ADVANCED COLORECTAL CANCER: UNRESECTABLE OR BORDERLINE RESECTABLE (GROUP 1) CHEMOTHERAPY +/- TARGETED AGENTS Andrés Cervantes Professor of Medicine
1995 One option Advances in the treatment of mcrc 2000 More options 2016 Many options 5-FU First-line efficacy RR 20% mttp 5 6 months mos 10 12 months Issues Low efficacy 5-FU Oral fluoropyrimidines Irinotecan Oxaliplatin RR 50% mttp 8 9 months mos 17-21 months Optimal regimens Sequencing Treatment duration 5-FU Oral fluoropyrimidines Irinotecan Oxaliplatin Cetuximab, Panitumumab Bevacizumab, Aflibercept, Ramucirumab Regorafenib, TAS-102 RR 50%+ mttp 9+ months mos 22+ months Cure Optimal regimens Correct sequencing & dosing Cost Biomarkers
SURVIVAL OF PATIENTS WITH METASTATIC CRC OVER DECADES Kopetz et al. JCO 2009
Targeting the EGFR pathway in CRC EGF TGF-α Amphiregulin Epiregulin EGFR expression 27 95% EGFR Sos KRAS KRAS mutation 30 50% Grb2 BRAF EGFR mutation <1% MEK BRAF mutation 5-10% MAPK TGF = transforming growth factor Adapted from Roberts and Der. Oncogene 2007
GENOMICS DRIVEN CANCER MEDICINE Garraway LA, Verwey J, Ballman K. J Clin Oncol 2013
ESMO GUIDELINES
GROUPS OF PATIENTS WITH METASTATIC COLORECTAL CANCER Group 0 Primarily technically R0-resectable liveror lung metastases and no biological relative contraindications Group 1 Potentially resectable metastatic disease with curative intention if downsizedbychemotherapy Group 2 Disseminated disease, technically never /unlikely resectable intermediateintensivetreatment Group 3 Never-resectable metastatic disease non-intensive sequential treatment Van Cutsem, E, Cervantes A, Nordlinguer B, Arnold, D. Ann Oncol 2014 (suppl 3) 25:iii1-iii9
RESECTION RATE OF METASTASES AND TUMOR RESPONSE,6,5,4 Studies includingselected patients (liver metastases only, no extrahepaticdisease) (r=0.96; p=0.002),3,2 Studies includingall patients with mcrc (solid line) (r=0.74; p<0.001),1 0,0,3,4,5,6,7,8,9 Response rate Phase III studies including all patients with mcrc (dashed line) (r=0.67; p=0.024) Folprecht et al. Ann Oncol 2005;16:1311 1319.
Bevacizumab in advanced CRC: ORR from randomized trials First-line Second-line 50 45 40 35 38 38 ORR (%) 30 20 22 10 9 0 Bevacizumab Placebo Bevacizumab Placebo Bevacizumab IFL XELOX/FOLFOX FOLFOX p=0.004 p=0.99 p<0.0001 Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007
Bevacizumab in advanced CRC: PFS from randomized trials 14 First-line Second-line PFS (months) 12 10 8 6 4 8,8 5,6 10,6 6,2 9,4 8 7,2 4.8 2 0 Bevacizumab Placebo Bevacizumab Placebo Bevacizumab Placebo Bevacizumab 5-FU/LV p<0.0001 Kabbinavar et al. JCO 2005 IFL XELOX/FOLFOX FOLFOX p<0.001 p<0.0001 p<0.0001 Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007
Bevacizumab in advanced CRC: OS from randomized trials OS (months) First-line 25 20 15 10 21,3 20,3 19,9 17,9 15,6 14,6 Second-line 12.9 10.8 5 0 Bevacizumab Placebo Bevacizumab Placebo Bevacizumab Placebo Bevacizumab 5-FU/LV p=0.008 Kabbinavar et al. JCO 2005 IFL XELOX/FOLFOX FOLFOX p<0.001 p=0.077 p=0.002 Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007
FOLFOXIRI combinations in first line therapy n RR PFS OS FOLFOXIRI/Bev 252 65% 12.1 31.0 FOLFIRI/Bev 256 53% 9.7 25.8 Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 Loupakis, NEJM 2014
FOLFOXIRI combinations in first line therapy n RR PFS (mo) OS (mo) FOLFOXIRI/Bev 252 65% 12.1 31.0 FOLFIRI/Bev 256 53% 9.7 25.8 Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 FOLFOXIRI 122 60% 9.8 22.6 FOLFIRI 122 34% 6.9 16.7 Falcone, JCO 2007 p<0.0001 HR 0.63; p<0.01 HR0.80;p=0.032 FOLFOXIRI/Bev 41 81% 18.8 NR FOLFOX/Bev 39 62% 12.0 32 *Grünberger, AoO 2015 p=0.061 p<0.01 * Liver only mets
PRIME trial FOLFOX4 ±panitumumab in 1 st -line treatment of mcrc mcrc (n = 1183) R 1:1 Panitumumab 6 mg/kg (Q2W) + FOLFOX4 (Q2W) FOLFOX4 (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 Design amended to focus on prospective hypothesis testing in the KRAS WT stratum Study endpoints: PFS (1º); OS, ORR, safety, HRQoL Douillard JY, et al. J C lin Oncol 2010;28:4697 705; www.amgentrials.com; protocol ID: 20050203; ClinicalTrials.gov identifier: NCT00364013. WT in codons 12 and 13. HRQoL, Health-related quality of life; mcrc, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; ORR, objective response rate.
KRAS, NRAS and BRAF mutation hotspots in the PRIME study EXON 1 KRAS EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 40% 4% 6% EXON 1 NRAS EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 3% 4% 1% EXON 1 BRAF EXON 15 EXON 16 600 8% All RAS mutation testing might identify an additional 15 20% mutants 15
PRIME RAS/RAF OS analysis* Proportion alive (%) 100 90 80 70 60 50 40 30 20 10 0 Original WT KRAS exon 2 testing HR = 0.83 (95% CI, 0.67 1.02) P = 0.072 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 325) 165 (51) 23.9 (20.3 28.3) FOLFOX4 (n = 331) 190 (57) 19.7 (17.6 22.6) Overall survival Proportion alive (%) 100 90 80 70 60 50 40 30 20 10 WT RAS HR = 0.78 (95% CI, 0.62 0.99) P = 0.043 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 (21.7 30.4) FOLFOX4 (n = 253) 148 (58) 20.2 (17.7 23.1) 1. Douillard JY, et al. J Clin Oncol 2010;28:4697 705; 2. Douillard JY et al New Engl J Medicine Sept 12 2013. *Predefined retrospective analysis; 7 patients harbouring Codon 59 mutations were not excluded from this analysis.
RAS mutation rates: first-line studies Patients with KRAS codon 12/13 wild-type tumors Study CALGB/SWOG 80405 Evaluable patients* Method Other RAS mutations, % 670 BEAMing 15.3 OPUS 118 BEAMing 26.3 CRYSTAL 430 BEAMing 14.7 FIRE-3 407 Pyrosequencing 16.0 PRIME 620 Dideoxy sequencing/wave 17.4 PEAK 221 Dideoxy sequencing/wave 23.1 *For other tumor RAS mutations 5% mutant/wild-type alleles diagnostic cutoff 1% mutant/wild-type alleles diagnostic cutoff KRAS codons 59 and 117 not considered KRAS and NRAS codon 59 not considered
CRYSTAL study design EGFR-expressing, previously untreated, mcrc Stratification factors: ECOG performance status Region R n=1198 (KRAS codon 12/13 WT, n=666: PCR clamping and melting curve analysis) FOLFIRI + cetuximab n=599 (KRAS codon 12/13 WT, n=316) FOLFIRI n=599 (KRAS codon 12/13 WT, n=350) FOLFIRI (q2w) Cetuximab Irinotecan LV 5-FU 180 mg/m 2, day 1 200 mg/m 2 *, day 1 400 mg/m 2 bolus, then 2400 mg/m 2 infusion over 46 h 400 mg/m 2 initial dose then 250 mg/m 2 weekly Treatment until disease progression, unacceptable toxicity, withdrawal of consent *L-form; 400 mg/m 2, racemic. 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; LV, leucovorin; PCR, polymerase chain reaction; R, randomization; WT, wild-type Van Cutsem E, et al. N Engl J Med 2009;360:1408-17 Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9 Presented by: Eric Van Cutsem
CRYSTAL EXTENDED RAS MUTATION: Overall survival KRAS codon 12/13 wild-type 1 RAS wild-type Probability of OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 No. of events Median, months 95% CI 0.2 0.1 FOLFIRI + cetuximab 0.0 FOLFIRI 0 6 12 18 24 30 36 42 48 54 Months 242 23.5 21.2 26.3 288 20.0 17.4 21.7 HR (95% CI) 0.80 (0.67 0.95) Probability of OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. of events Median, months 95% CI HR (95% CI) 0.69 (0.54 0.88) FOLFIRI + cetuximab FOLFIRI 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Months 130 28.4 24.7 31.6 154 20.2 17.0 24.5 Number of patients at risk 316 281 237 198 144 108 82 65 21 4 350 311 246 179 132 92 64 48 18 2 Number of patients at risk 178 174 163 155 142 140 128 108 97 89 73 66 56 52 45 29 16 5 3 0 189 182 171 160 135 115 98 85 79 70 58 47 38 32 28 20 10 6 2 0 1 Van Cutsem E, et al. J Clin Oncol 2011;29:2011-9 Ciardiello F, et al WGICC 2014
FIRE-3 study design mcrc 1st-line therapy KRAS wild-type Randomize 1:1 FOLFIRI + Cetuximab Cetuximab: 400 mg/m 2 i.v. 120min initial dose 250 mg/m 2 i.v. 60min q 1w FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v. 30-90min q 2w FOLFIRI q2w: 5-FU: 400 mg/m 2 (i.v. bolus); folinic acid: 400mg/m 2 irinotecan: 180 mg/m 2 5-FU: 2,400 mg/m 2 (i.v. 46h) Primary endpoint: Overall response rate (RECIST 1.0) Amendment in October 2008 to include only KRAS wild-type patients 150 active centers in Germany and Austria Stintzing S et al. Proc ECCO 17 th 2013
Overall survival Final RAS* wild-type population Probability of survival 1.0 0.75 0.50 0.25 Δ = 8.1 months Events n/n (%) FOLFIRI + Cetuximab 107/199 (53.8%) FOLFIRI + Bevacizumab 133/201 (66.2%) Median (months) 95% CI 33.1 24.5 39.4 25.0 23.0 28.1 HR 0.697 (95% CI: 0.54 0.90) p (log-rank)= 0.0059 No. at risk 0.0 199 201 12 24 36 48 60 72 months since start of treatment 147 147 79 82 46 34 23 11 7 1 * KRAS and NRAS exon 2, 3 and 4 wild-type
Independent evaluation of response CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 wt n= 493 66.5 60.1 72.5 55.6 49.3 61.8 1.58 (1.10-2.28) 0.016 Final RAS wt n= 330 72.0 64.3 78.8 56.1 48.3 63.6 2.01 (1.27-3.19) 0.003 p = Fisher s exact test (two-sided)
Evaluation of ETS Rate (Early Tumor Shrinkage) Rate of Early Tumor Shrinkage* CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 wt n= 493 62.3 55.8 68.5 47.9 41.6 54.2 1.80 (1.26-2.58) 0.0015 Final RAS wt n= 330 68.2 60.3 75.4 49.1 41.5 56.8 2.22 (1.41-3.47) 0.0005 *ETS: early tumor shrinkage 20% at 6 weeks p = Fisher s exact test (two-sided)
Evaluation of Depth of Response (DpR*) median DpR FOLFIRI + Cetuximab FOLFIRI + Bevacizumab % SE % SE p KRAS exon 2 wt n= 493-44.1 (±54.6%) - 32.9 (± 44.3%) 0.0003 Final RAS wt n= 330-48.9 (±54.8%) - 32.3% (± 42.3%) <0.0001 Depth of response correlated significantly with OS and PFS (two-sided Bravais Pearson test) *DpR: percentage of maximal tumor shrinkage observed at the nadir compared with baseline SE = standard error; p = two-sided
CALGB/SWOG 80405: FINAL DESIGN mcrc 1st-line KRAS wild type (codons 12,13) STRATA: FOLFOX/FOLFIRI Prior adjuvant Prior XRT FOLFIRI or FOLFOX MD choice Chemo + Cetuximab Chemo + Bevacizumab N = 1140 1 Endpoint: Overall Survival
CALGB/SWOG 80405: Overall Survival Arm Chemo + Cetux N (Events) OS (m) Median 95% CI 578 (375) 29.9 27.0-32.9 Chemo + Bev 559 (371) 29.0 25.7-31.2 P=0.34 HR 0.925 (0.78-1.09) Presented by:
Efficacy: RAS Subgroups Subgroup Chemo + BV N Chemo + CET N Response Rate (%)* BV vs CET p-value PFS time Hazard ratio 95% CI p-value OS time Hazard ratio 95% CI p-value RAS evaluable** 324 346 56.0 vs 68.8 p<0.01 11.4 vs 10.9 1.1 0.9-1.3 p=0.34 30.3 vs 30.8 0.9 0.8-1.1 p=0.49 RAS wild-type 256 270 53.8 vs 68.6 p<0.01 11.3 vs 11.4 1.1 0.9 1.3 p=0.31 31.2 vs 32.0 0.9 0.7 1.1 p=0.40 *406 RAS evaluable and 319 RAS WT patients evaluable for response **Patients with KRAS codon 12/13 wild-type tumors for which tumor DNA samples were evaluable for other RAS mutations Median, months
Overall Survival By Arm (All RAS Wild Type Patients) Arm Chemo + Bev Chemo + Cetux N (Events) 256 (178) 270 (177) Median (95% CI) 31.2 (26.9-34.3) 32.0 (27.6-38.5) HR (95% CI) 0.9 (0.7-1.1) p 0.40
CALGB/SWOG 80405 Efficacy: RAS Subgroups Subgroup Chemo + BV N Chemo + CET N Response Rate (%)* BV vs CET p-value PFS time Hazard ratio 95% CI p-value OS time Hazard ratio 95% CI p-value RAS evaluable** 324 346 56.0 vs 68.8 p<0.01 11.4 vs 10.9 1.1 0.9-1.3 p=0.34 30.3 vs 30.8 0.9 0.8-1.1 p=0.49 RAS wild-type 256 270 53.8 vs 68.6 p<0.01 11.3 vs 11.4 1.1 0.9 1.3 p=0.31 31.2 vs 32.0 0.9 0.7 1.1 p=0.40 *406 RAS evaluable and 319 RAS WT patients evaluable for response **Patients with KRAS codon 12/13 wild-type tumors for which tumor DNA samples were evaluable for other RAS mutations Median, months
CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132) Arm All Patients N (Events) 132 (45) Median (95% CI) 64.7 (59.8-78.9)
: Phase III trials Anti-EGFRs + CT combinations in first line therapy in extended RAS WT patients: Phase III trials n RR PFS (mo) OS (mo) FOLFOX + Panitumumab 252 -- 10.1 26.0 FOLFOX 256 -- 7.9 20.2 Douillard, NEJM 2013 HR 0.72 p<0.004 HR 0.78 p<0.04 FOLIRI+Cetuximab 178 66.3% 10.4 28.4 FOLFIRI 189 38.6% 8.4 20.2 Van Cutsem, JCO 2015 p<0.001 HR 0.56; p<0.01 HR0.69;p=0.002 FOLFIRI+Cetuximab 199 72.1% 10.4 33.1 FOLFIRI+Bevacizumab 201 56.0% 10.2 25.0 *Heinemann, Lancet Oncol p=0.001 HR 0.69 p:0.005 2014 FOLFIRI/OX+Cetuximab 270 68.6% 11.4 32.0 FOLFIRI/OX+Bevacizumab 256 53.8% 11.3 31.2 AoO 2014 p<0.01
Randomized Controlled Trial of Cetuximab Plus CT for Patients KRAS Wild-Type Unresectable Colorectal Liver-Limited Metastases Ye CH et al. J Clin Oncol 2013;31:1931 1938.
CONCLUSIONS- All advanced colorectal cancer patients should be commented in a multidisciplinary team before any therapeutic decision Patients with unresectable liver only metastases should recieve intensive chemotherapy plus biologicals to get optimal downsizing to make an R0 resection possible RAS status mandatory. Patients with RAS wt can get chemotherapy plus anti-egfrs antibodies to get maximal and early shrinkage.patients with RAS mutations and good performance status are candidates to FOLFOXIRI+/- Bevacizumab
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