN examined 0.79 ( ) MSI (MSI-H vs MS-L/S) 0.54 ( ) BRAF 1.17 ( ) KRAS 1.05 ( ) Variable HR (95%, CI) T stage (T4 vs T3) 1.94 ( ) No of LN examined 0.73 ( ) MSI (MSI-H vs MS-L/S) 0.43 ( ) BRAF 1.56 ( ) KRAS 1.10 ( ) Roth et al., J Natl Cancer Inst 2012

37 Addition of OXL is not supported in Stage II (MOSAIC and NSABP C-07) DFS: 73.6 vs 75.2 HR = 0.89 (95% CI, ) DFS: 80.1 vs 82.1 HR = 1.04 (95% CI, ) André et al., JCO 2015; Yothers et al., JCO 2011

38 What s the question in Stage III

39 IDEA: adjuvant 3 vs 6 months Folfox/Xelox

40 IDEA Trials Summary Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

41 Non-inferiority Hypothesis Testing Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

42 Results: RFS/DFS Overall Population Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

43 Primary Efficacy Analysis Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

44 Primary DFS Analysis (mitt), cont. Presented By Qian Shi at 2017 ASCO Annual Meeting

45 DFS Comparison by Risk Groups, cont. Presented By Qian Shi at 2017 ASCO Annual Meeting

46 DFS Comparison by Regimen, cont. Presented By Qian Shi at 2017 ASCO Annual Meeting

47 DFS Comparison by Risk Group and Regimen Presented By Qian Shi at 2017 ASCO Annual Meeting

48 DFS Comparison by Risk Group and Regimen, cont. Presented By Qian Shi at 2017 ASCO Annual Meeting

49 CÁNCER COLORRECTAL Grothey A, et al. LBA21. ESMO 2017

50 What about the elderly population Do they need or deserve the same treat Sharper Balance toxicity-efficacy and life expectancy

51 ACCENT DATABASE 5FU CHX Sargent et al, 2001

52 Upper limit 75y as per inclusion criteria female patients years had the same oxaliplatin benefit as younger patients DFS and OS benefits in patients years were similar to those of younger patients for the first 3 years of follow-up, but were lost later on due to deaths from other causes.

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56 Oral capecitabine improved outcomes when compared with bolus 5-FU/LV in the X-ACT trial in patients 70 years

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58 Summary of the evidence LV5FU2 vs bolus 5FULV vs capecitabine LV5FU2 infusion non-inferior and better safety Capecitabine non-inferior (maybe better) than bolus 5FULV, better safety than bolus, but worse than LV5FU2 Oxaliplatin Folfox/Xelox adds both efficacy and toxicity in stage III Stage II high risk (T4MSS): 5FULV2 (or capecitabine) 3 months Xelox is an option in low risk stage III (T3N1) Elderly Balance between life expectancy, efficacy and safety Geriatric assesment

59 Questions?

60 Questions? 75 y-old female T4N1 No comorbidities, good surgical recovery PS 0 How would you treat her

61 Questions? 75 y-old male T4N0 No comorbidities PS 0 How would you treat him

62 Questions? 75 y-old male T4N0 No comorbidities PS 0 How would you treat him If MSI?

63 Prognostic signatures in early-stage CRC <br />are not predictive of chemotherapy benefit Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting

64 Prognosis in early-stage CRC is dictated by microenvironment features Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting

65 Slide 29 Presented By Rodrigo Dienstmann at 2017 ASCO Annual Meeting