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Axel Grothey Professor of Oncology Mayo Clinic Rochester
Mutational Testing and Its Role in Therapeutic Decision-making for Colorectal Cancer Axel Grothey Professor of Oncology Mayo Clinic Rochester
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A number of agents is currently available for the treatment of mCRC
5-FU Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Regorafenib Aflibercept Panitumumab
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Negative Predictive Biomarkers (Exclusion of Patients)
Cetuximab Panitumumab
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Positive Predictive Biomarkers (Selection of Patients)
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Overview of EGFR and VEGFR Growth Signaling Pathways
Tumor Cell Endothelial Cell VEGF EGFR KIT PDGFR-β VEGFR Targeted by bevacizumab and aflibercept* Targeted by cetuximab and panitumumab RAS *Ziv-aflibercept also targets PIGF Pl3K RAF BRAF AKT NCCN GL Dept. Review: <Added “ziv-” to “aflibercept” twice. Centered protein names in their ovals for better visibility.> (DFC, 2/18/15) MEK mTOR ERK ONCOGENESIS ANGIOGENESIS TUMOR MICROENVIRONMENT Krasinskas AM. Patholog Res Int. 2011;2011:932932; Sitohy B, et al. Cancer Res 2012;72: ; Bendardaf R, et al. Anticancer Res. 2008;28: ; Kitadai Y, et al. Am J Pathol. 2006;169: ; Jayson GC, et al. J Clin Oncol. 2005;23: G.SM.ON
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Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy
IFL+ Placebo (n=411) IFL+ Bevacizumab (n=402) P Value Median survival (mo) 15.6 20.3 PFS (mo) 6.2 10.6 < ORR (%) CR PR 35 2.2 32.5 45 3.7 41.2 0.0036 Duration of resp. (mo) 7.1 10.4 0.0014 Hurwitz et al. N Engl J Med 2004 Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646.
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Phase III Trial of IFL +/-Bevacizumab in MCRC: PFS
1.0 HR=0.54, P< Median PFS: 6.2 vs 10.6 mo 0.8 0.6 Proportion progression-free 0.4 Treatment Group 0.2 IFL + placebo IFL + bevacizumab 10 20 30 Progression-free survival (mo) Hurwitz et al. N Engl J Med 2004 Hurwitz et al. ASCO, Late breaking abstract 3646 and oral presentation.
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Although OS Continues to Improve, PFS Has Been Mostly Stable With First-line Therapy in the Chemobiologic Era Months 2004 2014 1. Hurwitz H, et al. N Engl J Med. 2004;350(23): ; 2. Saltz LB, et al. J Clin Oncol. 2008;26(12): ; 3. Bokemeyer C, et al. Ann Oncol. 2011;22(7): ; 4. Van Cutsem E, et al. J Clin Oncol. 2011;29(15): ; 5. Douillard JY, et al. J Clin Oncol. 2011;(suppl 29):abstract 3510^; 6. Heinemann V, et al. J Clin Oncol. 2013;(suppl 31):abstract LBA3506; 7. Falcone A, et al. J Clin Oncol. 2013;(suppl 31):abstract 3505. 1. Hurwitz H, et al. N Engl J Med. 2004;350(23): ; 2. Saltz LB, et al. J Clin Oncol. 2008;26(12): ; 3. Bokemeyer C, et al. Ann Oncol. 2011;22(7): ; 4. Van Cutsem E, et al. J Clin Oncol. 2011;29(15): ; 5. Douillard JY, et al. N Engl J Med. 2013;369(11): ; 6. Heinemann V, et al. J Clin Oncol. 2013;(suppl 31):abstract LBA3506; 7. Falcone A, et al. J Clin Oncol. 2013;(suppl 31):abstract 3505.
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TRIBE Study Design R FOLFIRI+bev FOLFOXIRI+bev INDUCTION 5-FU/LV +Bev
PD 508 mCRC pts 1st line unresectable stratified by center PS 0/1-2 adjuvant CT FOLFIRI+bev (up to 12 cycles) 5-FU/LV +Bev R NCCN GL Dept. Review: <Repositioned and shrunk reference for easier visibility.> (DFC, 2/18/15) Logo removed RKJ 2/19/15 FOLFOXIRI+bev (up to 12 cycles) 5-FU/LV +Bev INDUCTION MAINTENANCE Loupakis et al., NEJM 2014
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TRIBE study primary endpoint: PFS (updated) –
ITT population FOLFIRI + bev FOLFOXIRI + bev Median follow up: 32.3 mos FOLFIRI + BEV, mPFS : 9.7 mos FOLFOXIRI + BEV, mPFS : 12.1 mos Unstratified HR: 0.77 [ ] p=0.006 Stratified HR: 0.75 [ ] p=0.003 Progression-free survival probability RR 53% vs 65% P=0.006 NCCN GL Dept. Review: <Repositioned and shrunk reference for easier visibility. Changed “F-up” to “Follow-up.” Added “TRIBE study” to title.> (DFC, 2/18/15) Follow-up time (months) FOLFIRI/bev 256 203 94 46 26 14 7 3 FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1 Loupakis et al., NEJM 2014
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TRIBE study secondary endpoint: OS (preliminary) – ITT population
FOLFIRI + bev FOLFOXIRI + bev Median follow up: 32.3 mos FOLFIRI + bev: N = 256 / Died = 155 FOLFOXIRI + bev: N = 252 / Died = 131 FOLFIRI + bev, mOS : 25.8 mos FOLFOXIRI + bev, mOS : 31.0 mos Unstratified HR: 0.83 [ ] p=0.125 Stratified HR: 0.79 [ ] p=0.054 Overall survival probability NCCN GL Dept. Review: <Repositioned and shrunk reference for easier visibility. Changed “F-up” to “Follow-up.” Added “TRIBE study” to title.> (DFC, 2/18/15) Follow-up time (months) FOLFIRI/bev 256 233 216 172 109 69 36 15 5 FOLFOXIRI/bev 252 234 205 175 119 70 35 4 Loupakis et al., NEJM 2014
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TRIBE study subgroup analyses of PFS – molecular characteristics
Factor N HR p 0.4 0.6 0.8 1 NCCN GL Dept. Review: <Added “TRIBE study” to title.> (DFC, 2/18/15) Logo removed RKJ 2/19/15 Experimental better Control Better Loupakis et al., NEJM 2014
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Tumor cell proliferation
BRAF Mutations in CRC BRAF is primary effector of KRAS signaling BRAF mutations: Occur most frequently in exon 15 (V600E) Found in 4%-14% of patients with CRC Mutually exclusive with KRAS mutations EGF Tumor Cell P P Ras P P Raf MEK Tumor cell proliferation and survival Erk Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.
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PETACC-3: Survival after relapse according to BRAF mutation status
BRAF wildtype Median OS: BRAF mut: 7.49 m BRAF wt: m (p = 1.9e-11) Tejpar et al, ASCO 2010 Roth, A. D. et al. JCO 2010
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BRAF V600E Inhibitor: PLX4032 (Vemurafenib)
Refractory Melanoma Refractory Colorectal 100 100 78% Response Rate 5% Response Rate 75 75 50 50 25 25 Low AKT activation Minimal hypermethylation High AKT activation Extensive hypermethylation %Change From Baseline (Sum of Lesion Size) %Change From Baseline (Sum of Lesion Size) -25 -25 -50 NCCN GL Dept. Review: <> (DFC, 2/18/15) Please query speaker about the reference. Is there a published Clinical Trials Planning Meeting report? I could not locate it on cancer.gov. -50 -75 -75 Flaherty et al NEJM ‘10 Kopetz et al ASCO ‘10 -100 -100 Oncogene mutation does not imply oncogene dependence Understand the biological context in which particular mutations occur Kopetz, CTPM Jan 2011
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Randomized Phase II of Dual BRAF + EGFR Inhibition in BRAFmut mCRC – SWOG 1406
Primary endpoint: PFS Study activated via CTSU October 2014 N=72 ~800 screened PI: Scott Kopetz
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mAbs Target Tumor Cell-Bound EGFR
Ligand Extracellular EGF-R Ras PI3K PTEN Raf Intracellular Akt MEK MAPK Cell survival DNA Cell Motility Proliferation Angiogenesis Metastasis
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mAbs Target Tumor Cell-Bound EGFR
Ligand Extracellular EGF-R Ras PI3K PTEN Raf Intracellular Akt MEK MAPK Cell survival DNA Cell Motility Proliferation Angiogenesis Metastasis
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NCIC/ AGITG CTG CO.17: Randomized Phase III Trial in mCRC Cetuximab vs BSC (no cross-over)
KRAS mut KRAS wild-type All patients BSC n=83 Cetux n=81 n=113 n=117 n=285 n=287 RR 0% 1.2% 12.8% 6.6% PFS (mos) 1.8 1.9 3.8 OS (mos) 4.6 4.5 4.8 9.5 6.1 <0.0001 <0.0001 <0.0001 0.0046 Karapetis et al. NEJM 2008
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CRYSTAL Study (1st Line)
FOLFIRI + Cetuximab N = 599 EGFR-expressing metastatic CRC R PFS Stratified by: Regions ECOG PS FOLFIRI N = 599 Primary Endpoint: PFS (independent review) Secondary Endpoints: RR, DCR, OS, Safety, QoL Sample Size: patients randomized, ITT: 1198 pts Van Cutsem et al. NEJM 2009
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5-FU/LV/IRI (FOLFIRI) ± Cetuximab: PFS Non-KRAS adjusted
1.0 Subgroup effect No benefit 0.8 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 HR = 0.851 P = 8.0 vs 8.9 mos PFS estimate The design of this trial is similar to the Hurwitz trial: 5-FU/LV/irino +/- a targeted agent, but the PFS curves look very different, in particular, when the KRAS mut CRC are included. FOLFIRI FOLFIRI + Cetuximab 2 4 6 8 10 12 14 16 18 20 PFS (mos) Van Cutsem et al, 2009
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FOLFIRI +/- Cetuximab PFS in patients with KRAS wt tumors
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 FOLFIRI (n=350) FOLFIRI + cetuximab (n=316) No of events 189 146 Median PFS 8.4 months 9.9 months [95% CI] [7.4‒9.2] [9.0‒11.3] HR [95% Cl] p-value 0.696 [0.558‒0.867] 0.0012 Probability of PFS FOLFIRI + cetuximab FOLFIRI 12 4 8 16 20 Time (months) Number of patients FOLFIRI 350 237 111 22 4 FOLFIRI + cetuximab 316 227 128 40 8 1 van Cutsem et al., J Clin Oncol 2011
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PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status
“Final Analysis” WT KRAS MT KRAS Median (mos) (95% CI) Panitumumab + FOLFOX4 10.0 (9.3 – 11.4) FOLFOX4 8.6 (7.5 – 9.5) Median (mos) (95% CI) Panitumumab + FOLFOX4 7.4 (6.9 – 8.1) FOLFOX4 9.2 (8.1 – 9.9) HR = 0.80 (95% CI: 0.67 – 0.95) Log-rank p-value = 0.01 HR = 1.27 (95% CI: 1.04 – 1.55) Log-rank p-value = 0.02 Douillard et al., JCO 2011
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Mutations beyond KRAS codon 12/13 17% additional mutations in
EXON 1 EXON 2 EXON 3 EXON 4 12 13 61 117 146 40% 4% 6% NRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 59 61 3% 4% NT BRAF EXON 11 EXON 15 17% additional mutations in KRAS and NRAS ! 600 NT 8% NT=not tested Douillard et al., NEJM 2013 24 24
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Hazard Ratios for RAS subgroups
Potential detriment NCCN GL Dept. Review: <Moved “Potential detriment” for better visibility.> (DFC, 2/18/15) Douillard et al., NEJM 2013
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FIRE-3 Phase III study design
FOLFIRI + Cetuximab Cetuximab: 400 mg/m2 i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w mCRC 1st-line therapy KRAS wild-type N= 592 C e t u x i m a b : 4 m g / m 2 i . v . 1 2 m i n i n i t i a l d o s e 2 5 m g / m 2 i . v . 6 m in q 1 w Randomize 1:1 FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v min q 2w B e v a c i z u m a b : 5 m g / k g i . v . 3 - 9 m i n q 2 w FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h) Primary objective: Overall response rate (ORR) (inv assessed) Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5% Heinemann et al., Lancet Oncol 2014
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FIRE-3 ORR Primary Endpoint
FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Odds ratio p ORR % 95%-CI ITT population 62.0 56.2 – 67.5 58.0 52.1 – 63.7 (N= 592) 1.18 0.183 Assessable for response (N= 526) 1.52 72.2 66.2 – 77.6 63.1 57.1 – 68.9 0.017 p = Fisher´s exact test (one-sided) Heinemann et al., Lancet Oncol 2014
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FIRE-3 PFS 10.0 10.3 Events Median (months) 95% CI n/N (%)
1.0 n/N (%) ― FOLFIRI + Cetuximab 250/297 8.8 – 10.8 (84.2%) 0.75 ― FOLFIRI + Bevacizumab 242/295 10.3 9.8 – 11.3 Probability of survival (82.0%) HR 1.06 (95% CI 0.88 – 1.26) Log-rank p= 0.547 0.50 NCCN GL Dept. Review: <Fixed number at risk at bottom and added labels for the 2 rows. Shrunk and moved reference.> (DFC, 2/18/15) 0.25 0.0 12 24 36 48 60 72 months since start of treatment Number at risk FOLFIRI+cetux 297 100 99 19 15 10 6 5 4 3 FOLFIRI+bev 295 Heinemann et al., Lancet Oncol 2014
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FIRE-3 Overall survival
Events n/N (%) Median (months) 28.7 95% CI ― FOLFIRI + Cetuximab ― FOLFIRI + Bevacizumab 0.75 1.0 0.50 0.25 Probability of survival 0.0 12 24 36 48 60 72 months since start of treatment PFS Split of curves 158/297 24.0 – 36.6 (53.2%) 185/295 25.0 22.7 – 27.6 (62.7%) HR 0.77 (95% CI: 0.62 – 0.96) Log-rank p= 0.017 NCCN GL Dept. Review: <Fixed number at risk at bottom and added labels for the 2 rows. Shrunk and moved reference.> (DFC, 2/18/15) Number at risk FOLFIRI+cetux 297 218 214 111 60 47 29 18 9 2 FOLFIRI+bev 295 Heinemann et al., Lancet Oncol 2014
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FIRE-3 Update: Tested Mutations 15% additional RAS mutations!
KRAS wt exon 2 subset KRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 61 146 wt 4.3% 4.9% NRAS EXON 1 EXON 2 EXON 3 EXON 4 12 13 59 61 3.8% 2% 0% BRAF EXON 11 EXON 15 15% additional RAS mutations! 600 0% 10% 30 30
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FIRE-3 ESMO/ECCO Update Overall survival All-RAS* wild-type
Events n/N (%) Median (months) 95% CI ― FOLFIRI + Cetuximab 91/171 (53.2%) 33.1 24.5 – 39.4 ― FOLFIRI + Bevacizumab 110/171 (64.3%) 25.6 22.7 – 28.6 HR 0.70 (95% CI: 0.53 – 0.92) p (log-rank)= 0.011 1.0 0.75 Probability of survival 0.50 Median Δ = 7.5 months 0.25 0.0 0.0 12 24 36 48 60 72 months since start of treatment No. at risk 171 128 127 71 68 39 26 20 9 6 1 Heinemann et al., Lancet Oncol 2014 RAS* wild-type: KRAS 61/146; NRAS Exon2, NRAS Exon3 31 31
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FIRE-3: Depth of Response (DpR) Correlates With OS
Time Since Start of Treatment OS ETS Tumor nadir Fire-3 Data PFS Tumor load at Baseline Lethal tumor load ETS predicts sensitivity to treatment DpR predicts OS NCCN GL Dept. Review: <Changed title to spell out “depth of response” and delete extra “(FIRE-3).”> (DFC, 2/18/15) FIRE-3 Study FOLFIRI + Cetux (n=157) FOLFIRI + Bev (n=173) P Value Median DpR (95% CI) 48.9 32.2 <0.0001 Median OS (95% CI) 33.1 ( ) 25.0 ( ) 0.0056 Stintzing S, et al. Presented at: ESMO (LBA 11).
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Subsequent lines of therapy
Better Time Estimates OS Lethal Subsequent lines of therapy Baseline ETS Tumor nadir PFS 10 30 Months Since Start of Treatment First-line therapy covers only 1/3 of the duration of OS
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Edited KA CALGB/SWOG 80405: H2H Bevacizumab vs Cetuximab in First-line KRAS WT mCRC Bevacizumab + FOLFOX or FOLFIRI q2w PD Untreated advanced or metastatic CRC (N=1137) Randomized patients with KRAS WT tumors Cetuximab + FOLFOX or FOLFIRI q2w Re-open: 6/09 Closed to accrual: 2/12 Patients enrolled: N=2334 (total) N=1177 (final endpoint) PD Approximately 70% FOLFOX 30% FOLFIRI Primary endpoint: OS Superiority trial with 90% power to detect an OS HR of 1.25 (2-sided α=0.05) Secondary endpoints: ORR, PFS, TTF, DOR, and safety H2H=head-to-head; TTF=time to treatment failure. Venook et al, ASCO NCT identifier: NCT
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CALGB/SWOG 80405: Progression-Free Survival and Overall Survival
PFS OS 100 80 60 40 20 12 24 36 48 Time, Months P=0.55 HR=1.04 ( ) 10.4 mos 10.8 % Event Free 100 CT + Bev CT + Cetux CT + Bev CT + Cetux 80 % Event Free 60 P=0.34 HR=0.925 ( ) 40 20 29.0 mos 29.9 mos 12 24 36 48 60 72 84 Time, Months Arm N (Events) mPFS, mos 95% CI CT + Bev 559 (498) 10.8 CT + Cetux 578 (499) 10.4 Arm N (Events) mOS, mos 95% CI CT+ Bev 559 (371) 29.0 CT + Cetux 578 (375) 29.9 Bev=bevacizumab; CT=chemotherapy; Cetux=cetuximab. Venook A, et al. Presented at: ASCO (abstr LBA3).
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CALGB/SWOG 80405: Overall Survival (FOLFOX and FOLFIRI Treated)
OS: FOLFOX Treated OS: FOLFIRI Treated 100 80 60 40 20 % Event Free 12 24 36 48 72 84 Time, Months P=0.09 HR=0.9 ( ) FOLFOX + Bev FOLFOX + Cetux 100 80 60 40 20 % Event Free 12 24 36 48 72 Time, Months P=0.28 HR=1.2 ( ) FOLFIRI + Bev FOLFIRI + Cetux 26.9 mos 30.1 mos 28.9 mos 33.4 mos Arm N (Events) Median OS, Mos 95% CI FOLFOX + Bev 409 (290) 26.9 FOLFOX + Cetux 426 (277) 30.1 Arm N (Events) Median OS, Mos 95% CI FOLFIRI + Bev 150 (81) 33.4 Cetux 152 (98) 28.9 FOLFIRI=fluorouracil, leucovorin, and irinotecan; FOLFOX=fluorouracil, leucovorin, and oxaliplatin. Venook A, et al. Presented at: ASCO (abstr LBA3).
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CALGB/SWOG 80405: RAS Mutations
670/1137 patients (59%) with KRAS codon 12/13 WT tumors evaluable 621/1137 analyzed (55%) analyzed 95/621 (15.3%) patients new RAS mutation identified 526 patients with RAS WT CRC available KRAS* EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 WT +1.3% 1.8% 5.9% NRAS*,† EXON 2 EXON 3 EXON 4 12 13 59 61 117 146 2.3% 4.2% 0% *Percentages relate to fraction of RAS evaluable patients with mutations in particular exons. †One patient had a mutation at both NRAS Exon1 codon12 and NRAS Exon3 codon 61. Lenz H-J, et al. Presented at: ESMO (abstr 501O).
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CALGB/SWOG 80405: PFS and OS in All RAS WT Patients
Progression-Free Survival (All RAS WT Patients) Overall Survival (All RAS WT Patients) CT + Bev CT + Cetux CT + Bev CT + Cetux Arm N (Events) mPFS, Mos HR (95% CI) P Value CT + Bev 256 (221) 11.3 ( ) 1.1 ( ) P=0.31 CT + Cetux 270 (241) 11.4 ( ) Arm N (Events) mOS, Mos HR (95% CI) P Value CT+ Bev 256 (178) 31.2 ( ) 0.9 ( ) P=0.40 CT + Cetux 270 (177) 32.0 ( ) Lenz H-J, et al. Presented at: ESMO (abstr 501O).
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CALGB/SWOG 80405: PFS in All RAS WT Patients by CT Regimen
Progression-Free Survival (All RAS WT FOLFOX Patients) Progression-Free Survival (All RAS WT FOLFIRI Patients) CT + Bev CT + Cetux CT + Bev CT + Cetux NCCN GL Dept. Review: <Moved reference so full text was on slide.> (DFC, 2/18/15) Arm N (Events) mPFS, Mos HR (95% CI) P Value CT+ Bev 192 (163) 11.0 ( ) 1.1 ( ) P=0.3 CT + Cetux 198 (177) 11.3 ( ) Arm N (Events) mPFS, Mos HR (95% CI) P Value CT+ Bev 64 (58) 11.9 ( ) 1.1 ( ) P=0.7 CT + Cetux 72 (64) 12.7 ( ) Lenz H-J, et al. Presented at: ESMO (abstr 501O).
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CALGB/SWOG 80405: OS in All RAS WT Patients by CT Regiment
Overall Survival (All RAS WT FOLFOX Patients) Overall Survival (All RAS WT FOLFIRI Patients) Arm N (Events) Median (95% CI) HR P CT + Bev 192 (137) 29.0 ( ) 0.86 ( ) 0.2 CT + Cetux 198 (129) 32.5 ( ) Arm N (Events) Median (95% CI) HR P CT + Bev 64 (41) 35.2 ( ) 1.1 ( ) 0.7 CT + Cetux 72 (48) 32.0 ( ) Lenz H-J, et al. Presented at: ESMO (abstr 501O).
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FIRE-3 and CALGB/SWOG 80405: Efficacy by RAS Status
CT + Bev vs CT + Cetux CALGB/SWOG 80405 Primary endpoint Response rate Overall survival CT backbone All FOLFIRI FOLFOX 74%/FOLFIRI 26% ITT (KRAS WT Exon 2) (n=295 vs 297) (n=559 vs 578) RR, % 58 vs 62 P=0.183 57.2 vs 65.6 P=0.02 PFS, months 10.3 vs 10.0; HR=1.06 (P=0.547) 10.8 vs 10.4; HR=1.04 (P=0.55) Median OS, months 25.0 vs 28.7 HR=0.77 (P=0.017) 29.0 vs 29.9 HR=0.92 (P=0.34) RAS WT (n=201 vs 199) (n=256 vs 270) 58.7 vs 65.3; OR=1.33 (P=0.18) 53.8 vs 68.6; (P<0.01) 10.2 vs 10.3; HR=0.97 (P=0.77) 11.3 vs 11.4; HR=1.1 (P=0.31) OS, months 25.0 vs 33.1 HR=0.70 (P=0.006) 31.2 vs 32.0 HR=0.9 (P=0.40) Stintzing S, et al. Presented at: ESMO. 2014 (abstr LBA11). Lenz H-J, et al. Presented at: ESMO (abstr 501O). Venook. Presented at: WCGC
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CALGB/SWOG 80405: Overall Survival (FOLFIRI Treated) Superimposed with FIRE-3
100 80 60 40 20 % Event Free 12 24 36 48 72 Time, Months P=0.28 HR=1.2 ( ) FOLFIRI + Bev FOLFIRI + Cetux FIRE-3 (Superimposed) P=0.017 HR=0.77 ( ) FOLFIRI + Bev FOLFIRI + Cetux CALGB/SWOG 80405 CALGB/SWOG 80405 FIRE-3 FOLFIRI + Bev (n=150) FOLFIRI + Cetux (n=152) (n=295) (n=297) Median OS, mos (95% CI) 33.4 ( ) 28.9 ( ) 25.0 ( ) 28.7 ( ) HR (95% CI) P value HR=1.2 ( ) P=0.28 HR= 0.77 ( ) P=0.017 Venook A, et al. Presented at: ASCO (abstr LBA3). Stintzing S, et al. Presented at: ESMO. 2014 (abstr LBA11).
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Conclusions EGFR mAbs Cetuximab and panitumumab are interchangeable (see ASPECCT trial results ECC 2013) Further molecular refinement of patient population beyond KRAS codon 12/13 essential To avoid detrimental effect of therapy To enrich patient population with better benefit/side-effect margin FIRE-3 and are more similar than different The outlier is the BEV arm in FIRE-3 Chemo + BEV and Chemo + EGFR mABs are viable options as first-line therapy in KRAS (RAS) wt mCRC
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Considerations for First-line Therapy in RAS wild-type CRC
Two competing approaches: Chemo + EGFR mAb Supported by FIRE-3, PRIME, 80405 Longest time on therapy Beware of toxicities Chemo + BEV with prolonged duration of VEGF inhibition Supported by CAIRO-3, 80405 Fewer subjective toxicities
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One Possible Optimized Treatment Strategy
mCRC, palliative setting, PS 0-1 Unresectable Liver and Retroperitoneal LN Metastases Molecular testing Any RAS mut (55%) All RAS wt (40%) BRAF mut (5%) VEGFi + CT doublet Regorafenib BSC Bevacizumab + CT doublet/triplet VEGFi + CT doublet EGFR inhibitor +/- irinotecan Regorafenib BSC Bevacizumab + CT doublet/triplet Bevacizumab + CT doublet Regorafenib BSC EGFR inhibitor + CT doublet Regorafenib BSC Bevacizumab + FOLFOXIRI EGFR inhibitor? + /- chemotherapy PD1 PD2 PD3 PD4 Adapted from Sridharan et al., Oncology 2014
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Colorectal Cancer: 20 Years after meta-analysis 1992
CALGB/SWOG 80405 CALGB/SWOG 80405 J Clin Oncol, 1992
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