Κίκα Πλοιαρχοπούλου Παθολόγος Ογκολόγος Ευρωκλινική Αθηνών
Time (months) Survival outcomes in mcrc have progressively improved over the past two decades Treatment options for many patients Multidisciplinary and multimodal treatment Individualised treatment Still unmet needs 30 Only limited treatment options Overall survival 20 10 PFS ceiling (1st line) 0 1990s 2000s 2010 2014 Increasing number of treatment options
Adjuvant FOLFOX Factors Driving First-Line Chemotherapy Selection Patient comorbidities Patient and physician bias Efficacy Side effects Irinotecan 5-FU/LV Oxaliplatin Capecitabine Prior adjuvant therapy Disease-free interval? Treatment duration and strategy Continuous 6 months 12 months Intermittent Partial break Maintenance 18 months 3
Phase III trials supporting biological agents for first-line treatment of mcrc Bevacizumab Cetuximab Panitumumab TRIBE AVEX FIRE3 NO16966 ARTIST AVF2017g FIRE3 CRYSTAL CALGB 80405 PRIME CALGB 80405 AGITG MAX
Comparing first-line treatment efficacy: phase III head-to-head trials FIRE-3 Primary endpoint Previously untreated KRAS WT (exon 2) mcrc (ITT n=592) R Bevacizumab + FOLFIRI Investigatorassessed ORR Cetuximab + FOLFIRI CALGB 80405 Previously untreated KRAS-WT (codons 12,13) mcrc R Bevacizumab + FOLFOX/FOLFIRI* (n=1,137) Cetuximab + FOLFOX/FOLFIRI* OS
Overall response rate (%) Cetuximab Bevacizumab OS estimate PFS estimate FIRE-3: key outcomes in the ITT population ORR in KRAS-WT patients Investigator-assessed 1.0 PFS in KRAS-WT patients Investigator-assessed 70 60 p=0.18 OR=1.18 (95% CI 0.85 1.64) 0.75 0.50 0.25 FOLFIRI + cetuximab FOLFIRI + bevacizumab HR=1.06 (95% CI: 0.88 1.26) p=0.547 50 0 10.0 10.3 40 1.0 OS in KRAS-WT patients 30 20 0.75 0.50 HR=0.77 (95% CI: 0.62 0.96) Log-rank p=0.017 10 0 0.25 0 Treatment arm 0 25.0 28.7 12 24 36 48 60 72 Time (months)
OS estimate FIRE-3: Overall Survival 1.0 Median duration of treatment = 5 months (all 3 agents) Cetuximab + FOLFIRI Avastin + FOLFIRI Events, n/n (%) 158/297 (53.2) 185/295 (62.7) 0.75 0.50 Median PFS = 10.0 months Median, months 28.7 25.0 HR (95% CI) p-value 0.77 (0.62 0.96) p=0.017 0.25 0 25.0 28.7 0 12 24 36 48 60 72 Time (months) Patients at risk 297 218 111 60 29 9 295 214 111 47 18 2 Median follow-up >33 months in both treatment arms Heinemann, et al. ASCO 2013; Bergsland, ASCO 2013
FIRE-3: Subsequent anticancer therapy FOLFIRI + cetuximab N=297 FOLFIRI + bevacizumab N=295 p Any 2nd-line therapy, % 65.7 61.7 0.347 2nd-line bevacizumab, % 48.2 17.6 2nd-line anti-egfr, % 14.4 42.9
FIRE-3: RAS analysis KRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 WT 61 146 4.3% 4.9% NRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 3.8% 2% 0% BRAF EXON 11 EXON 15 600 0% 10%
FIRE-3: RAS evaluable population n=752 mcrc 1L unselected patients KRAS unknown=30 No treatment=13 No treatment KRAS MT=4 n=592 KRAS exon 2 WT ITT population n=113 KRAS exon 2 MT population* n=407 (69%) RAS evaluable population n=58 Cetuximab + FOLFIRI n=55 Avastin + FOLFIRI n=342 RAS WT n=65 (16%) 'New' RAS MT n=171 Cetuximab + FOLFIRI n=171 Avastin + FOLFIRI n=34 Cetuximab + FOLFIRI n=31 Avastin + FOLFIRI
PEAK study: phase II Metastatic CRC WT KRAS exon 2 (n = 285) 1:1 R mfolfox6 (Q2W) + panitumumab 6 mg/kg (Q2W) mfolfox6 (Q2W) + bevacizumab 5 mg/kg (Q2W) Tumour Assessment Q8W (±7 days); Treatment administered until disease progression, death, or withdrawal from study E n d o f t r e a t m e n t 30 days (+ 3 days) S a f e t y f o l l o w u p P o s t t r e a t m e n t f o l l o w u p Every 3 months (±28 days) until end of study E n d o f s t u d y Study endpoints: PFS (1 ); OS, ORR, safety, exploratory biomarker analysis
PFS estimate PFS estimate PEAK: KRAS/NRAS analysis PFS 1.0 WT KRAS exon 2 (ITT set) 1.0 WT RAS (exons 2, 3, 4 of KRAS/NRAS) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0 0.2 10.1 10.9 0 10.1 13.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (months) Time (months) Panitumumab +mfolfox6 (n=142) Avastin + mfolfox6 (n=143) Events, n/n (%) 100/142 (70) 108/143 (76) Median, months 10.9 10.1 Stratified HR (95% CI) p value 0.84 (0.64 1.11) 0.22 Panitumumab +mfolfox6 (n=88) Avastin + mfolfox6 (n=82) Events, n/n (%) 57/88 (65) 66/82 (80) Median, months 13.0 10.1 Stratified HR (95% CI) p value 0.66 (0.46 0.95) 0.03
OS estimate OS estimate PEAK: KRAS/NRAS analysis OS 1.0 WT KRAS exon 2 (ITT set) 1.0 WT RAS (exons 2, 3, 4 of KRAS/NRAS) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0 0.2 24.3 34.2 0 28.9 41.3 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 3234 36 38 40 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Time (months) Time (months) Panitumumab +mfolfox6 (n=142) Avastin + mfolfox6 (n=143) Events, n/n (%) 52/142 (37) 78/143 (55) Median, months 34.2 24.3 Stratified HR (95% CI) p value 0.62 (0.44 0.89) 0.009 Panitumumab +mfolfox6 (n=88) Avastin + mfolfox6 (n=82) Events, n/n (%) 30/88 (34) 40/82 (49) Median, months 41.3 28.9 Stratified HR (95% CI) p value 0.63 (0.39 1.02) 0.058 Schwartzberg, et al. ASCO 2013; data cut-off 3 January 2013
CALGB/SWOG 80405: Phase III trial of FOLFIRI or FOLFOX with Bevacizumab or Cetuximab for patients w/ KRAS wild type untreated metastatic adenocarcinoma of the colon or rectum A Venook, D Niedzwiecki, HJ Lenz, F Innocenti, M Mahoney, B O Neil, J Shaw, B Polite, H Hochster, R Goldberg, R Mayer, R Schilsky, M Bertagnolli, C Blanke for the ALLIANCE and SWOG
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 Primary endpoint : ΟS
CALGB/SWOG 80405: Patient Characteristics ARM A CHEMO + BEV N=559 (%) ARM B CHEMO + CETUX N=578 (%) TOTAL* N=1137 (%) ge median (range) 59 (21-85) 59 (20-89) 59 (20-89) ale 348 (62.3) 349 (60.4) 697 (61.3) on-caucasian 80 (14.6) 93 (16.5) 173 (15.6) rimary in place 157 (28) 154 (27) 311 (28) OLFOX / FOLFIRI (%) 73 / 27 74 / 26 73 / 27 alliative Intent 465 (86.4) 458 (82.5) 923 (84.4) rior Radiation 81 (14.5) 79 (13.7) 160 (14.1) rior Adjuvant Chemo 50 (8.9) 52 (9.0) 102 (9.0) Presented by:
CALGB/SWOG 80405: Overall Survival OS (m) Arm N (Events) Median 95% CI Chemo + Cetux 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:
CALGB/SWOG 80405: Progression-Free Survival (Investigator Determined) Arm N (Events) PFS (m) Median 95% CI Chemo + Bev 559 (498) 10.8 9.7-11.4 Chemo + Cetux 578 (499) 10.4 9.6-11.3 P=0.55 HR 1.04 (0.91-1.17) Presented by:
CALGB/SWOG 80405: Overall Survival FOLFOX Treated Arm N (Events) OS (m) Median 95% CI FOLFOX + Cetux 426 (277) 30.1 26.6-34.8 FOLFOX + Bev 409 (290) 26.9 24.7 30.0 P=0.09 HR 0.9 (0.7-1.0) Presented by:
CALGB/SWOG 80405: Overall Survival FOLFIRI Treated Arm N(Events) OS (m) Median 95% CI FOLFIRI + Bev 150 (81) 33.4 27.3-41.3 FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2 P=0.28 HR 1.2 (0.9-1.6) Presented by:
Grade 3-4 Toxicities Toxicity Chemo + Bev N = 534 (%) Chemo + Cetux N = 547 (%) Total Grade 3 278 (52) 295 (54) Hematologic 142 (26.6) 150 (27.4) Non-Hem 234 (43.8) 259 (47.3) Total Grade 4 66 (12.4) 75 (13.7) Total Grade 5 7 (1.3) 3 (0.5) Neuropathy Gr 3 71 (14) 68 (12) Rash Gr 3 0 40 (7) Diarrhea Gr 3 45 (8) 59 (11) Hypertension Gr 3 35 (7) 3 (1) GI Events Gr 3 10 (2) 2 (0.5) Presented by:
Mutations in BRAF may have a role in disease course or the response to treatment EGF TGF- HB-EGF Epiregulin EGFR (HER1) BRAF MUTATIONS RAS PI3K EXON 11 EXON 15 600 RAF Src PIP2 PTEN PIP3 Transcription of growth factor genes MEK ERK AKT MTOR Raptor p70s6k MTOR Rictor BRAF is part of the EGFR signalling pathway and is a negative prognostic biomarker
Overall survival (proportion) CRYSTAL: BRAF mutations are associated with reduced overall survival Patients with KRAS wild-type/ BRAF wild-type tumours Patients with KRAS wild-type/ BRAF mutant tumours FOLFIRI (n=289) FOLFIRI (n=33) Cetuximab + FOLFIRI (n=277) Cetuximab + FOLFIRI (n=26) 1.0 0.8 HR=0.830 (95% Cl: 0.687 1.004) log-rank p=0.0547 1.0 0.8 HR=0.908 (95% Cl: 0.507 1.624) log-rank p=0.74 0.6 0.6 0.4 0.2 0.0 21.6 (95% CI: 20.0 24.9) Time (months) 0.4 (95% Cl: 8.4 14.9) 25.1 0.2 (95% CI: 22.5 28.7) 10.3 14.1 0.0 (95% Cl: 8.5 18.5) 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 Time (months) Predictive value of BRAF mutations for anti-egfr antibody treatment remains controversial
NEJM 2014
Treatment choice: more than efficacy Clinical presentation Tumour biology RAS mutation status BRAF mutation status Expectations Toxicity profile Flexibility Socio-economic factors Quality of life Patient preference Tumour characteristics 1L treatment Patient characteristics Age Performance status Prior adjuvant treatment Comorbidities
Treatment strategies for patients with mcrc mcrc patient, palliative setting Unresectable metastatic disease Molecular testing Any RAS MT (55%) All RAS WT (40%) BRAF MT (5%) Bevacizumab + CT doublet Bevacizumab + CT doublet EGFR inhibitor + CT doublet Bevacizumab + FOLFOXIRI VEGF inhibitor + CT doublet VEGF inhibitor + CT doublet Bevacizumab + CT doublet CT ± EGFR inhibitor Regorafenib EGFR inhibitor ± irinotecan Regorafenib Regorafenib BSC Regorafenib BSC BSC BSC
Impact of tumour characteristics on treatment decisions Better prognosis Worse prognosis Slow progressing, limited tumour load Resectable Primary/secondary resection Wild-type Rapidly progressing, high tumour load Non-resectable RAS mutation BRAF-positive/right-side tumour Treatment intensity Monotherapy + antibody Doublet + antibody Induction + maintenance Triplet + antibody Induction + maintenance
ESMO guidelines: treatment goals Group 0 Group 1 Group 2 Group 3 Patient Primarily resectable Potentially resectable Symptomatic with worsening disease Asymptomatic Goal Cure Maximum shrinkage Rapid tumour shrinkage/ disease control Disease control/ low toxicity Surgery Treatment intensity Triplet + antibody Induction + maintenance Doublet + antibody Continuous treatment Induction + maintenance Monotherapy + antibody Not all patients need high-intensity treatment
Take-home messages The criteria for first-line treatment selection are based on patient and tumor characteristics, as well as, patient preference Determination of treatment goal and strategy The option of liver resection should be considered upfront Expanded Ras evaluation is a prerequisite for anti-egfr therapy Need for strategy trials