Adjuvant treatment of colon cancer: What are the actual recommendations?
Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium Do not duplicate or [email protected] without permission from author and ESO Outcome of early colon cancer: T4 Stage => Poor Outcome
SEER database 1991-2000 (n = 119,363): 5-yr survival 100% p < .001 90% 93 80% 85 83 70% 72 60% 64 50%
40% 44 30% 20% 10% 8 0% I(T1-2N0) IIA (T3N0) IIB (T4N0) IIIA (T1-2N1) IIIB (T3-4N1) IIIC (TanyN2) IV (M1)
✓ Stage II colon cancer +/- adj 5FU : 5-yr risk of death = 17.5% overall • 17% had T4 tumorsDo not (stage duplicate IIB) with 27.8% or risk distribute of death without • 83% had T3 tumorspermission (stage IIA) with from15.3% risk author of death (nearand average ESO risk for all stage II) ✓ T4 = high risk; T3 = average risk (not necessarily low risk)
O’Connell JB, et al. J Natl Cancer Inst. 2004;96:1420-1425. AJCC V7
Do not duplicate or distribute without permission from author and ESO
Gunderson et al, JCO 2009 Adjuvant Therapy for Stage III Colon Cancer
1990 12 months 5-FU/Levamisole
1996 6 months 5-FU/Folinic Acid
2004 6 months FOLFOX4 is better than LV5FU2 Capecitabine at least as active as IV 5-FU/FA UFT/LV similar activity compared to IV 5-FU/FA
2005 bolus 5-FU/FA/oxaliplatin better than bolus 5-FU/FA
Do not duplicate 2008or distribute without Capecitabine/oxaliplatinpermission from author better than and bolus ESO 5-FU/FA 2017 3 months as good as 6 months for low risk stage III colon cancer Adjuvant therapy for stage III colon cancer: Which benefit ?
Surgery plus No benefit of % 100 Chemotherapy 20% chemotherapy to exposed toxicity 80
20% 20% Cured by 60 chemotherapy Surgery alone 40 60% Cured by surgery 20 already Disease Disease Free Survival 0 Do not duplicate or distribute without 0 1permission 2 3 from 4 author 5 and ESO Years 12 Months of Adjuvant Therapy of Dukes C colon cancer becomes SOC in 1990
Do not duplicate or distribute without permission from author and ESO INT 0089: 6 Months of Bolus 5-FU/LV = SOC
• No formal non-inferiority hypothesis • No appropriate control arm (6 vs 12 m of 5-FU/ LEV) • No hazard ratios given in paper for comparisons between arms • We truly do not know if 5-FU/LV over 12 months might be best • Oncology community was eager to accept a shorter duration
Do not duplicate or distribute without permission from author and ESO
Haller D et al, ASCO 1997; JCO 2005 Adjuvant therapy increases the chance of survival: evidence in 13,793 colon cancer patients
Stage III Colon cancer
1.0
0.8
0.6 p<0.0001
Surgery alone 10.3% 0.4 8-year OS rate (95% CI): 42.7% (39.9% to 45.7%) OS estimate 0.2 Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 53.0% (50.2% to 55.9%) 0 Do not0 duplicate 1 2 3 or 4 distribute 5 6 7 8 without permissionFollow-up from time author (years) and ESO
Sargent D et al. JCO 2009 Oxaliplatin + Fluoropyrimidines
MOSAIC: Study design NSABP C07: Study design
LV5FU2 FUFOL Roswell Park R R FLOX : FUFOL Roswell Park and oxaliplatin FOLFOX4: LV5FU2 + oxaliplatin N=2246 N=2407 Stage 2 (40%) low-risk 15% high-risk (25%) Stage 2: 29% Stage 3 (60%) <4N (44.5%)≥4N (15.1%) Stage 3: 71% N1 (46% ) N2 (26%)
André, NEJM 2004 J Clin Oncol 2009
XELOXA N016968: Study design Primary end-point for FUFOL Mayo or Roswell Park these 3 studies: R Disease-free Survival Do not duplicateXELOX: capecitabine or distribute+ oxaliplatin without permissionN=1886 from author and ESO
André T et al, N Engl J Med 2004 Yothers G et al , J Clin Oncol 2011 Haller D et al, J Clin Oncol 2011 MOSAIC 2004 FOLFOX4 vs LV5FU2 : DFS by tt arm (ITT)
Probability 3-year 1 FOLFOX4 (n=1123) 78.2% LV5FU2 (n=1123) 72.9%
0,9
0,8
23% risk reduction 0,7 5.3% in the FOLFOX4 arm
0,6 Hazard ratio: 0.77 [0.65 – 0.91] p =0.002
0,5 0Do 5 not10 duplicate 15 20 or 25 distribute 30 35 without 40 45 50
permission fromDFS (months)author and ESO
André, et al. N Engl J Med 2004;350:2343–2351 MOSAIC 2009 5 Year Disease-free Survival: Stage II and Stage III
1.0
0.9 p=0.258 0.8 3.8% p=0.005 0.7 0.6 7.5% 0.5
0.4
Probability 0.3 FOLFOX4 stage II HR [95% CI] p-value LV5FU2 stage II 0.2 Stage II 0.84 [0.62 1.14] 0.258 – FOLFOX4 stage III 0.1 StageDo IIInot 0.80 duplicate [0.65–0.93] or0.005 distribute withoutLV5FU2 stage III 0 permission from author and ESO 0 6 12 18 24 30 36 42 48 5460 66 72 Data cut-off: June 2006 Months André et al. J Clin Oncol. 2009 ; 27 :3109 -15. Adjuvant treatment of colon cancer 3 positive phase III trials in favor of oxaliplatin
Δ 3y DFS Δ 5y DFS Δ 5-6y 0S
Mosaic + 5.3% + 5.9% + 2.5% LV5FU ± HR 0.84 oxaliplatin (median FU:82 months) C-07 + 4.3% + 5.2% + 4.2% Bolus 5FU/LV ± HR 0.85 oxaliplatin (median FU: 67 months) XeloxA Do not +duplicate 4.5% or distribute+ 6.3% without+ 3.4% Xelox vs boluspermission from author and ESO HR 0.85 5FU/FA (median FU: 57mo) Mosaic long term follow-up in stage III: OS with 10 yr Follow Up : ITT
+ 4,2% + 8,1%
FOLFOX4: n=672 n.events=209 LV5FU2: n=675 n.events=250 Log-rank p=0.015
HR - 95%CI: 0.797 [0.663-0.958]
OverallProbability Survival 0.0 0.2 0.4 0.6 0.8 1.0 0 1 2 3 4 5 6 7 8 9 10 Time since enrollment in years FOLFOX4 n at risk 672 637 592 553 519 491 457 356 279 262 205 events 0 28 68 104 133 158 178 185 195 199 203 LV5FU2 Do notn atduplicate risk 675 642 581 533 or 499 distribute454 417 324 241 219 without 163 permissionevents 0 25 from81 126 153author 186 206 223 and 238 244 ESO249 Hazard ratio 0,80 95% CI 0,66 to 0,96 P = 0,015 André T et al et al. JCO 2015 Mosaic trial: Overall Survival: Stage III
Stage III N2 (≥ 4N+) Stage III N1 (1 to 3 N+) +
- 5;5%
+6% + 13% + 6%
Do not duplicate or distribute without permission from author and ESO
André T et al et al. JCO 2015 Stage III ACCENT Database Fluoropyrimidines ± Oxali (n=8993)
• Higher risk of recurrence over time was associated with higher T and N Stage • OxaliplatinDo demonstrating not duplicate more benefit or indistribute patients with more without advanced T and nodal stagepermission from author and ESO • Addition of oxaliplatin to FU is associated with benefit for T4 and T3, however this benefit exist but is little for T1 and T2
Shah MA et al et al. JCO 2016 MOSAIC Proportion of patients treated by FOLFOX4 with peripheral sensory neuropathy
At 48 months Evaluable patients n=811
Grade 0 84.3%
Grade 1 12.0%
Grade 2 2.8%
Grade 3 0.7%
Do not duplicate or distribute without permission from author and ESO
André et al. J Clin Oncol. 2009 ; 27 :3109 -15 IDEA collaboration: Study Overview
• Objective: Reduce side-effects of therapy without giving up (too much) anti-cancer efficacy of 3 months therapy Non-inferiority design: Stage III FOLFOX* • Colon * As agreed upon by patient advocates and R or CAPOX oncologists, shorter duration of therapy Cancer should not sacrifice more than 12% of benefit of adjuvant therapy 12,834 patients 6 months • In statistical terms: upper 95% confidence interval of Hazard Ratio (HR) of disease free *Investigator’s choice, no randomization survival (DFS) should not exceed Do not duplicate or distribute1.12 without permission from author and ESO Patient Characteristics by Study
TOSCA SCOT IDEA France C80702 HORG ACHIEVE Patient Characteristics (N=2402) (N=3983) (N=2010) (N=2440) (N=708) (N=1291) Median Age, years 64 65 64 61 67 66 ECOG PS* 0 95% 71% 74% 71% 82% 96% 1 5% 29% 25% 28% 18% 4% T Stage T1-2 13% 12% 12% 18% 8% 15% T3T4 12%75% 29% 59% 18% 70% 15% 67% 14% 78%28% 57% T4 12% 29% 18% 15% 14% 28% N Stage N1 73% 69% 75% 73% 67% 74% N2 27% 31% 25% 27% 33% 26% Chemotherapy MedianCAPOXCAPOX follow-up 35%6235% 67% 37 67% 10% 51 10% 0% 35 0% 58% 48 58%75% 37 75% time,FOLFOX m Do not 65%duplicate 33% or distribute 90% 100% without 42% 25% Median follow-up time, m 62 37 51 35 48 37 *1% of PS 2 in IDEA Francepermission and C80702 trials from author and ESO
Grothey A et al. NEJM 2018 IDEA: Adverse Events
FOLFOX CAPOX Adverse Events 3m Arm 6m Arm p-value1 3m Arm 6m Arm p-value1 Overall 50 50 G2 45 32% 32% <.0001 45 41% 48% <.0001 40 40 G3-4 35 38% 57% 35 24% 37% 30 30 Neurotoxicity 25 25 20 20 G2 15 14% 32% <.0001 15 12% 36% <.0001 10 10 G3-4 5 3% 16% 5 3% 9% 0 0 Diarrhea 3mG2/3 G4 6m 3mG2/3 6m G2 11% 13% <.0001 10% 13% 0.0117 G3-4Do not duplicate5% 7% or distribute7% without9% 1Chi-squared test for trend;permission Total of 19 grade 5 events; from Adverse author events only collected andon first ESO617 patients enrolled to SCOT trial
Grothey A et al. NEJM 2018 IDEA: Primary Outcomes Analysis
Duration 100 90 3 Months 6 Months 80 70 60 Duration 3-yr DFS 50 3m 74.6 % 40 DFS HR = 1.07 30 6m 75.5 % Percent Without Event Without Percent 95% CI, 1.00 to 1.15 20 3-yr DFS diff. = -0.9% , 10 95% CI, (-2.4 to 0.6%) 0 0 1 2 3 4 5 6 Years from Randomization N Patients 6424Do not 5446 duplicate 4464 or distribute 3000 1609 without 826 321 At risk 6410permission 5530 4477from author 3065 and 1679 ESO 873 334
Grothey A et al. NEJM 2018 IDEA: Primary DFS Analysis (mITT)
Statistical Conclusions
3m TRT better 6m TRT better
DFS HR = 1.07 Not proven 95% CI, 1.00 to 1.15
1.0 1.12 Hazard Ratio
Non-Inferiority Margin Do not duplicate or distribute without TRT: treatment permission from author and ESO
Grothey A et al. NEJM 2018 IDEA: DFS Comparison by Risk Groups mITT all patients independently of the duration of chemotherapy
T1-3 N1 (59%) T4 or N2 (41%)
Do not duplicate or distribute without permission from author and ESO
IDEA, Shi Q et al , personal data mITT: DFS Comparison by N Groups: N1 vs N2
N1 N2
Do not duplicate or distribute without permission from author and ESO
IDEA, Shi Q et al , personal data mITT: DFS Comparison by N Groups: T1-T3 vs T4
T1-T3 T4
Do not duplicate or distribute without permission from author and ESO
IDEA, Shi Q et al , personal data Analysis by Risk Groups and Regimens
• Large difference in overall prognosis observed between (T1-3 N1) and (T4 and/or N2) cancers – 3-year DFS ∆ 20% (~80% vs 60%) – Preplanned subgroup analysis for T and N ➢ Analysis of 3m vs 6m adjuvant therapy by risk groups
• Two different adjuvant regimens used, FOLFOX (N=7763) and CAPOX (N=5071) – Preplanned analysis of 3m vs 6m based on regimen Do not duplicate or distribute without permission from author and ESO
Grothey A et al. NEJM 2018 IDEA: DFS Comparison by Regimen
FOLFOX CAPOX
3m TRT better 6m TRT better 3m TRT better 6m TRT better
DFS HR = 1.16 DFS HR = 0.95 95% CI, 1.06 to 1.26 95% CI, 0.85 to 1.06 Inferiority Non-Inferiority
HR 1.0 1.12 HR 1.0 1.12
NI Margin NI Margin TRT: treatmentDo not duplicate or distribute without permission from author and ESO
Interaction p-value = 0.0051 Grothey A et al. NEJM 2018 3 yr DFS in trial of 3 v 6 months CAPOX in 5071 stage 3 patients proves non inferiority for 3 month regimen!
CAPOX
100 Duration 90 3 Months 6 Months 3m TRT better 6m TRT better 80 70 60 Duration 3-yr DFS DFS HR = 0.95 50 95% CI, 0.85 to 1.06 40 3m 75.9 % 30 Percent Without Without Event Percent 6m 74.8 % Non-Inferiority 20 3-yr DFS diff. = 1.1% 10 95% CI, (-1.3 to 3.5%) 0 HR 1.0 1.12 0 1 2 3 4 5 6 Years from Randomization N Pts 2554 2219 1903 1175 488 193 30 NI Margin At risk 2517 2222Do 1844 not 1185 duplicate 529 207 or 25 distribute without permission from author and ESO
Grothey A et al. NEJM 2018 3 yr DFS in trial of 3 v 6 months FOLFOX in 7763 stage 3 patients shows inferiority of 3 month regimen!
FOLFOX
100 Duration 90 3 Months 6 Months 3m TRT better 6m TRT better 80 70 Duration 3-yr DFS 60 3m 73.6 % DFS HR = 1.16 50 6m 76.0 % 95% CI, 1.06 to 1.26 40 30 Percent Without Without Event Percent 3-yr DFS diff. = -2.4% Inferiority 20 95% CI, (-4.3 to -0.5%) 10 HR 1.0 1.12 0 0 1 2 3 4 5 6 Years from Randomization NI Margin N Pts 3870 3227 2561 1825 1121 633 291 At risk 3893 3308 2633Do not 1880 duplicate 1150 666 or 309 distribute without permission from author and ESO
Grothey A et al. NEJM 2018 mITT: DFS Comparison by Regimen, N, T and Low versus High risk
+2.4% - 1.1% +1.1% +0.2% +0.3% + 3.3% +0.2% +1.7% Do not duplicate or distribute without permission from author and ESO
Grothey A et al. NEJM 2018 IDEA Recommendations
Regimen
CAPOX FOLFOX
Low-risk (T1-3 N1) 3 months (3-)6 months ~60% Risk group High-risk (T4 and/or N2) 3(-6) months 6 months ~40% Do not duplicate or distribute without permission from author and ESO
Non-inferior Not proven Inferior Adjuvant chemotherapy for Stage II colon cancer: What is the benefit ??
Surgery plus chemotherapy 100 Chemotherapy 15% without benefit
80 3-5 % 5% C I T Y T O X I Surgery alone Cured by 60 chemotherapy
40 80% allready cured by surgery
Overall Survival Overall 20
0 Do not duplicate or distribute without 0 1permission 2 3 from 4 author 5 and ESO Years QUASAR 1: survival in patients with uncertain indication for adjuvant chemotherapy
5-FU + AF (Mayo or Roswell Park 6 mth) levamisole R ± Observation 100
80 Chemo
60 n Deaths 5y survival p No chemo Chemo 1622 281 80.3 0.02 No 1617 328 77.4 40 Survival patients) (% Survival HR 0.83 (95% CI: 0.71-0.97) 20 Do not duplicate or distribute without 0 permission from author and ESO 0 1 2 3 4 5 6 7 8 9 10
Years of follow-up Gray R et al. Lancet 2007 Adjuvant therapy increases the chance of survival: evidence in 7,105 colon cancer (stage II) patients
Stage II colon cancer 1.0
0.8 5.4% 0.6 p=0.026
Surgery alone 0.4 8-year OS rate (95% CI): 66.8% (63.7% to 70.0%) OS estimate OS 0.2 Surgery + FU-based chemotherapy 8-year OS rate (95% CI): 72.2% (69.3% to 75.2%) 0 Do not duplicate0 1 2 or 3 distribute 4 5 6 7without 8 permission Follow-upfrom author time (years) and ESO
Sargent D et al. JCO 2009 MOSAIC 2009 5 Year Disease-free Survival: Stage II and Stage III
1.0
0.9 p=0.258 0.8 3.8% p=0.005 0.7 0.6 7.5% 0.5
0.4
Probability 0.3 FOLFOX4 stage II HR [95% CI] p-value LV5FU2 stage II 0.2 Stage II 0.84 [0.62 1.14] 0.258 – FOLFOX4 stage III 0.1 StageDo IIInot 0.80 duplicate [0.65–0.93] or0.005 distribute withoutLV5FU2 stage III 0 permission from author and ESO 0 6 12 18 24 30 36 42 48 54 60 66 72 Data cut-off: June 2006 Months André et al. J Clin Oncol. 2009 ; 27 :3109 -15. Adjuvant! Online Prediction: Cancer and non-cancer related 5-year-Mortality
Improvement of cancer specific survival by 1.7% (FU) and 2.3% (FOLFOX) 80 T3 NO MO 80 T4 NO MO 70 70 60 60 50 50 40 40 30 30 20 20 10 Do not duplicate or distribute10 without 0 0 40 50permission 60 70 80 from 90 author 40and 50 ESO 60 70 80 90 T3 death other cause T4death other cuase Death other cause Death other cause Assumption of Gill model Proposed Stage II Algorithm - 2010
Deficient = MMR Intact= MSS MSI No Adjuvant
Clinical Risk
High Not High
Adjuvant No Adjuvant Do not duplicate or distribute without Or permission from author and ESOAdjuvant *all decisions require discussion with patient Meropol N, Ed. Session ASCO 2010 Defective mismatch repair as predictive marker for adjuvant therapy (Accent meta-analysis)
Stage II MSI-H Stage III MSI-H
Stage II MSS Stage III MSS Do not duplicate or distribute without permission from author and ESO
Sargent D J et al. JCO 2010;28:3219-3226 Factors influencing prognosis in stage II Concept of high risk stage II
Molecular Tumor invasion (T4) markers or signatures Perforation MSS-MSI Occlusion T3N0 without favorable prognostic factors and or MSI : prognosis close to Stage I
T 3-4 N0 with unfavorable prognositic factors : No. of nodes Age prognosis close to Stage III examined Less to 8-12
Do Lymphaticnot duplicate or distribute without permissionVenous from author and ESO Perineural Poor Differentiation invasion CEA increase What we need for optimal selection in adjuvant treatment?
Low DON’T TREAT ?
TREAT Recurrence Recurrence Risk Do not duplicate or distribute without High permission from author and ESO Low Life Expectancy High Adjuvant treatment: conclusions (1)
✓ Optimal surgery and adequate staging are mandatory in patients with colon cancer.
✓ Multidisciplinary approach is important.
✓ Benefit of adjuvant chemotherapy in stage II colon cancer has been demonstrated, but is limited. Selection of patients is important. Do not duplicate or distribute without permission from author and ESO Adjuvant treatment: conclusions (2)
✓ The oral fluoropyrimidines (capecitabine) have a similar efficacy compared IV 5-FU/FA ✓ Oxaliplatin increases the activity of 5-FU/FA and capecitabine, mainly in stage III. ✓ Fluoropyrimidine/oxaliplatin is the actual standard in stage III and may be also in selected stage II patients. ✓ Stage III: low risk: 3 months probably as good as 6 months; in high risk stage III: uncertainty
✓ Bevacizumab and cetuximab are not an option. Do not duplicate or distribute without ✓ The use of moleculars markers has to be implemented in future trials.permission from author and ESO Greetings from Leuven, Belgium
Health Sciences Campus Leuven
Hospital Research
Do not duplicate or distribute without permission from author andTeaching ESO
[email protected] Do not duplicate or distribute without permission from author and ESO
Treatment of metastatic CRC: Towards a personalized treatment in mCRC
Prof Eric Van Cutsem, MD, PhD Digestive Oncology Leuven, Belgium Do not duplicate or [email protected] without permission from author and ESO Leuven, Belgium
Hospital Research
Teaching
▪ 25 km east of Brussel: ~ 100,000 inhibitants ▪ KUL: University founded in 1425: > 55,000 students: o Times ranking of innovation: Nr 5 worldwide; Nr 1 in EU Do not duplicate or distribute without ▪ Largest Beer Brewery in world (>25% of world production) permission from author and ESO Progress in the treatment of mCRC
❑ CHEMOTHERAPY: combination of cytotoxic and biological targeted drugs Cytotoxic agents Biological agents
✓ 5-FU/capecitabine (S1) ✓ bevacizumab ✓ irinotecan ✓ cetuximab ✓ oxaliplatin ✓ panitumumab ✓ raltitrexed ✓ aflibercept ✓ (mitomycine) ✓ ramucirumab ✓ trifluridine/tiparicil ✓ regorafenib ✓ pembrolizumab ✓ nivolumab ✓ early: Sym004, dabrafenib, vemurafenib, encorafenib, trametinib, binimetinib, cobimetinib, atezolizumab, darvulamab, tremelimumab, ipilimumab,,alpelisib, Do not duplicate or distribute napabucasinwithout, vantictumab , cabozantinib bispecific antibodies (eg: RO6958688: permission from author andantiCD3-CEA, ESO crossMab RG7716 …), larotrectinib, (nintedanib, MABp1, ….) ….. ❑ Other contributing factors to improved outcome: surgery, locoregional treatment…. The continuum of care of mCRC
Fluoropyrimidines: 5FU, capecitabine, S1, Triflurdine/tipiracil Oxaliplatin Irinotecan Locoregional therapy: SIRS Surgery (RFA) 1st line cytotoxic 2nd line cytotoxic 3rd line cytotoxic
How to start? Maintenance strategy What is best strategy? Independent How to select? At progression change sequences? What to do for liver chemo, biologic or both? (lung/peritoneal) metastases?
1st line biologicDo not duplicate2nd line or biologic distribute without3nd line biologic
Bevacizumab/aflibercept/ramucirumabpermission from author and ESO Cetuximab/panitumumab Regorafenib Pembrolizumab/nivolumab Patients with metastatic CRC: Resectable metastases (liver/lung)
Upfront Classification resectable Borderline resectable Unresectable
10% 20% 70%
*Or postoperative Perioperative FOLFOX FOLFOX*
1 1 ≈8% CT ± ≈12% CT ± Treatment strategy Resection biologic biologic
FOLFOX 14%2 Relapse
Required DoCurative not duplicatesurgery orOverall distribute survival / long-term without disease control outcome permission4% from author and96% ESO
1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg 2007 3. Van Cutsem E et al. Ann Oncol 2014; 4. Adam R … Van Cutsem E et al. Cancer Treat Rev 2015 Resection of liver metastases
• Technically non-resectable/resectable – MDT discussion in expert team after optimal diagnostic imaging – Localisation, remaining liver tissue and liver function, oligometastatic/multiple metastases • Oncologic non-resectable/resectable – Criteria of tumor biology: e.g. synchronous/metachronous, spread of the disease, pTN of primary tumour, CEA, BRAF mutation,…. – Patient related criteria
Do not duplicate or distribute without permission from author and ESO Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016 Patients with unresectable liver metastases: Borderline/potentially resectable
Upfront Borderline/potentially Classification Unresectable resectable resectable
10% 20% 70%
1 1 ≈8% CT + ≈12% CT ± Treatment strategy Resection biologic biologic
14%2 Relapse
Required DoCurative not duplicatesurgery orOverall distribute survival / long-term without disease control outcome permission4% from author and96% ESO
1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg 2007 3. Van Cutsem E et al. Ann Oncol 2014; 4. Adam R … Van Cutsem E et al. Cancer Treat Rev 2015 Conversion therapy
❑ In potentially resectable patients, a regimen leading to high RRs and/or a large tumour size reduction (shrinkage) is recommended [II, A]. ❑ There is uncertainty surrounding the best combination to use as only few trials have addressed this specifically: ❑ In patients with RAS wild-type disease, a cytotoxic doublet plus an anti-EGFR antibody seems to have the best benefit risk/ratio, although the combination of FOLFOXIRI plus bevacizumab may also be considered and, to a lesser extent, a cytotoxic doublet plus bevacizumab [II, A]. ❑ In patients with RAS-mutant disease: a cytotoxic doublet plus bevacizumab or FOLFOXIRI plus bevacizumab [II, A]. ❑ Patients must be re-evaluated regularly in order to prevent the overtreatment of resectable patients as the maximal response is expected to be achieved after 12–16 weeks of therapy in most patients. Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016 Meta-Analysis in RAS-WT patients three randomized trials with 2.014 patients
response rates in RAS wt
Odds ratio Gewichtung, Studie ORR (95%-KI) %
FIRE-3 1,28 (0,83 - 1,99) 35,65
PEAK 1,12 (0,57 - 2,18) 15,28
CALGB 1,75 (1,21 - 2,54) 49,07
total 1,46 (1,13 - 1,90) 100,00 p = 0,004 Do not duplicate or distribute without 0,75 1 1,5 2 permissionAnti-VEGF from Anti-EGFR author and ESO
Khattak MA, et al. Clin Colorectal Cancer 2015 [Epub ahead of print]; Patients with unresectable liver metastases: OS is the primary treatment goal
Upfront Classification resectable Borderline resectable Unresectable
10% 20% 70%
1 1 ≈8% CT + ≈12% CT ± Treatment strategy Resection biologic biologic
14%2 Relapse
Required DoCurative not duplicatesurgery orOverall distribute survival / long-termwithout disease control outcome permission4% from author and96% ESO
1. Wong, et al. Ann Oncol 2011; 2. Zakaria, et al. Ann Surg 2007 3. Van Cutsem E et al. Ann Oncol 2014; 4. Adam R … Van Cutsem E et al. Cancer Treat Rev 2015 Drivers for first-line treatment
Treatment Tumour characteristics Patient characteristics characteristics
Clinical presentation:
Tumour burden Age Toxicity profile
Tumour localisation
Tumour biology Performance status Flexibility of treatment administration
RAS mutation status Organ function Socio-economic factors
Comorbidities, patient attitude, BRAF mutation status Quality of life expectation and preference Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016 Treatment of metastatic disease
Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016 Treatment of metastatic disease
Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016 Head to Head-Meta-Analysis based on three phase 2/3 RCTs in the first-line setting of mCRC patients.
Trials, which were considered in the meta-analysis:1
FIRE-32 (Phase 3) Cetuximab + FOLFIRI KRAS-WT mCRC† (n = 592) R Bevacizumab + FOLFIRI
†Retrospektive RAS-Analyse
PEAK3 (Phase 2) Panitumumab + mFOLFOX6 KRAS-WT mCRC† (n = 285) R Bevacizumab + mFOLFOX6 †Präspezifierte RAS-Analyse
CALGB/SWOG 804054,5 (Phase 3) Cetuximab + FOLFOX/FOLFIRI KRAS-WT mCRC† (n = 1137) Do not duplicateR or Bevacizumabdistribute + FOLFOX/FOLFIRI without †Explorative RAS-Analyse Ein dritter Bevacizumab + Cetuximab + FOLFOX/FOLFIRI permission from authorStudienarm wurde amand 10.09.2009 geschlossen ESO
1. Khattak MA, et al. Clin Colorectal Cancer 2015 [Epub ahead of print]; 2. Heinemann V, et al. Lancet Oncol 2014;15:1065−75; 3. Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7; 4. Venook AP, et al. J Clin Oncol 2014;32:5s(Suppl):abstract LBA3 (und Vortrag); 5. Lenz H, et al. Ann Oncol 2014;25(Suppl 4):abstract A5010 (und Vortrag). Metaanalysis: Head to Head studies of anti-VEGF vs anti- EGFR therapy in first line RAS-WT mCRC
OS in RAS-WT Patients, PFS and ORR in RAS-WT Patients, per trial and total total
Study HR (95% KI) % Weight HR (95% KI) % Weight p-value
PFS 0,92 (0,71−1,18) 100 0,50 FIRE-3 0,70 (0,53–0,92) 37,01 ORR 1,46 (1,13−1,90) 100 0,004 PEAK 0,63 (0,39–1,02) 15,87 CALGB 0,90 (0,70–1,10) 47,12 total 0,77 (0,63–0,95) 100,00 A first line anti-EGFR-strategy in patients with mCRC and RAS-WT p= 0,016 status might be superior in terms of OS and ORR compared to anti-VEGF- 0,75 1 based treatment Anti-EGFRDo Anti- VEGFnot duplicate or distribute without permission from author and ESO 2014 patients
Khattak MA, et al. Clin Colorectal Cancer 2015 [Epub ahead of print]. What I want to know today in all my patients? Established predictive biomarkers
Do not duplicate or distribute without permission from author and ESO
Punt CJ et al. Nat Rev Clin Oncol. 2017;14:235. Hotspots of Mutations in KRAS and NRAS
Initially: KRAS testing identifies mutations in codons 12 and 13 of exon 2
KRAS EXON 2 EXON 3 EXON 4
12 13 61 117 146 30-35% ~8% 4% 6–7% RAS NRAS EXON 2 EXON 3 EXON 4
12 13 61 117 146 3–5% 4–6% 0-1%
KRAS/NRAS mutations outside KRAS exon 2 are now tested before using cetuximab and panitumumab Do not duplicate or distribute without permission from author and ESO Excluding additional mutant tumors increases the relative proportion of responsive wt tumors
Increasing relative proportion Detection of additional mutant of wild (wt) population Other tumors that are resistant to responsive to EGFR mAbs mts EGFR mAbs (cetuximab, panitumumab) Resistant wt KRAS 12/13 mt
Responsive wt Enhanced benefit profile for EGFR inhibitors in the more selected populationDo not duplicate or distribute without permission from author and ESO Molecular subtypes in CRC
Can predict lack of response to therapy
Do not duplicate or distribute without permission from author and ESO Midgut vs Hindgut: Right vs Left
Do not duplicate or distribute without permission from author and ESO
World J Gastroenterol. May 7, 2015; 21(17): 5167-5175 • Left sided tumors have a better prognosis than right sided tumors. • Sidedness is predictive in first line treatment of RAS Wt tumours: – Left sided tumors benefit more for anti-EGFR antibodies. – RightDo sided not tumors duplicate benefit slightly or distribute more from bevacizumab without permission from author and ESO Can this COLON biology and “TUMOR biology” be translated into distinct prognostic markers?
Function
Embryology Microbiome
Epigenetics Epigenetics Genetics Methylation Methylation Mutations Proteome Proteome Do not duplicate or distribute without permission from author and ESO
1. Dejea CM, et al. Proc Natl Acad Sci USA 2014;111:18321–18326; 2. Lee MS et al. ASCO 2016 (Abstract 3506); slide: modified from D Aderka 3. Floch M & Netter F. (2010). Netter's gastroenterology. Philadelphia: Saunders/Elsevier; 4. Venook A et al. ASCO 2016. Abstract 3504. Prevalence of CMS According to Sidedness
608 patients with stage I-IV CRC FIRE-3
FIRE-3
Do not duplicate or distribute without permission from author and ESO
Loree JM, et al. Clin Cancer Res 2018 Specific questions/situations for treatment decision in first line treatment
❑ Molecular subgroups in first line ✓ BRAF V600E mutant ✓ MSI ❑ Locoregional treatment ✓ Intraarterial chemotherapy ✓ Radioembolisation ❑ More intense chemotherapy or less intense therapy: ✓ Triplet + anti-EGFR antibody ✓ Oral fluoropyrimidine + bevacizumab Do not duplicate or distribute without permission from author and ESO Pan Asian adapted ESMO guidelines for mCRC
Do not duplicate or distribute without permission from author and ESO
Yoshino T et al, Ann Onc 2018 Preferred choices in first line treatment of mCRC
Goal / condition Molecular Prefered 1st line regimen
Cytoreduction all WT Left: Doublet (FOLFOX)/EGFR (cetuximab) Right: FOLFOX/beva or FOLFOXIRI/beva or FOLFOX/EGFR
RAS mut FOLFOX/beva or FOLFOXIRI/beva
BRAF mut FOLFOXIRI/beva or FOLFOX/beva
Disease stabilization all WT Left: Doublet (FOLFOX)/EGFR (cetuximab) Right: Doublet (FOLFOX)/beva RAS mut Doublet (FOLFOX)/beva
BRAF mut Doublet (FOLFOX)/beva or FOLFOXIRI/beva
„frail“, or chosen no BRAF ! Capecitabine/beva sequentialDotreatment not duplicate or distribute without permission from author and ESO
Adapted from Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus - Ann Oncol, 2016 Arnold D et al. Ann Oncol 2017 Treatment of metastatic disease
Do not duplicate or distribute without permission from author and ESO
Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016 ______
Do not duplicate or distribute without permission from author and ESO Regorafenib and trifluridine/tipiracil in refractory mCRC: CORRECT: regorafenib
______RECOURSE: trifluridine/tipiracil
Do not duplicate or distribute without permission from author and ESO
Grothey, Van Cutsem E et al, Lancet 2013; Mayer R, Van Cutsem E, Ohtsu A et al NEJM, 2015 Optimal Sequence in chemorefractory patients?
Regorafenib Trifluridine/tipiracil
or
Trifluridine/tipiracil Regorafenib
Considerations: ➢ Regorafenib: more patients with long term benefit? ➢ DoTrifluridine/tipiracil: not duplicate more or distributefavourable safety without patterns, but ??permission if compared to from lower authordose of regorafenib and ESO Slide 5
Do not duplicate or distribute without permission from author and ESO COLON CANCER Female, 66y
• Lynch syndrome, germline MSH2 mutation • 2008: endometrium carcinoma – R/ surgery • 7/2013: sigmoidadenocarcinoma pT4N2M1 (MSI-H, RAS mt) – Resection of the primary tumor – 9/2013 – 12/2013: mFolfiri-bevacizumab – 1/2015: Progressive Disease (PD): restart mFolfiri-bevacizumab – 7/2015: PD with cutaneous metastases, retroperitoneal and inguinal lymph nodes – 9/2015: PD, mFolfox-bevacizumab – 11/2015: PD
Do not duplicate or distribute without permission from author and ESO 11/2015: start ipilimumab + nivolumab COLON CANCER Female, 66y
11/2015: start ipilimumab + nivolumab 3/2018 6/2018
Do not duplicate or distribute without permission from author and ESO COLON CANCER Female, 66y
11/2015: start ipilimumab + nivolumab Pseudoprogression
10/2015 11/2015
02/2016 12/2018
Do not duplicate or distribute without permission from author and ESO Mismatch-repair status predicted clinical benefit of immune checkpoint blockade in CRC
Treatment with pembrolizumab (anti-PD-1 antibody) (n=11 mismatch repair-deficient CRC, n=21 mismatch-repair proficient CRC, n=9 mismatch-repair deficient non-CRC) Radiographic responses* OS in CRC
Immune-related ORR in mismatch- Adjusted OS HR for mismatch-repair Do not repairduplicate deficient vs proficientor distribute CRC: deficientwithout vs proficient CRC: 0.18, permission40% vs 0% from author andp=0.05 ESO
Le DT, et al. N Engl J Med 2015. KEYNOTE-164 in MSI-H CRC: Cohort B: Best Percentage Change From Baseline in Target Lesion Sizea
Median duration of follow-up: 100 N=63 12.6 months (range, 0.1-15.4 months) 90 Prior lines of therapy Of 20 responders, 15 had duration of 80 1 70 response ≥6 mo 60 2 50 ≥3 40 30 20 +20% increase in tumor size 10 0 -10 -20 -30 ‒30% decrease in tumor size
Change From Baseline, % Baseline, From Change -40 -50 -60 -70 -80 -90 RR:Do 32 not (21-45)% duplicate or distribute without -100 DCR:permission 57 (44-70)% from author and ESO
aRECIST v1.1 per IRC. Data cutoff: September 12, 2017. Le DT et al, Ann Oncol, ESMO GI/WCGIC Barcelona 2018 Nivolumab in MSI-H mCRC
Do not duplicate or distribute without permission from author and ESO Overman M et al, Lancet Oncol 2017 Durable Responses with nivolumab + ipilimumab in MSI-H mCRC
Do not duplicate or distribute without permission from author and ESO
Overman M….Van Cutsem E et al, J Clin Onc 2018 I-O Therapies as a Critical Backbone for Cancer Treatment
Where we want to be* I-O Combination with I-O therapy COMBINATION THERAPY Survival I-O monotherapy Where we are Targeted therapy Chemotherapy/TKI Time
I-O combination therapies have demonstrated durable benefit across a number of tumor types1,2 • Nivolumab + ipilimumab demonstrated benefit over SOC in NSCLC, melanoma, and RCC3-5 • Pembrolizumab + chemotherapy, atezolizumab + chemotherapy demonstrated benefit over SOC in NSCLC6-8 Many ongoing efforts are investigating I-O therapies as the backbone for novel combinations *Hypothetical chart illustratingDo a scientific not concept thatduplicate is beyond data available so far. or This chart distribute is not intended to predict what without may actually be observed in clinical studies. 1. Voena C, Chiarle R. Discov Med. 2016;21(114):125-133. 2. Sharma P, Allison JP. Cell. 2015;161(2):205-214. 3. Bristol-Myers Squibb [press release]. February 5, 2018. 4. Larkin J et al. N Engl J Med 2015;373(13):1270-1271. 5. Motzer RJ et al. Oral presentation at SITC 2017. O38. 6. Merck & Co. [press release]. January 18, 2018. 7. Reck et al. Oral Presentation at ESMO IO 2017. LBA1.permission 8. Roche [press release]. March 20, 2018.from author and ESO
40 Phase III trial of Cobimetinib and Atezolizumab in chemotherapy-refractory mCRC (COTEZO – IMBlaze 370)
Atezolizumab + PD Patients with cobimetinib unresectable locally advanced or metastatic CRC R Atezolizumab PD (received at least 2 chemotherapy regimens)* n=360 Regorafenib PD 2:1:1
Primary endpoint = OS
*Experienced Dodisease notprogression duplicate or was intolerant orto at distribute without least two systemic chemotherapy regimens including fluroropyrimidines,permission irinotecan, or oxaliplatin from author and ESO
NCT02788279 Phase III trial of Cobimetinib and Atezolizumab in chemotherapy-refractory mCRC Overall survival (COTEZO – IMBlaze 370) Atezo + cobi Atezo Rego (n = 183) (n = 90) (n = 90) Median OS, mo 8.9 7.1 8.5 (95% CI) (7.00, 10.61) (6.05, 10.05) (6.41, 10.71) HR vs rego 1.00 1.19 N/A (95% CI) (0.73, 1.38) (0.83, 1.71) P value 0.9871 0.3360a N/A 12-mo OS, % 38.5% 27.2% 36.6%
Do not duplicate or distribute without permission from author and ESO
N/A, not applicable. HRs are from stratified log-rank tests. Data cutoff: March 9, 2018. a For descriptive purposes only. Bendell J et al, ESMO GI/WCGIC 2018 Conclusions: check-point inhibitors in mCRC o Pembrolizumab provided durable responses in MSI-H CRC patients who received ≥1 prior therapy o Nivolumab with or without ipilimumab provided durable responses in MSI-H CRC patients who received ≥1 prior therapy o Nivolumab and pembrolizumab (chemorefractory) and atezolizumab (maintenance): no activity in MSS patients o Nivolumab + ipilumumab: no activity (very modest) in MSS patients o Atezolizumab + cobimetinib no activity in pretreated MSS patients o Darvalumab + tremelimumab: modest survival benefit, but no PFS improvement in randozimed phase 2 compared to BSC in MSS patients - TBC o Ongoing phase 3 studies in earlier lines in MSI tumors: eg ✓ Stage III: FOLFOX ± CPI ✓ First lineDo compared not toduplicate chemo in MSI (KEYNOTE-177 or distribute study (NCT0256300 without2)) permission from author and ESO Major immunotherapeutic approaches
Many novel approaches over and above the NOBEL checkpoint inhibitors:
Adoptive transfer: Anti-cancer transfer of Checkpoint vaccines cells into blockade patients
Microen- Do not duplicatevironment or distribute without permission from author and ESO BRAFV600E mutation in mCRC
▪ Occurs in 10%–15% of patients and confers a poor prognosis1,2 MAPK Signaling in Colorectal Cancer10 ▪ Standard therapies have limited benefits after ≥1 line of treatment: ▪ Median OS 4–6 mo, median PFS ~2 mo and ORR <10%1,3-5 ▪ SWOG S1406 results with vemurafenib, irinotecan, cetuximab (VIC): Median OS of 9.6 mo, median PFS of 4.3 mo, and ORR in 16% (confirmed + unconfirmed)6
▪ BRAF inhibitors cause feedback activation of EGFR in BRAF-mutant CRC, leading to continued cell proliferation7,8 ▪ Feedback may be overcome by targeting multiple nodes in the pathway
▪ Updated mature phase 2 results with doublet of ENCO + CETUX*: MedianDo OS not of 9.3 duplicate mo, median PFS or of 4.2distribute mo and without ORR in 24%9
* Data cut-off January 2018; last patientpermission enrolled 14 April 2015. Full updatedfrom data to authorbe presented at future and meeting. ESO
1. Loupakis F, et al. Br J Cancer. 2009;101:715. 2. Tie J, et al. Int J Cancer. 2011;128:2075. 3. De Roock W, et al. Lancet Oncol. 2010;11(8):753. 4. Mitani S, et al. Ann Oncol. 2017;28(5s). 5. Ulivi P, et al. J Transl Med. 2012;10:87. 6. Kopetz S, et al. J Clin Oncol. 2017;35(15):3505. 7. Corcoran RB, et al. Cancer Disc. 2012;2(3):227. 8. Prahallad A, et al. Nature 2012;100:100. 9. Tabernero J, et al. J Clin Oncol. 2016;34:3544. 10. Adapted From: Strickler JH. Cancer Treatment Reviews. 2017; 60:109. BEACON Study: lead in part
Triple combination: EGFR inhibitor (cetuximab) + BRAF inhibitor (encorafenib) + MEK inhibitor (binimetinib)
1 1 0 0 Cetuximab + Irinotecan from SWOG S1406
8 0 Partial Response (n=11) 6 0 Complete Response (n=3)
4 0
2 0
0
-2 0 Confirmed RR: 48% -4 0 PFS: 8.0 mo -6 0 Med Surv: 15.3 mo
-8 0 Best % Best % Change from Baseline
-1 0 0 26 1 17 2 16 9 14 7 8 13 28 25 24 23 27 15 12 4* 22 21 19 20 18 11 6* 10 3 5* Do not duplicatePatients †or distribute without Best Percentage Change in Tumor Measurements from Baseline *Patients with lymph node diseasepermission with decreases in short axis dimensions from consiste authornt with RECIST 1.1 definedand Complete ESO Response. †One patient had no baseline sum of longest diameters and is not presented. 1. Kopetz S, et al. J Clin Oncol. 2017;35:Abstr 3505, with permission.
Van Cutsem E et al, ESMO GI/WCGIC –Barcelona Ann Onc 2018;29(suppl 5):abstr A-O-027 Van Cutsem E et al, J Clin Oncol 2019 Phase III: BEACON Study
Do not duplicate or distribute without permission from author and ESO
ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02928224. Accessed October 26, 2017. Non-V600 BRAF mutations
✓ Codon 594/596 kinase activity impaired ✓ Favorable prognosis ✓ L sided ✓ Male > female ✓ Low grade; not mucinous ✓ (+) KRAS mut; (-) MSI ✓ No peritoneal spread a ✓ Codon 601/597 similar to V600E Do not duplicate or distribute without permission from author and ESO Cremolini et al. Ann Oncol 2016; Jones et al. J Clin Oncol 2017; Schirripa et al. J Clin Oncol, 2018 (suppl; abstr 3590) Van Cutsem E et al, J Clin Oncol 2017 Molecular subtypes in CRC
Can predict response to therapy
Do not duplicate or distribute without permission from author and ESO New Molecular Subtypes in Colorectal Cancer May Help to Predict Response to Therapies
Colorectal cancer subtypes: CMS
Transverse MSI Immune (14%) colon • MSI, CIMP high, hypermethylation • BRAF mutations • Immune infiltration/activation • Worse survival after relapse Ascending colon Sigmoid Descending Canonical (37%) colon • SCNA high colon • WNT and MYC activation
Mesenchymal (23%) • SCNA high • Stromal infiltration, TGF-β activation, angiogenesis • Worse relapse-free and overall survival
Metabolic (13%) Rectum • Mixed MSI status, SCNA low, CIMP low • KRAS mutations Do •notMetabolic duplicate deregulation or distribute without permission from author and ESO CMS: consensus molecular subtypes Guinney J et al. Nat Med. 2015;21:1350.. CRC subtypes
Do not duplicate or distribute without permission from author and ESO
Dienstmann R et al, Nat Rev Cancer, 2017 Do not duplicate or distribute without permission from author and ESO