ESMO Preceptorship Programme Colorectal Cancer Valencia, 18th May 2018 Review of the ESMO consensus conference on metastatic colorectal cancer Basic strategies and groups Chemotherapy and targeted agents in 1st line Chiara Cremolini University of Pisa Azienda Ospedaliero-Universitaria Pisana
Disclosures Consultant/Honoraria: Amgen, Bayer, Eli Lilly, Merck, Roche
Drivers of first-line choice according to ESMO guidelines Patient clinical characteristics Treatment characteristics Performance status Comorbidities Expectations/Attitu de QoL Toxicity profile Age Prior adjuvant treatment Organ function Flexibility of tx administration Socioeconomic factors Tumour molecular characteristics Tumour clinical characteristics RAS BRAF Tumour burden and localisation Related symptoms Resectability Tumour biology (Aggressiveness)
1 st -line choice TODAY BIOMARKERS CLINICAL FACTORS
Van Cutsem et al., Ann Oncol 17 1st line treatment of mcrc: ESMO consensus guidelines 1 - Patient 2 - Treatment intent 3 - RAS/BRAF
On top of ESMO algorithm 1 - Patient a) According to medical condition not due to malignant disease Van Cutsem et al, Ann Oncol 16
On top of ESMO algorithm 1 - Patient 2 - Treatment intent a) According to medical condition not due to malignant disease Van Cutsem et al, Ann Oncol 16
Multidisciplinary Assessment EASILY RESECTABLE MARGINALLY RESECTABLE POTENTIALLY RESECTABLE NEVER RESECTABLE Group* 0 Group* 1 Group* 2 High load Group* 3 Low load CURE!!!!!! DISEASE CONTROL Integration with surgery More intensive tx approach Less intensive tx approach *According to ESMO 2012 clinical guidelines
To cure? Yes, WE CAN! Survival following hepatectomy for colorectal liver metastases 10yr OS 28% 10yr OS 20% Jones and Poston, Annu Rev Med 2017
Treatment goal Clearly resectable mets Surgery +/- adjuvant oxaliplatin-based chemo (favourable prognostic criteria) Oxa-based doublet Surgery Oxa-based doublet (unfavourable prognostic criteria) No targeted agents
Technically easily resectable disease: which choice? Adapted from Van Cutsem et al., Ann Oncol 2016
Treatment goal Clearly resectable mets OMD CYTOREDUCTION (Shrinkage)
Resectability: an evolving scenario 1) Surgeons not always agree Surgical review by surgeons with experience in hepatobiliary surgery in CELIM study Febbraio 2010 embolizzazione portale 41% disagreement Folprecht et al, Lancet Oncol 2010
Multidisciplinary Assessment EASILY RESECTABLE MARGINALLY RESECTABLE POTENTIALLY RESECTABLE NEVER RESECTABLE Surgical and locoregional approaches Active systemic regimens
Surgical treatment after CT+Cetux or Beva in FIRE-3 Technically resectable after treatment Resected 22% of patients were considered potentially eligible for surgery at study entry Modest, EJC 2017
Overall survival according to surgical treatment in FIRE-3 Resectable Resected Unresectable Resectable NOT Resected Modest, EJC 2017
Multidisciplinary Assessment EASILY RESECTABLE MARGINALLY RESECTABLE POTENTIALLY RESECTABLE NEVER RESECTABLE Biologically-informed estimation of tumor biology (BRAF MSI gene signatures) Surgical and locoregional approaches Active systemic regimens
Resected liver mets: outcome according to RAS/BRAF mutations - RFS No previous chemotherapy Resected after FOLFOXIRI + bev Schirripa et al, Br J Cancer 15 Cremolini et al, Eur J Cancer 17
New Prognostic Biomarkers 20 genes expression assay Molecular Risk Score Balachandran et al, Clin Cancer Res 2016
Doublet + anti-egfr vs bev in RAS wt mcrc: meta-analysis of head-to-head trials Overall Response Rate Heinemann et al, EJC 2016
Mean Change From Baseline, % FIRE-3 and PEAK: Depth of response Tumor Response-Related Efficacy RAS WT Population Panitumumab + Bevacizumab + DoR, months (95% CI) 11.4 (10.0, 16.3) 9.0 (7.6, HR (95% CI); P value 0.59 (0.39, 0.88); 0.011 CI) 2.3 (1.9, 3.7) 3.8 (2.1, HR (95% CI); P value 1.19 (0.81, 1.74); 0.37 DpR, months (Q1, Q3) 65.0 (45.7, 89.5) 46.3 (29.5, P value 0.0018 Stintzing et al, Lancet Oncol 16 Mean (95% CI) Percentage Change From Baseline In Tumor Load O 0-20 -40-60 -80-100 Bmab + mfolfox6 Pmab + mfolfox6 p<0.0001 0 8 16 24 32 40 48 56 64 72 80 Weeks Pmab + mfolfox6 88 80 70 63 53 42 42 27 25 17 17 Bmab + mfolfox6 81 74 66 57 45 36 26 22 13 11 8 CI, confidence interval; DoR, dura Rivera et al, DpR, depth ECC Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014. of response; 15 ETS, earl
FOLFOXIRI+Bev: OLIVIA trial * Primary end-point: Radical resection rate 3 mets: 92-95% *no upfront R0/R1 resection <30% estimated residual liver Disease in contact with major vessels FOLFOXIRI + bev N = 41 mfolfox-6 + bev N = 39 Overall Response Rate 81% 62% R0/R1/R2 surgery 61% 49% R0 surgery 49% 23% Median PFS 18.5 11.5 Median OS NR 32.2 Gruenberger et al, Ann Oncol 2014
FOLFOXIRI+Bev in liver-limited mcrc: pooled analysis by GONO Pooled analysis of patients with liver-limited disease (LLD) from FOIB, TRIBE and MOMA Patients with clearly initially unresectable LLD, not selected with conversion intent n=205 RECIST response n=137 (69%) R0/R1 resection n=75 (37%) Characteristics, % patients n=205 Synchronous metastases 90% 4 metastases 61% Bilobar distribution 79% Larger metastasis >5cm 42% Median PFS, months R0/R1 resected (n=75) R0 resected (n=63) 18.1 18.3 5-year PFS rate 10% 12% Median OS, months 44.3 56.6 5-year OS rate 42% 43% Cremolini et al, Eur J Cancer 17
FOLFOXIRI+Bev in initially unrectable mcrc: pooled analysis Tomasello et al, JAMA Oncol 2017
Triplet + biologic agent vs Doublet + biologic agent: METHEP-2 trial Ychou et al., ASCO 2016
FOLFOXIRI+Cet: MACBETH trial 116 RAS/BRAF wt Unresectable mcrc pts R 1:1 FOLFOXIRI+Cet N=59 Maintenance Cet Primary end-point: 10m-PFR FOLFOXIRI+Cet N=57 Maintenance Bev Arm A Arm B All % patients N = 59 N = 57 N = 116 Overall Response Rate 68% 75% 72% R0/R1/R2 surgery 47.5% 29.8% 38.8% R0 secondary surgery 35.6% 21.1% 28.4% Liver-only subgroup N = 28 N = 24 R0/R1/R2 surgery 75.0% 58.3% 67.3% R0 secondary surgery 60.7% 41.7% 51.9% Cremolini et al, JAMA Oncol 18
MACBETH main results Safety G3/4 adverse events, % patients Arm A N = 59 Arm B N = 57 Overall N = 116 Nausea 1.7% 0% 0.9% Vomiting 3.4% 1.0% 2.6% Diarrhea 20.3% 15.8% 18.1% Stomatitis 6.8% 5.3% 6.0% Neutropenia 28.8% 33.3% 31.0% Febrile neutropenia 3.4% 1.8% 2.6% Skin rash 18.6% 12.3% 15.5% Cremolini et al, JAMA Oncology 18
Arm B Arm A VOLFI trial: activity results mcrc pts: Unresectable disease Previously untreated for mts disease RAS wt R 2:1 mfolfoxiri* + Panitumumab up to 12 cycles FOLFOXIRI up to 12 cycles *irinotecan 150mg/sqm; oxaliplatin 85 mg/sqm; LV 200 mg/sqm; 5FU: 3000 mg/sqm Primary endpoint: Objective Response Rate mfolfoxiri+pa n N=63 Activity FOLFOXIRI N=33 Response Rate 85.7% 60.6% 3.90 0.0096 RAS/BRAF wt Left-sided tumors Right-sided tumors N=43 N=17 86.0% 64.7% N=53 N=25 90.6% 68.0% N=10 N=8 60.0% 37.5% OR p 3.36 0.0806 4.52 0.0210 2.50 0.64 Progression-free Survival 10.8 mos 10.5 mos 1.11 0.66 Resection Rate (potentially resectable cohort, n=31) 70.0% 36.4% - 0.13 Geisseler et al, ESMO Congress 2017
TRIPLETE study by G.O.N.O. Phase III random mfolfox6+pani (up to max 12 cycles) 5-FU/LV +Pani RAS and BRAF wt mcrc pts 1st line unresectable R PD mfolfoxiri+pani (up to max 12 cycles) 5-FU/LV +Pani Stratification factors: PS 0-1 vs 2; primary tumor location (right vs left or rectum); previous adjuvant chemotherapy; liver-only metastases. INDUCTION MAINTENANCE Primary endpoint: Response Rate Target accrual: 432 pts
First-line options: cytoreduction intent Goal / condition Molecular Cytoreduction all WT RAS mut BRAF mut Preferred 1st line regimen Doublet/anti-EGFR FOLFOXIRI (Doublets)/beva FOLFOXIRI/beva Van Cutsem et al, Ann Oncol 16
Main ingredients according to ESMO guidelines Patient clinical characteristics Treatment characteristics Performance status Comorbidities Expectations/Attitu de QoL Toxicity profile Age Prior adjuvant treatment Organ function Flexibility of tx administration Socioeconomic factors Tumour molecular characteristics Tumour clinical characteristics RAS BRAF Tumour burden and localisation Related symptoms Resectability Tumour biology (Aggressiveness) Primary tumour location
Right versus Left colon
Right versus Left BRAF-like signature PIK3CA mutations dmmr CIMP-high Low AREG-EREG expression CMS1(Immune) mir-31-3p high EGFR promoter methylation ALK/ROS1/NTRK rearrangements Lee et al., Br J Can 16 Missiaglia et al., Ann Oncol 14 Guinney et al., Nat Med 15 Laurent-Puig et al., ESMO 16 Puzzoni et al, ASCO GI 17 Pietrantonio et al, JNCI 17
Right versus Left RAS wt: metanalysis of head-to-head trials - OS
Right versus Left RAS wt: metanalysis of head-to-head trials - PFS J. W. Holch et al, EJC 2016
Right versus Left RAS wt: metanalysis of head-to-head trials - RR
TRIBE: sidedness subgroups- OS FOLFIRI plus bev, left N= 129 FOLFOXIRI plus bev, left N = 113 FOLFIRI plus bev, right N = 44 FOLFOXIRI plus bev, right N = 72 Left-sided: HR= 0.99 [95%CI: 0.73-1.35] Right-sided: HR= 0.56 [95%CI: 0.37-0.85] p for interaction=0.030 Cremolini et al, Ann Oncol 18
FOLFOXIRI+bev vs FOLFIRI+bev: HRs according to sidedness and mutational status 2.1 1.6 1.74 2.02 1.1 0.6 0.1 0.540.50 0.67 0.67 0.33 0.22 1.02 0.85 0.88 0.88-0.4 Modified by Cremolini et al, Ann Oncol 18 HRs for PFS HRs for OS
First-line options: cytoreduction intent Goal / condition Molecular Preferred 1st line regimen Cytoreduction all WT Left: Doublet/anti-EGFR Right: FOLFOXIRI/beva (Doublet/anti-EGFR) RAS mut FOLFOXIRI (Doublets)/beva BRAF mut FOLFOXIRI/beva Waiting for more robust data with triplet plus anti-egfr Arnold et al, Ann Oncol 17
Treatment goal Clearly resectable mets OMD CYTOREDUCTION (Shrinkage) DISEASE CONTROL
First-line options: disease stabilization intent Goal / condition Disease stabilization Molecular all WT RAS mut Preferred 1st line regimen Doublet/anti-EGFR or Doublet/bev Doublet/bev BRAF mut FOLFOXIRI/bev Van Cutsem et al, Ann Oncol 16
First-line options: disease stabilization intent Goal / condition Disease stabilization Molecular Preferred 1st line regimen all WT Left: Doublet/anti-EGFR Right: Doublet/bev (FOLFOXIRI/bev) RAS mut Doublet/bev BRAF mut FOLFOXIRI/bev Arnold et al, Ann Oncol 17
1st line treatment of mcrc: updated evidence-based algorithm 1 - Patient Cremolini et al, Nat Rev Clin Oncol 17
FOLFOXIRI + bev provides consistent efficacy results FOIB 1 n=57 TRIBE 2 n=252 OPAL 3 n=97 STEAM 4 n=93 MOMA 5 n=232* CHARTA 6 n=125 QUATTRO 7 n=69 JACCRO CC-11 8 n=62** Response rate 77% 65% 64% 60% 63% 70% 72% 76% Disease control rate Median PFS, mos 100% 90% 87% 91% 91% N/A 99% NA 13.1 12.3 11.1 11.9 9.5 12.0 13.3 11.5 Median OS, mos 30.9 29.8 32.2 34.0 Too early 28.0 Not reached Not reached *>70% patients with RAS or BRAF mutation ** only RAS mutant 1. Masi et al. Lancet Oncol 2010; 2. Cremolini et al. Lancet Oncol 2015 3. Stein et al. Br J Cancer 2015; 4. Bendell et al. ASCO GI 2017 5. Falcone et al. ESMO 2016; 6. Schmoll et al. ASCO 2017 7. Yamazaki et al. JSCO 2017; 8. Miyamoto et sl. JSCO 2017
TRIBE: Secondary endpoint - OS MEDIAN F-UP 48.1 mos (74% events) FOLFIRI + bev: N = 256 / Died = 200 FOLFOXIRI + bev: N = 252 / Died = 174 FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 29.8 mos HR: 0.80 [0.65-0.98] p=0.030 Cremolini et al, Lancet Oncol 2015
with consistent safety results Grade 3/4 Adverse Events, % TRIBE 1 n=252 OPAL 2 n=97 STEAM 3 n=93 MOMA 4 n=232 CHARTA 5 n=125 Diarrhoea 18.8% 11% 10% 13% 16% Stomatitis 8.8% 4% 3% 4% 3% Neutropenia 50.0% 26% 57% 52% 21% Hypertension 5.2% 3% 22% 4% 7% VTE events 7.2% 5.0% 7% 3% 2% 1. Loupakis et al. N Engl J Med 2014 2. Stein et al. Br J Cancer 2015; 3. Bendell et al. ASCO GI 2017 4. Falcone et al. ESMO 2016; 5. Schmoll et al. ASCO GI 2017
Decision drivers for FOLFOXIRI plus bev FOLFOXIRI plus bev appropriateness
1st line treatment of mcrc: updated evidence-based algorithm 1 - Patient Cremolini et al, Nat Rev Clin Oncol 17
1st line treatment of mcrc: updated evidence-based algorithm 1 - Patient 2 - RAS/BRAF 3 - Tumor location Cremolini et al, Nat Rev Clin Oncol 17
1st line treatment of mcrc: future perspectives Triplet + anti-egfr Cremolini et al, Nat Rev Clin Oncol 17
A turning point in MSI-high mcrc Le et al, Science 2017
The first tissue-agnostic indication 23rd May 2017
EMA opinion
Nivolumab +/- ipilimumab in MSI-high chemorefractory mcrc Overall Survival (%) No. at Risk Progression-free survival (%) c 100 90 80 70 60 50 40 30 20 10 0 Nivolumab + ipilimumab Nivolumab Nivolumab + ipilimumab a,b 0 3 6 9 12 15 18 21 24 Months Nivolumab 1,e,f 9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5] 12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4] 27 30 Nivolumab + ipilimumab 119 95 86 78 39 12 11 10 3 0 0 Nivolumab 74 48 41 32 17 12 12 11 6 3 0 100 90 80 70 60 50 40 30 20 10 0 Nivolumab + ipilimumab Nivolumab Nivolumab + ipilimumab a,d 0 3 6 9 12 15 18 21 24 Months Nivolumab 1,e,f 9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7] 12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1] 27 30 33 119 113 107 104 78 33 19 17 11 0 0 0 74 64 59 55 37 21 19 17 11 6 1 0 Overman et al, ASCO GI 18 and Lancet Oncol 17 Andrè et al, ASCO GI 18 and J Clin Oncol 18
Ongoing phase III trials in first-line Title NCT Target population Trial Design Status Primary Endpoint Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dmmr) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177) 02563002 dmmr or H-MSI stage IV CRC not pretreated for metastatic disease. Arm A: Pembrolizumab 200mg IV q21d for up to 35 administrations. Arm B Standard of care (mfolfox6 or FOLFIRI + bevacizumab/cetuximab Active, not recruiting PFS OS Colorectal Cancer Metastatic dmmr Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mfolfox6/bevacizumab Combination Chemotherapy With or Without Atezolizumab or Atezolizumab Monotherapy in the First-Line Treatment of Patients With Deficient DNA Mismatch Repair (dmmr) Metastatic Colorectal Cancer 02997228 dmmr metastatic CRC ArmA (control): mfolfox6+bevacizumab ArmB Atezolizumab ArmC mfolfox6+bevacizumab+ atezolizumab Recruiting PFS Clinicaltrials.gov
1st line treatment of mcrc: future perspectives Microsatellite instability MSS MSI-high Immunotx Triplet + anti-egfr Cremolini et al, Nat Rev Clin Oncol 17
Take home message The choice of the first-line treatment has a crucial mission in mcrc: to achieve disease control, in order to allow further interventions (systemic treatments and locoregional tools) Though recognizing the importance of exposing mcrc patients to all available treatment options across different lines of treatment (sequencing, continuum of care ), the impact of the first-line treatment on the disease history is the most relevant Today a mix of clinical and molecular factors contribute to the therapeutic decision-making process the contribution of molecular markers will probably increase in the next future
chiaracremolini@gmail.com