What to do after 1 st line failure?

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1 ESMO Preceptorship Programme Colorectal Cancer BARCELONA NOVEMBER, 25-26, 2016 What to do after 1 st line failure? Andrés Cervantes Professor of Medicine

2 mcrc: Howtomaximizesurvival? Improving 1st line therapy efficacy - and selecting the best treatment for the individual patient Using the chance for cure by resection of metastases (and other local ablative treatments) Using the continuum of care with optimizing treatment at different lines Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

3 ESMO consensus: Sequences Schmoll,..., Arnold, Ciardiello, Poston,... Cervantes; Ann Oncol 2012

4 Factors that affect treatment decisions 1st line Treatment goal Disease-related factors Patient-related factors Biomarkers Anticipated toxicity 2nd and further line Pretreatment Information from pretreatment (including reported toxicity) Disease-related factors Patient-related factors Treatment goal Biomarkers

5 ESMO consensus: Sequences FOLFOX FOLFIRI vs. FOLFIRI FOLFOX Tournigandet al., J ClinOncol2004: Median OS 20.6 months Schmoll,..., Arnold, Ciardiello, Poston,... Cervantes; Ann Oncol 2012

6 2L in anti-vegf naive patients: E3200 Study; BevacizumabwithFOLFOX FOLFOX-Bevacizumab FOLFOX Bevacizumab alone FOLFOX vs. FOLFOX-Bevacizumab HR = 0.75; p=0.011 Median OS: 10.8 vs mos ESMO PRECEPTORSHIP PROGRAM Giantonio et al., J Clin Oncol 2007

7 Treatment lines : Scenarios Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

8 Antiangiogenic treatmentin mcrc c Arnold & Tabernero, J Oncopathol 2013

9 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

10 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 Cutsem E et al., J Clin Oncol 2012

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

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

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;

11 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). Tabernero et al., GI Cancer Symposium 2015

12 RAISE: Ramucirumabin 2nd linemcrc Tabernero et al., Lancet Oncology 2015

13 VEGF Resistance occurs but when? Chemo (A) Anti-VEGF R R Chemo (B) other(anti-egfr) Chemo (A) R Anti-VEGF Chemo (B) R ESMO PRECEPTORSHIP PROGRAM

14 ML18147 (TML): Study design (phase III) BEV + standard firstline CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomize 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) Study conducted in 220 centres in Europe and Saudi Arabia Arnold et al., ASCO 2012 Benounna et al., Lancet Oncol 2013

15 Sequentialtreatment: anti-vegf islonger activethanwith1l chemotherapy TML phase III study 2L chemo alone or plus continued Bevacizumab after progression with chemotherapy plus Bevacizumab Benounna, Arnold et al., Lancet Oncol 2013

16 2 nd line mcrctreatment with anti-vegf combinations E3200 TML VELOUR RAISE Bev + FOLFOX4 (n=286) FOLFOX (n=291) Bev + CT (n=410) CT (n=409) Aflib + FOLFIRI (n=612) Plac + FOLFIRI (n=614) Ramu + FOLFIRI (n=536) Bev before? none all 30% all Plac + FOLFIRI (n=536) mos, months mpfs, months ORR, % HR=0.75 p= HR=0.81 p= HR=0.82 p= HR=0.84 p= HR=0.61 p< HR=0.68 p< HR=0.76 p= HR=0.79 p= p< ns p= ns Plac = placebo Giantonio, et al. J Clin Oncol 2007; Benounna, Arnold et al, Lancet Oncol 2012; Van Cutsem, et al. J Clin Oncol 2012 ; Tabernero et al., ASCO GI Langer, et al. ESMO 2008; 2. Peeters, et al. JCO 2010; 3. Van Cutsem, et al. WCGC Giantonio, et al. J Clin Oncol 2007; 5. Roche data on file

17 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

18 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

19 OS, high crossover-rate PFS Sobrero et al., J Clin Oncol 2008

20 2L FOLFIRI +/-Panitumumab, expanded RAS testing: OS Peeters, et al. Clin Cancer Res. 2015

21 2nd line: SequencefollowingFOLFIRI/bev Study conducted in 11 centers in Italy PFS BEV + FOLFIRI (n=110) PD R 1:1 Irinotecan/ CETUXIMAB FOLFOX FOLFOX Irinotecan/ CETUXIMAB 101 events were required to achieve a power of 80% of detecting a HR of 0.57 in favor of one of the two sequences, translating in an increase of median overall PFS from 4 to 7 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the logrank test. 110 assessable patients were needed to reach the target number of events. Primary endpoint Secondary endpoints Progression-free survival (PFS) Overall survival (OS) from randomisation; PFS 2 and 3 line; Overall response rate; Safety Clinicaltrials.gov: NCT Research Funding Source: AIFA (Agenzia Italiana del Farmaco) Code FARM 6XB38F Cascinu et al., ECC 2015

22 2nd line: SequencefollowingFOLFIRI/bev A: CPT-11 + Cetuximab -> Folfox-4 B: Folfox-4 -> CPT 11 + Cetuximab PFS Progression Free Survival Number of events A: 49 (90.7%) B: 48 (87.3%) Overall Arm A Arm B HR 0.83 PFS ( ); p=0.37 Log-rank: Chi2=0.79 df=1 p=0.373 Patients at Risk Time to Event (months) Time A B OS A: CPT-11 + Cetuximab -> Folfox-4 B: Folfox-4 -> CPT 11 + Cetuximab Overall Survival Number of events A: 46 (85.2%) B: 43 (78.2%) Log-rank: Chi2=1.30 df=1 p=0.255 Patients at Risk Time to Event (months) Time A B Cascinu et al., ECC 2015

23 Treatment sequences: Strategies Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014 ESMO PRECEPTORSHIP PROGRAM

24 FollowingFOLFOX/bev: 2nd linefolfiri/p mabvs. FOLFIRI/Bev KRAS wild-type; N=182 Hecht et al., Clin Colorectal Cancer 2015

25 2nd line treatment: Antibodies Bevacizumab-naïve should be considered for bevacizumab 2 nd line Who received bevacizumab 1 st line should be considered for treatment with: AG-E1 Bevacizumab post continuation (TML) strategy Aflibercept (or ramucirumab, if available) in combination with FOLFIRI when treated in first line with oxaliplatin EGFR antibodies in combination with FOLFIRI for patients with RAS wild-type (& BRAF wild-type) in 2 nd line Patients who are fast progressors should be considered for treatment with the (likely) most active treatment (anti-egfr in the RAS wild-type and aflibercept in RAS mutant). ESMO Consensus 2015; in preparation ESMO PRECEPTORSHIP PROGRAM

26 Slide 25 AG-E1 What does TML stands for please? Aude GALLI - ESMO, 22/09/2015

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

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

29 Treatment of metastatic disease Anti-EGFR s in later lines In RAS wild-type and BRAF wild-type patients not previously treated with EGFR antibodies cetuximab or panitumumab therapy should be considered Cetuximab and panitumumab equally active as single agents The combination of cetuximab with irinotecan is more active than cetuximab alone, in irinotecan refractory patients There is no unequivocal evidence to administer the alternate anti- EGFR antibody, if a patient is refractory to one of the anti-egfr antibodies. ESMO PRECEPTORSHIP PROGRAM

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

30 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

Up to 30% of Patients Receive 3 rd line Therapy % patients 100 80 60 40 20 0 Patients with mcrc 1 Analysis of the US IntelliDose database (mcrc) 53% 28% n= 4877 2575 1373 13% First Second Third

7% 640 n= 3388 1620 1022 690 498 398 First Second Third Fourth Fifth Sixth % patients 100 80 60 40 20 Patients with mbc 3 Analysis of SEER-Medicare (dx2001-5) 40.8% 24.

31 Up to 30% of Patients Receive 3 rd line Therapy % patients Patients with mcrc 1 Analysis of the US IntelliDose database (mcrc) 53% 28% n= % First Second Third Fourth % patients Patients with Ovarian Cancer 2 Follow-up of 3 1 st -line phase III Trials (N=3388) 47.8% 30.2% 20.4% 14.7% 11.7% 640 n= First Second Third Fourth Fifth Sixth % patients Patients with mbc 3 Analysis of SEER-Medicare (dx2001-5) 40.8% 24.6% n= First Second Third Patients receiving targeted therapy, by line Of patients who received 1 st - line targeted therapy, % Patients with ansclc 4 Analysis of SEER-Medicare (2007) 1. Abrams T, et al. JNCI. 2014;106(2):djt371; 2. Hanker L, et al. Ann Oncol. 2012;23: and online supplement; 3. Taylor D, et al. J Clin Oncol. 2011;29(27 Sept 20 suppl):abstract 150; 4. Penrod J, et al. J ClinOncol. 2014;32(15 May 20 suppl):abstract % 17.2% n= First Second Third Patients receiving targeted therapy, by line 30

32 Goals of Treatment Change with Line of Therapy Realistic Treatment Goals Adjuvant Cure Reduce risk of recurrence Line of Systemic Treatment First-line Second-line Third-line Subsequent lines Durable Tumor response Long duration of low/no tumor burden Tumor response if needed Durable disease control Durable disease control Maintenance of QoL and PS Disease Control and Maintenance of QOL; Palliation OS Courtesy of Dirk Arnold; Prime Reports. 2014;6:108.

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

33 Regorafenib(BAY ): an oral multikinaseinhibitor 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):

34 CORRECT Trial: Regorafenibor 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

35 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:

36 Treatment forrefractorycoloncancer: Regorafenib 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)

37 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:

38 Treatment-emergent hepatic and hematologic laboratory values, regardless of relation to study drug Proportion of patients (%) ALT increased Grade 3 Grade 4 AST increased Grade 3 Grade 4 Blood bilirubin increased Grade 3 Grade 4 Anemia Grade 3 Grade 4 Neutropenia Grade 3 Grade 4 Thrombocytopenia Grade 3 Grade 4 CORRECT CONCUR Regorafenib Placebo Regorafenib Placebo 5 <1 5 < <1 <1 0 2 <1 3 <1 4 < < < < ALT, alanine aminotransferase; AST, aspartate aminotransferase.

39 TAS-102; Mechanism of Action TPase F 3 dthd (FTD) FTY (inactive form) TPI F 3 dtmp Inhibition of tumor growth TAS-102 (Oral Combination Drug) F 3 dtdp DNA dysfunction FTD TPI F 3 dttp FTD incorporation into DNA Molar ratio = 1 : 0.5 FTD:Trifluridine TPI:Tipiracil-HCl

40 RECOURSE Trial: TAS-102 vs. placebo Mayer et al., NEJM 2015

41 Key Subgroup Analysis of OS Subgroup Favors TAS-102 Favors Placebo Events/N HR [95% CI] Median (mos) TAS-102 : PBO All Subjects 574 / [0.58, 0.81] 7.1 : 5.3 KRAS Status Wild Type 280 / [0.45, 0.74] 8.0 : 5.7 Mutant Type 294 / [0.63, 1.02] 6.5 : 4.9 Geographic Region Japan 227 / [0.57, 1.00] 7.8 : 6.7 West (AU/EU/US) 347 / [0.52, 0.80] 6.5 : 4.8 Refractory to 5-FU when given as last therapy prior to randomization* 317 / [0.59, 0.96] 6.8 : Hazard Ratio: TAS-102 versus Placebo (95% CI) *Not prespecified subgroup Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

42 Non-Hematologic Adverse Events Occurring in >10% of Patients (as-treated population) Non-Hema Adverse events, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Nausea Decreased appetite Fatigue Diarrhea Vomiting Pyrexia Asthenia Constipation Abdominal pain Cough Dyspnoea Oedema peripheral Weight decreased One treatment-related death was observed in TAS-102 Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

43 Hematologic Laboratory Abnormalities Occurring in >10% of Patients (as-treated population) Lab abnormalities, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Hematology Leukopenia Anemia * Neutropenia Lymphocytopenia Thrombocytopenia *One case of grade 4 was reported in AE Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

44 Occurring in < 10% of Patients but Clinically Important Adverse Events (as-treated population) Adverse events, % TAS-102 (N=533) Placebo (N=265) All Gr. Gr. 3 Gr. 4 All Gr. Gr. 3 Gr. 4 Febrile neutropenia Stomatitis Hand-foot syndrome Cardiac ischaemia events, % Acute myocardial infarction Angina pectoris Myocardial ischaemia Yoshino T, et al., 16 th ESMO-GI, 2014: O-0022

45 Kavuri SM et al, Cancer Discovery 2015

46 Kavuri SM et al, Cancer Discovery 2015

47 HERACLES treatment and assessments Presented By Salvatore Siena at 2015 ASCO Annual Meeting

48 Sartore-Bianchi A, et al, Lancet Oncol 2016

49 Sartore-Bianchi A, et al, Lancet Oncol 2016

50 Response Presented By Salvatore Siena at 2015 ASCO Annual Meeting

What to do after 1 st line failure?

ESMO Preceptorship Programme Colorectal Cancer Valencia 21 st May 2016 What to do after 1 st line failure? Andrés Cervantes ESMO Preceptorship Programme Colorectal Cancer Valencia 21 th May 2016 Dirk Arnold,