What to do after 1 st line failure?

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1 ESMO Preceptorship Programme Colorectal Cancer Prague July 6-7 th 2016 JY Douillard MD PhD What to do after 1 st line failure?

2 mcrc: How to maximize survival? Improving 1st line therapy efficacy- and selecting the best treatment for the individual patient Usingthe chanceforcure byresectionof metastases(and other local ablative treatments) Using the continuum of care with optimizing treatment at different lines Van Cutsem, Cervantes, Nordlinger& Arnold; Ann Oncol2014 ESMO PRECEPTORSHIP PROGRAM

3 A semantical issue: Notion of line, how to define progression Improved efficacy in 1st line ORR 50% DCR 80% PFS 8-10 m Cumulative toxicity, patients desire Strategies to preserve QoL Maintenance Stop and GO Re-introduction OS 30 m: Most of the patients will receive several lines

4 Strategic scenarios in the continuum of care of metastatic colorectal cancer. E. Van Cutsem et al. Ann Oncol 2014;25:iii1-iii9

5 Conventional and nonconventional (drug rechallenge and treatment beyond progression) therapy regimens in medical oncology Kuczynski, E. Kuczynski, A. et al. E. (2013) A. et al. Drug (2013) Drug rechallenge and treatment beyond beyond progression implications for drug for drug resistance Nat. Rev. Clin. Oncol. Oct 2013;10: Nat. Rev. Clin. Oncol. Oct 2013;10:

6 S. R. Berry et al. Ann Oncol 2015;26:

7 Meta-analysis for overall survival: all trials. S. R. Berry et al. Ann Oncol 2015;26: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please oup.com

Sequential 1 st and 2 nd Line Combinations Randomized, multicentric, open-label, prospective, phase III trial Arm A FOLFIRI until progression FOLFOX6 until progression R CPT-11

8 Sequential 1 st and 2 nd Line Combinations Randomized, multicentric, open-label, prospective, phase III trial Arm A FOLFIRI until progression FOLFOX6 until progression R CPT mg/m 2 IV + simplified LV5FU Arm B FOLFOX6 until progression FOLFIRI until progression Oxaliplatin 100 mg/m 2 IV + simplified LV5FU Tournigand at al. J Clin Oncol 2004; 22: 23-30

9 Efficacy Arm A Arm B FOLFIRI FOLFOX FOLFOX FOLFIRI P n ORR (CR) % 53 (3) (5) ORR+SD % Median TTP Median surv Progressionfree at 15 mo 49 40

10 Efficacy Endpoints Time to progression in 1 st line Time to progression in 2 nd line Probability Median (months) Folfiri 8.5 Folfox 8.1 Logrank p = 0.21 Probability Median (months) Folfiri 2.5 Folfox Months Months

11 Outcome of Targeted Agents according to chemotherapy backbone

12 WJOG 4407G: Study design mfolfox6 + bevacizumab (n = 198) mccr 1 st line years PS 0-1 (n = 395)* R 1:1 Oxaliplatin 85 mg/m 2 (iv 2h) Leucovorin 200 mg/m 2 (iv 2h) 5-FU 400 mg/m 2 (iv bolus) 5-FU 2400 mg/m 2 (iv 46h) Bevacizumab 5 mg/kg (iv 0,5-1,5h) FOLFIRI + bevacizumab (n = 197) Q 2 weeks Irinotecan 150 mg/m 2 (iv 1,5h) Leucovorin 200 mg/m 2 (iv 2h) 5-FU 400 mg/m 2 (iv bolus) 5-FU 2400 mg/m 2 (iv 46h) Bevacizumab 5 mg/kg (iv 0,5-1,5h) Q 2 weeks Stratification factors Centre Adjuvant CT Y/N LLD Y/N ASCO 2014 AdaptedfromYamazakiK et al. Abstract 3534

13 WJOG4407G: Results 100 PFS 100 OS PFS (%) HR = 0,90 IC 95 : 0,72-1,13 p = 0,003 (non-inferiority) p = 0,43 (superiority) Months mfolfox6 + bevacizumab Months FOLFIRI + bevacizumab Events Median IC 95 Events Median IC 95 n/n (%) (m) n/n (%) (m) 160/198 10,7 9,8-12,1 1060/198 28,9 26,7-36,5 (81 %) (53 %) 152/197 12,0 11,0-13,8 95/197 31,8 27,5-38,0 (71 %) (48 %) OS (%) HR = 0,90 IC 95 : 0,68-1,19 p = 0,38 ASCO 2014 AdaptedfromYamazakiK et al. Abstract 3534

14 PLANET study Panitumumab + FOLFOX4 or FOLFIRI in patients with WT KRAS exon mcrc and LLD mcrc, LLD (n = 77) R 1:1 Panitumumab 6 mg/kg (Q2W) + FOLFOX4 (Q2W) Panitumumab 6 mg/kg (Q2W) + FOLFIRI (Q2W) Treatment until progression or resectability achieved Response evaluation Q8W Study endpoints: ORR for entire panitumumab+ CTxtreatment period (1 ), PFS, OS, liver metastases resection rate, time to resection, safety, peri-operative safety Exploratory endpoint: protocol predefined RAS analysis PD Or additional surgery PD Or additional surgery Follow-up Q3 ±1M after safety evaluation (up to 36M) Safety: 30±3 days after last study drug administration RAS ascertainment rate: 83.1%. WT RAS = WT KRAS/NRAS exons 2, 3, 4. Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (and poster 551P);

PLANET study Efficacy by RAS Status According to RAS status Patients (%) 100 Panitumumab + FOLFOX Panitumumab + FOLFIRI 90 80 77.8 73.1 70 60 57.

15 PLANET study Efficacy by RAS Status According to RAS status Patients (%) 100 Panitumumab + FOLFOX Panitumumab + FOLFIRI ORR (WT RAS) ORR (MT RAS) RAS, KRAS & NRAS exons 2/3/4; ORR = objective response rate (not confirmed since patients were resected before response confirmation). Abad A, et al. J Clin Oncol. 2014;32:5s(suppl):abstract 3560 (and poster).

16 PLANET study PFS Proportion event free (%) WT KRAS exon 2 P log rank = P Wilcoxon = Proportion event free (%) P log-rank = P Wilcoxon = Months Months WT RAS Median, months (95% CI) Panitumumab + FOLFOX ( ) Panitumumab + FOLFIRI 12.6 ( ) Median, months (95% CI) Panitumumab + FOLFOX ( ) Panitumumab + FOLFIRI 14.8 ( ) WT RAS, WT KRAS & NRAS exons 2/3/4. Abad A, et al. J Clin Oncol. 2014;32:5s(suppl):abstract 3560 (and poster).

17 PLANET OS study Proportion event free (%) WT KRAS exon 2 P log rank = P Wilcoxon = Proportion event free (%) P log-rank = P Wilcoxon = Months Months WT RAS Median, months (95% CI) Median, months (95% CI) Panitumumab + FOLFOX (20.6 NA) Panitumumab + FOLFOX (26.4 NA) Panitumumab + FOLFIRI 42.4 ( ) WT RAS, WT KRAS & NRAS exons 2/3/4. Panitumumab + FOLFIRI 45.8 ( ) Abad A, et al. J Clin Oncol. 2014;32:5s(suppl):abstract 3560 (and poster).

18 PLANET study Summary of AEs (WT RAS population) Grade 3 4 treatment-related AEs, % Panitumumab + FOLFOX4 (n = 27) Panitumumab + FOLFIRI (n = 26) P-value Neutropenia Conjunctivitis Diarrhoea Asthenia Neuropathy Decreased appetite There were no grade 5 AEs related to panitumumab and/or chemotherapy. Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (and poster 551P).

19 Continuous Blockade of Angiogenesis Bevacizumab Beyond Progression (BBP) 2 randomized studies: TML BEBYP 1.Bennouna J et al. The Lancet Oncology. Jan 2013;14:29-37; 2.Masi G, ESMO Vienna 2012 LBA 17.

20 ML18147 Study Design (phase III) BEV + standard firstline CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomise 1:1 CT switch: Oxaliplatin Irinotecan Standard second-line CT (oxaliplatin or irinotecan-based) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD Irinotecan Oxaliplatin Primary endpoint Secondary endpoints included Stratification factors Overall survival (OS) from randomisation Progression-free survival (PFS) Best overall response rate Safety First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS ( 9 months, >9 months) Time from last BEV dose ( 42 days, >42 days) ECOG PS at baseline (0/1, 2) Bennouna J et al. The Lancet Oncology.Jan 2013;14:29-37.

21 BEBYP: Study Design * I-line CT * + BV Stratification - Center - PS 0/1-2 - CT-free interval (> vs 3 mos) - II-line FOLFIRI CT FOLFOX FOLFOXIRI Fluoropyrimidine mono-tx R A N D O M I Z E B. Second-line CT + BV A. Second-line CT FOLFIRI mfolfox-6 Study conducted in 19 Italian centers Supported by AIFA Masi G, Annals of Oncology 00: 1 8, 2015 doi: /annonc/mdv012

22 Bevacizumab beyond progression PFS Analysis TML (2 nd EP) BEBYP (1st EP) 1.0 CT (n=410) BEV + CT (n=409) 0.8 PFS estimate HR: 0.68 (95% CI: ) p< (log-rank test) HR=0.70 (95%CI ) p= No. Time at risk: (months) CT BEV + CT m 6.8 m Bennouna J et al. The Lancet Oncology.Jan 2013;14:29-37; Masi G, Annals of Oncology 00: 1 8, 2015 doi: /annonc/mdv012

23 Bevacizumab beyong progression OS analysis TML BEBYP OS estimate HR: 0.81 (95% CI: ) p= (log-rank test) Time (months) No. at risk CT BEV + CT Bennouna J et al. The Lancet Oncology.Jan 2013;14:29-37; Masi G, Annals of Oncology 00: 1 8, 2015 doi: /annonc/mdv012

24 Bevacizumab beyong progression OS analysis TML BEBYP OS estimate HR: 0.81 Esmo Magnitude of Benefit Scale (MCBS) =1 (95% CI: ) p= (log-rank test) Time (months) No. at risk CT BEV + CT Bennouna J et al. The Lancet Oncology.Jan 2013;14:29-37; Masi G, Annals of Oncology 00: 1 8, 2015 doi: /annonc/mdv012

25 Survival in TML by treatment group and tumor KRAS mutation status: (A) PFS and (B) OS. 241/316 received anti EGFR in later lines Kubicka S et al. Ann Oncol 2013;24:

26 The issue of cost for continuous angiogenic blockade

27 2L in anti-vegf naive patients: E3200 Study; Bevacizumab with FOLFOX FOLFOX-Bevacizumab FOLFOX Bevacizumab alone FOLFOX vs. FOLFOX-Bevacizumab HR = 0.75; p=0.011 Median OS: 10.8 vs mos ESMO PRECEPTORSHIP PROGRAM Giantonioet al., J ClinOncol2007

28 VELOUR Study Design Metastatic Colorectal Cancer Stratification factors: - ECOG PS (0 vs 1 vs 2) - Prior bevacizumab (Y/N) R A N D O M I Z E 600 Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks 1:1 Disease Progression 600 Placebo IV, day 1 + FOLFIRI q2 weeks Death Primary endpoint: Overall survival Sample size: HR 0.8, 90% power and a 2-sided type I error 0.05 Final analysis of OS: Analyzed at 863 th death event using a 2-sided nominal significance level of (α spending function)

29 Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) in the primary analysis population. Eric Van Cutsem et al. JCO 2012;30:

30 VELOUR: Tolerance profile Esmo Magnitude of Benefit Scale (MCBS) =1 Eric Van Cutsem et al. JCO 2012;30:

31 Grade 3-5 adverse events TML (Bevacizumab) and Velour (Aflibercept) Grade 3-4 TML VELOUR Diarrhea Asthenia Stomatitis Nausea NA 1.8 Infection NA 12.3 Hypertension Hemorrhage 2 3 ATE NA 1.8 VTE GI Fistula NA 0.3 Neutropenia Neutropenic complications NA 5.7

32 Phase III VELOUR trial: FOLFIRI +/- Aflibercept PFS: HR 0.76, p<0.001 med. 4.7 vs. 6.9 mos. OS: HR 0.82, p< med vs mos. Van Cutsem et al., J Clin Oncol 2012

33 VELOUR Study: Toxicity Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611 All Grades Grade 3-4 All Grades Grade 3-4 Diarrhea Neutropenia Complicated neutropenia Asthenic conditions (HLT) Stomatitis & ulceration (HLT) Thrombocytopenia Infections (SOC) Decrease appetite Weight decreased Palmar plantar erythrodysaesthesia Skin hyperpigmentation Dehydration ** From lab Van CutsemE et al., J ClinOncol2012

34 VELOUR Study: Toxicity Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611 All Grades Grade 3-4 All Grades Grade 3-4 Diarrhea Neutropenia Complicated neutropenia Asthenic conditions (HLT) Esmo Magnitude of Benefit Scale (MCBS) =1 Stomatitis & ulceration (HLT) Thrombocytopenia Infections (SOC) Decrease appetite Weight decreased Palmar plantar erythrodysaesthesia Skin hyperpigmentation Dehydration ** From lab Van CutsemE et al., J ClinOncol2012

RAISE: Study Design Progression during or after bevacizumab, oxaliplatin, and a fluoropyrimidine R A N D O M I Z E (1:1) Stratification

FOLFIRI* every 2 weeks per cycle N=525 Placebo and FOLFIRI* every 2 weeks per cycle N=525 Treatment until disease progression or

ratio of 0.8 Median overall survival of 10 months in the control arm vs 12.5 months with ramucirumab with a 2-sided α level of 0.

PFS=progression-free survival; PK=pharmacokinetics; OS=overall survival; ORR=objective response rate.

35 RAISE: Study Design Progression during or after bevacizumab, oxaliplatin, and a fluoropyrimidine R A N D O M I Z E (1:1) Stratification factors: Geographic regions KRAS mutation status Time to disease progression after beginning first-line therapy Ramucirumab (8 mg/kg) and FOLFIRI* every 2 weeks per cycle N=525 Placebo and FOLFIRI* every 2 weeks per cycle N=525 Treatment until disease progression or unacceptable toxicity Primary endpoint: Overall survival Secondary endpoints: PFS, ORR, PRO, Safety, PK, IG Sample size assumptions Hazard ratio of 0.8 Median overall survival of 10 months in the control arm vs 12.5 months with ramucirumab with a 2-sided α level of 0.05 Enrollment of 1050 patients with 756 events for 85% power Gatekeeping from OS to PFS to ORR Abbreviations: IG=immunogenicity; PFS=progression-free survival; PK=pharmacokinetics; OS=overall survival; ORR=objective response rate. *Irinotecan: 180 mg/m 2 ; Folinic acid: 400 mg/m 2 ; 5-Fluorouracil: 400 mg/m 2 bolus, followed by 2400 mg/m 2 administered intravenously over 46 to 48 hours (continuously). Taberneroet al., GI Cancer Symposium 2015

36 Taberneroet al., GI Cancer Symposium 2015

37 RAISE: Ramucirumab in 2nd line mcrc Taberneroet al., Lancet Oncology2015

38 RAISE: Ramucirumab in 2nd line mcrc Taberneroet al., Lancet Oncology2015

39 RAISE: Ramucirumab in 2nd line mcrc Esmo Magnitude of Benefit Scale (MCBS) =1 Taberneroet al., Lancet Oncology2015

40 Anti EGFR MoAbsin 2nd line Folfiri-Panitumumab

41 Study Study design Metastatic CRC (n = 1186) R 1:1 FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W) FOLFIRI (Q2W) Disease assessment every 8 weeks E n d o f t r e a t m e n t L o n g t e r m f o l l o w u p Study endpoints: PFS and OS (1 ), ORR, safety Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster). ORR, objective response rate

42 study RAS analysis PFS (primary analysis) Proportion event-free (%) WT KRAS exon 2*,1 HR = 0.73 (95% CI, ) Log-rank p-value = Proportion event-free (%) WT RAS #,2 HR = 0.70 (95% CI, ) Log-rank p-value = Months Months Events n (%) Median, months (95% CI) Events n (%) Median, months (95% CI) Panitumumab + FOLFIRI (n = 303) 178 (59) 5.9 ( ) Panitumumab + FOLFIRI (n = 208) 120 (58) 6.4 ( ) FOLFIRI (n = 294) 203 (69) 3.9 ( ) FOLFIRI (n = 213) 139 (65) 4.6 ( ) Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster); 1. Peeters M, et al. J Clin Oncol 2010; 28: *KRAS ascertainment rate: 91%; # RAS ascertainment rate: 85%; WT RAS, KRAS & NRAS exons 2/3/4

43 study RAS analysis OS (primary analysis) Proportion alive (%) WT KRAS exon 2*,1 HR = 0.85 (95% CI, ) Log-rank p-value = 0.12 Proportion alive (%) WT RAS # HR = 0.81 (95% CI, ) Log-rank p-value = Months Months Events n (%) Median, months (95% CI) Events n (%) Median, months (95% CI) Panitumumab + FOLFIRI (n = 303) 200 (66) 14.5 ( ) Panitumumab + FOLFIRI (n = 208) 130 (63) 16.2 ( ) FOLFIRI (n = 294) 207 (70) 12.5 ( ) FOLFIRI (n = 213) 143 (67) 13.9 ( ) Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster); 1. Peeters M, et al. J Clin Oncol 2010; 28: *KRAS ascertainment rate: 91%; # RAS ascertainment rate: 85%; WT RAS, KRAS & NRAS exons 2/3/4

44 Study RAS analysis ORR (primary analysis) Panitumumab + FOLFIRI FOLFIRI WT RAS, n Objective response rate, n (%) (95% CI) (34, 48) (6, 15) WT KRAS exon 2, n Objective response rate, n (%) (95% CI) (30, 41) (7, 14) MT RAS, n Objective response rate, n (%) (95% CI) (11, 20) (9, 17) MT KRAS exon 2, n Objective response rate, n (%) (95% CI) (9, 18) (10, 19) Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster). WT RAS, WT KRAS & NRAS exons 2/3/4; ORR, objective response rate

45 PRIME study post-hoc analysis Post progression treatment OS in patients WT RAS receiving a 2 nd line with or without Bevacizumab Peeters M, et al. Eur J Cancer 2013;49(Suppl 4):abstract MC (and poster).

46 PRIME study post-hoc analysis OS according with the use of Anti-VEGF post-progression (WT RAS population) Overall With panitumumab + FOLFOX4 FOLFOX HR = 0.63 (95% CI, ) P = HR = 0.64 (95% CI, ) P = HR = 0.62 (95% CI, ) P = Kaplan-Meier estimate Kaplan-Meier estimate Kaplan-Meier estimate Months Months Months Events n (%) Median (95% CI) months Received anti-vegf (n = 100) 80 (80) 38.1 No anti-vegf treatment (n = 246) 208 (85) 23.6 Events n (%) Median (95% CI) months Received anti-vegf (n = 55) 39 (71) 40.0 No anti-vegf treatment (n = 114) 91 (80) 26.0 Events n (%) Median (95% CI) months Received anti-vegf (n = 45) 41 (91) 36.2 No anti-vegf treatment (n = 132) 117 (89) 20.6 Peeters M, et al. Eur J Cancer 2013; 49 (suppl 4):abstract MC (and poster). Data are from an exploratory analysis, data cut-off: 24 January 2013.

47 Are there «optimal sequences»? STRATEGIC-1 Phase III, GERCOR PI: Benoist Chibaudel

48 Are there «optimal sequences»? CR_Sequence trial Continued cfdna analysis (q 6-8 weeks) Int lphase III (TTD et al.) PI: Alfredo Carrato, Ramon Salazar & Jean-Yves Douillard

Treatment of metastatic disease Third and further line therapy Regorafenib is recommended in patients pretreated with fluoropyrimidines,

of overall survival, although there are safety / toxicity concerns in frail patients.

49 Treatment of metastatic disease Third and further line therapy Regorafenib is recommended in patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with anti-egfr antibodies Regorafenib is superior to placebo in terms of overall survival, although there are safety / toxicity concerns in frail patients. TAS 102 is a new option for patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with anti-egfr antibodies ESMO PRECEPTORSHIP PROGRAM

Regorafenib (BAY 73-4506): an oral multikinase inhibitor 1,2,3 Inhibition of roliferation Inhibition pf signalling In tumor microenvironment Inhibition of angiogenesis 1.

50 Regorafenib (BAY ): an oral multikinase inhibitor 1,2,3 Inhibition of roliferation Inhibition pf signalling In tumor microenvironment Inhibition of angiogenesis 1. Wilhelm SM, et al. Int J Cancer. 2011;1219(1): Mross K, et al. Clin Cancer Research 2012;18(9): Strumberg D, et al. Expert Opin Investig Drugs. 2012;21(6):

51 CORRECT Trial: Regorafenib or Placebo after failure of standard therapy Regorafenib + BSC (n=505) Pat. mit vorbehandeltem mcrc (n=760)* R 2:1 Placebo + BSC (n=255) Preceding treatment MUST have been contained Fluoropyrimidine, Oxaliplatin, Irinotecan, Bevacizumab, and (in KRAS wt) Cetuximab or Panitumumab Van Cutsem, E, et al. J Clin Oncol. 2012;30(15S): Abstract 3502

52 Baseline characteristics Regorafenib (n=505) CORRECT Placebo (n=255) Regorafenib (n=136) CONCUR Placebo (n=68) Median age, years(iqr) 61 (54 67) 61 (54 68) 58 (50 66) 56 (49 62) Male, % Race,% Asian Median body mass index, kg/m ECOG PS 0/1, % 52/48 57/43 26/74 22/78 KRAS wild-type/mutant/unknown, % 41/54/5 37/62/2 37/34/29 43/26/31 >3 prior treatment lines for metastatic disease, % Previous targeted biological treatment, % None Any (anti-vegf, anti-egfr, or both) Anti-VEGF, but not anti-egfr Anti-EGFR, but not anti-vegf Anti-VEGF and anti-egfr ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IQR, interquartile range; VEGF, vascular endothelial growth factor. Grothey A, Van Cutsem E, et al. Lancet 2013;381: ; Li J, et al. Lancet Oncol 2015;16:

53 Regorafenib trials outcome CORRECT& CONCUR& Grothey&A,&Van&Cutsem&E,&et#al.#Lancet#2013;381: ;&Li&J,&et#al.#Lancet#Oncol#2015;16: # Grothey et al., WCGC 2015 (oral presentation)

54 Selected drug-related grade 3 adverse events* Proportion of patients (%) Regorafenib (n=500) CORRECT Placebo (n=253) Regorafenib (n=136) CONCUR Placebo (n=68) Hand foot skin reaction 17 < Fatigue Hypertension Diarrhea Hypophosphatemia 4 <1 7 0 Lipase increase 3 <1 4 1 Rash *Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR). Safety analyses are based on 753 patients who initiated treatment. Grothey A, Van Cutsem E, et al. Lancet 2013;381: ; Li J, et al. Lancet Oncol 2015;16:

55 Selected drug-related grade 3 adverse events* Proportion of patients (%) Regorafenib (n=500) CORRECT Placebo (n=253) Regorafenib (n=136) CONCUR Placebo (n=68) Hand foot skin reaction 17 < Fatigue Esmo Magnitude of Benefit Scale (MCBS) =1 Hypertension Diarrhea Hypophosphatemia 4 <1 7 0 Lipase increase 3 <1 4 1 Rash *Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR). Safety analyses are based on 753 patients who initiated treatment. Grothey A, Van Cutsem E, et al. Lancet 2013;381: ; Li J, et al. Lancet Oncol 2015;16:

56 Difference between 5-FU and TAS FU TAS-102 dump FdUMP Inhibit TS dtmp F3dTMP F3dTDP FTD F3dTTP Phosphorylation Incorporation into DNA DNA duplication Inhibit DNA duplication dttp T T FTD Thymidine (T) DNA damage

57 RECOURSE Trial: TAS-102 vs. placebo Mayer R J et al N Engl J Med 2015;372:

58 TAS 102 (Longsurf ): tolerance Mayer R J et al N Engl J Med 2015;372:

59 TAS 102 (Longsurf ): tolerance Esmo Magnitude of Benefit Scale (MCBS) =2 Mayer R J et al N Engl J Med 2015;372:

Limited Evidence for Retreatment with Anti-EGFR in mcrc Author n Study Design Population Outcome Comments Saif M, etal. 1 Metges J, et al. PANERB 2 Liu X, et al. 3 Santini D, et al.

60 Limited Evidence for Retreatment with Anti-EGFR in mcrc Author n Study Design Population Outcome Comments Saif M, etal. 1 Metges J, et al. PANERB 2 Liu X, et al. 3 Santini D, et al Retrospectivecase review ofcases at 2 institutions (Yale and St Francis) 106 Prospective case series of on-label therapy in 22 institutions in Canada 104 Retrospective analysis of patients re-treated with an anti-egfr agent in phase I/II studies 39 Phase IImulticenter single-arm trial in patients retreated with CETUX-IRI after prior clinical benefit with the same regimen Level IV Evidence Patients who had tolerated panitumumab with clinical benefit after failure on cetuximabtherapy Patients with KRASWT mcrcwho had received Level a IV CETUX-based Evidence regimen and, after progression, monotherapy with panitumumab KRAS wild type mcrc; prior cetuximab or panitumumab Level IV Evidence therapy; retreatment anti-egfr agents were cetuxumab+ oxaloplatinor iritonecanbased regimen (n= 77) or cetuxumab+ erlotinib(n=15) or cetuxumab+ sirolimus(n=12). Median interval between prior anti-egfrand retreatment was 4.55 mo Patientswith clinical benefit after a line ofcetux + IRI-based therapy and then Level PD ( IRI-refractory ) III Evidence who had received a new line of therapy after PD, and then progressed after treatment with this new line of therapy. MR in 3/11;SD in 3/11.Median duration of SD: 4mo Prior response to CETUX-based regimen correlated with better response to panitumumab(n=48; ORR=31%; SD=16%) vs no prior response (n=28; ORR=7%; SD=7%) CR/PR/SD rate was 56% for anti- EGFRretreatment, and had been 38% for initial anti-egfr therapy. Prior CR/PR/SD with anti-egfr correlated with ~3.5 higher ORR; longer interval between initial and retreatment correlated with ~2 higher ORR. ORR was 53.8%;19 (49%) PRs and 2 (5%) CRs;SD in 36% ptsmedian PFS: 6.6 mo (must have had at least SD with prior CETUX + IRI-based therapy) Grade 3/4 skin rash in 5 (33%) patients and asthenia in 1 patient Panitumumab monotherapy has limited benefit for mcrcthat did not respond to prior CETUX-based regimen Prior responders to cetuximab-based treatment with longer interval length between initial and retreatment were more likely to respond to anti-egfr therapy when re-treated (P <.001) Correlation between skin toxduring first CETUX + IRI-based therapy and rechallenge (P = 0.01) 1. Saif M, et al. ClinCRC. 2010;9: ; 2. Metges J, et al. ESMO. 2012: Ab 572P; 3. Liu X, et al. ASCO Ab 3607; 4. SantiniD, et al. Ann Oncol. 2012;23: ; Levels per Howick J, et al. Oxford Centre for Evidence-Based Medicine. 2011; G.SM.ON

Limited Evidence for Retreatment with Oxaliplatin in mcrc Author n Study Design Population Outcome Comments Chibaudel, et al 1 285 Retrospective pooled analysis of OPTIMOX-1 (n=165) and -2(n=120),

61 Limited Evidence for Retreatment with Oxaliplatin in mcrc Author n Study Design Population Outcome Comments Chibaudel, et al Retrospective pooled analysis of OPTIMOX-1 (n=165) and -2(n=120), looking at Oxaloplatin-Free Interval (OFI) Patients who received FOLFOX reintroduction which was scheduled or recommended at progression during maintenance or chemotherapy free interval for patients initially sensitive to oxaloplatinand in the absence of residual sensory neuropathy Level IV Evidence PFS and OS higher if prior response to Oxaliplatin. OFI of >6 mo identifies a subgroup of patients in which FOLFOX has efficacy comparable to that in oxaliplatin-naive patients (ORR: 14%; SD: 31%) A sensitive subset of patients may benefit from Oxaliplatin reintroduction: defined by the efficacy of induction therapy followed by an OFI of at least 6 mobetween 2 periods of FOLFOX therapy Bhadkamkar, et al Retrospective database analysis (Prior oxaliplatin for Adjuvant, n=29; UnresectablemCRC, n=75; perioperative for metastasectomy, n=22) Patients with mcrcwho were retreated with an Oxaliplatin regimen Level IV Evidence Median time to progression or discontinuationof Oxali was mo Cumulative neurotoxicity and hypersensitivity Yau, et al 3 28 Prospective, open-label, single arm phase II ; Efficacy and safety of capecitabine, oxaloplatin and irinotecan(capeoxiri) in patients with treatmentrefractory mcrc. Patients with PDduring or within 2 moafter prior last standard therapy. Patients had PD with prior 5FU, irinotecanor oxaloplatin. All KRASWT patients had progressed with prior cetuxumab-based therapies. Level III Evidence Overall, 6 (21%) PR, and 12 (43%) SD;64% with clinical benefit (PR or SD). Median PFS was 6.2 monthsand median OS was 10.3 months AEs included neuropathy (41%), diarrhea (41%),malaise (30%). Most common Gr3-4 AEs : neutropenia (37%), thrombocytopenia (15%), anemia (15%) Townsend, et al 4 20 Retrospective analysis of Australian database for rechallenge with FOX Patients with mcrcpreviously treated with Oxaliplatin, 5-FU, and irinotecan, chemotherapy (± bevacizumab) and anti-egfr (if KRAS WT) or patients who had progressed within 12 moof adjuvant Oxaliplatin-basedtherapy who were rechallenged with FOX Level IV Evidence ORR was 18%, and 47% had SD. The median PFS was 3.7 mo median OS was 7.8 mo and 1-year survival was 37% 12% with worsening neuropathy; allergic reaction to Oxaliplatinin 1 patient (treatment continued with premedication) FOX, fluoropyrimidine+oxaliplatin; OFI, oxaliplatin-free interval; ORR, objective response rate; OS, overall survival; PD, progressive disease; SD, stable disease. 1. Chibaudel B, et al. Eur J Cancer. 2013;49: ; 2. Bhadkamkar N, et al. J Clin Oncol. 2013;31(4 suppl): Abstract 500; G.SM.ON Yau TC, et al. J Clin Oncol. 2014;32(suppl): Abstract e14511; 4. Townsend A, et al. Am J Clin Oncol. 2013:36:49-52.

62 What to do after 1 st -line failure? Conclusion Most patients will receive several lines of treatment in a concept of continuum of care Surgery, loco-regional treatments (RFA, RTX, IACT, CT embolization, SIRT) are lines of treatment like chemotherapy Several factors are to be considered: Goal of treatment Patient willingness and expectations, tolerance, QoL Tumour biology and molecular biomarkers Outcome or previous treatments Use of all available treatments during the disease history is associated to longer survival The best sequence of chemotherapy lines remains to be determined

What to do after 1 st line failure?

ESMO Preceptorship Programme Colorectal Cancer Singapore 20-22 nd 2016 JY Douillard MD PhD ESMO CMO What to do after 1 st line failure? mcrc: How to maximize survival? Improving 1st line therapy efficacy