ADVANCED COLORECTAL CANCER: UNRESECTABLE OR BORDERLINE RESECTABLE (GROUP 1) CHEMOTHERAPY +/- TARGETED AGENTS. Andrés Cervantes. Professor of Medicine

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1 ADVANCED COLORECTAL CANCER: UNRESECTABLE OR BORDERLINE RESECTABLE (GROUP 1) CHEMOTHERAPY +/- TARGETED AGENTS Andrés Cervantes Professor of Medicine

2 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 months Issues Low efficacy 5-FU Oral fluoropyrimidines Irinotecan Oxaliplatin RR 50% mttp 8 9 months mos 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

3 SURVIVAL OF PATIENTS WITH METASTATIC CRC OVER DECADES Kopetz et al. JCO 2009

4 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

5 GENOMICS DRIVEN CANCER MEDICINE Garraway LA, Verwey J, Ballman K. J Clin Oncol 2013

6 ESMO GUIDELINES

7 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

8 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:

9 Bevacizumab in advanced CRC: ORR from randomized trials First-line Second-line ORR (%) Bevacizumab Placebo Bevacizumab Placebo Bevacizumab IFL XELOX/FOLFOX FOLFOX p=0.004 p=0.99 p< Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007

10 Bevacizumab in advanced CRC: PFS from randomized trials 14 First-line Second-line PFS (months) ,8 5,6 10,6 6,2 9,4 8 7, Bevacizumab Placebo Bevacizumab Placebo Bevacizumab Placebo Bevacizumab 5-FU/LV p< Kabbinavar et al. JCO 2005 IFL XELOX/FOLFOX FOLFOX p<0.001 p< p< Hurwitz et al. NEJM 2004 Saltz et al. JCO 2008 Giantonio et al. JCO 2007

11 Bevacizumab in advanced CRC: OS from randomized trials OS (months) First-line ,3 20,3 19,9 17,9 15,6 14,6 Second-line 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

12 FOLFOXIRI combinations in first line therapy n RR PFS OS FOLFOXIRI/Bev % FOLFIRI/Bev % Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 Loupakis, NEJM 2014

13 FOLFOXIRI combinations in first line therapy n RR PFS (mo) OS (mo) FOLFOXIRI/Bev % FOLFIRI/Bev % Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 FOLFOXIRI % FOLFIRI % Falcone, JCO 2007 p< HR 0.63; p<0.01 HR0.80;p=0.032 FOLFOXIRI/Bev 41 81% 18.8 NR FOLFOX/Bev 39 62% *Grünberger, AoO 2015 p=0.061 p<0.01 * Liver only mets

14 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: ; protocol ID: ; ClinicalTrials.gov identifier: NCT 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.

15 KRAS, NRAS and BRAF mutation hotspots in the PRIME study EXON 1 KRAS EXON 2 EXON 3 EXON % 4% 6% EXON 1 NRAS EXON 2 EXON 3 EXON % 4% 1% EXON 1 BRAF EXON 15 EXON % All RAS mutation testing might identify an additional 15 20% mutants 15

16 PRIME RAS/RAF OS analysis* Proportion alive (%) Original WT KRAS exon 2 testing HR = 0.83 (95% CI, ) P = Months Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 325) 165 (51) 23.9 ( ) FOLFOX4 (n = 331) 190 (57) 19.7 ( ) Overall survival Proportion alive (%) WT RAS HR = 0.78 (95% CI, ) P = Months Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 ( ) FOLFOX4 (n = 253) 148 (58) 20.2 ( ) 1. Douillard JY, et al. J Clin Oncol 2010;28: ; 2. Douillard JY et al New Engl J Medicine Sept *Predefined retrospective analysis; 7 patients harbouring Codon 59 mutations were not excluded from this analysis.

17 RAS mutation rates: first-line studies Patients with KRAS codon 12/13 wild-type tumors Study CALGB/SWOG Evaluable patients* Method Other RAS mutations, % 670 BEAMing 15.3 OPUS 118 BEAMing 26.3 CRYSTAL 430 BEAMing 14.7 FIRE 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

18 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 mg/m 2 *, day 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: Van Cutsem E, et al. J Clin Oncol 2011;29: Presented by: Eric Van Cutsem

19 CRYSTAL EXTENDED RAS MUTATION: Overall survival KRAS codon 12/13 wild-type 1 RAS wild-type Probability of OS No. of events Median, months 95% CI FOLFIRI + cetuximab 0.0 FOLFIRI Months HR (95% CI) 0.80 ( ) Probability of OS No. of events Median, months 95% CI HR (95% CI) 0.69 ( ) FOLFIRI + cetuximab FOLFIRI Months Number of patients at risk Number of patients at risk Van Cutsem E, et al. J Clin Oncol 2011;29: Ciardiello F, et al WGICC 2014

20 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 min 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

21 Overall survival Final RAS* wild-type population Probability of survival Δ = 8.1 months Events n/n (%) FOLFIRI + Cetuximab 107/199 (53.8%) FOLFIRI + Bevacizumab 133/201 (66.2%) Median (months) 95% CI HR (95% CI: ) p (log-rank)= No. at risk months since start of treatment * KRAS and NRAS exon 2, 3 and 4 wild-type

22 Independent evaluation of response CT evaluable population FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI Odds ratio p KRAS exon 2 wt n= ( ) Final RAS wt n= ( ) p = Fisher s exact test (two-sided)

23 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= ( ) Final RAS wt n= ( ) *ETS: early tumor shrinkage 20% at 6 weeks p = Fisher s exact test (two-sided)

24 Evaluation of Depth of Response (DpR*) median DpR FOLFIRI + Cetuximab FOLFIRI + Bevacizumab % SE % SE p KRAS exon 2 wt n= (±54.6%) (± 44.3%) Final RAS wt n= (±54.8%) % (± 42.3%) < 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

25 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 = Endpoint: Overall Survival

26 CALGB/SWOG 80405: Overall Survival Arm Chemo + Cetux N (Events) OS (m) Median 95% CI 578 (375) Chemo + Bev 559 (371) P=0.34 HR ( ) Presented by:

27 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** vs 68.8 p< vs p= vs p=0.49 RAS wild-type vs 68.6 p< vs p= vs 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

28 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 ( ) 32.0 ( ) HR (95% CI) 0.9 ( ) p 0.40

29 CALGB/SWOG 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** vs 68.8 p< vs p= vs p=0.49 RAS wild-type vs 68.6 p< vs p= vs 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

30 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 ( )

31 : 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 FOLFOX Douillard, NEJM 2013 HR 0.72 p<0.004 HR 0.78 p<0.04 FOLIRI+Cetuximab % FOLFIRI % Van Cutsem, JCO 2015 p<0.001 HR 0.56; p<0.01 HR0.69;p=0.002 FOLFIRI+Cetuximab % FOLFIRI+Bevacizumab % *Heinemann, Lancet Oncol p=0.001 HR 0.69 p: FOLFIRI/OX+Cetuximab % FOLFIRI/OX+Bevacizumab % AoO 2014 p<0.01

32 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:

33 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

34 THANKS 34