Axel Grothey Professor of Oncology Mayo Clinic Rochester

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

A number of agents is currently available for the treatment of mCRC
5-FU Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Regorafenib Aflibercept Panitumumab

Negative Predictive Biomarkers (Exclusion of Patients)
Cetuximab Panitumumab

Positive Predictive Biomarkers (Selection of Patients)

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

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.

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.

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.

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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

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

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).

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).

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).

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).

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).

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).

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

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).

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

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

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

Colorectal Cancer: 20 Years after meta-analysis 1992
CALGB/SWOG 80405 CALGB/SWOG 80405 J Clin Oncol, 1992

Axel Grothey Professor of Oncology Mayo Clinic Rochester

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