Advanced Colorectal Cancer: Which biologic agent and for whom? Axel Grothey Professor of Oncology Mayo Clinic Rochester

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

ESMO Guidelines 2012 Schmoll et al., Ann Oncol 2012

Landscape in mCRC before ASCO 2013 Bevacizumab and EGFR mAbs competing for first-line patients in KRAS wt CRC Bevacizumab and Aflibercept competing for second-line patients with each other, and with EGFR mAbs in KRAS wt CRC Best sequence of therapies (VEGFi vs EGFRi) still to be established Regorafenib as salvage therapy option

Questions How can biologics be used to their full potential? Duration of therapy Predictive markers Can a patient population be identified which would benefit most from one specific treatment strategy?

Anti-VEGF Agents

XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 XELOX N=317 XELOX + placebo N=350 XELOX + bevacizumab N=350 FOLFOX4 N=317 FOLFOX4 + placebo N=351 FOLFOX4 + bevacizumab N=350 Initial 2-arm open-label study (N=634) Protocol amended to 2x2 placebo- controled design after bevacizumab phase III data1 became available (N=1401) Cassidy & Saltz, JCO 2008 1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

NO16966 PFS Subgroup Analyses: On-Treatment Population XELOX Group FOLFOX Group 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 Survival Survival 7.0 m 9.5 m 8.4 m 10.6 m 0 100 200 300 400 500 0 100 200 300 400 500 Study day Study day HR = 0.61 [97.5% CI 0.48–0.78] P ≤ .0001 HR = 0.65 [97.5% CI 0.50–0.84] P = .0002 XELOX + placebo XELOX + Bev FOLFOX4 + placebo FOLFOX-4 + Bev VS VS Saltz et al., ASCO GI 2007

AVEX - PFS HR=0.53 (95% CI: 0.41–0.69) P<0.001 Cape + BEV (n=140) Cape (n=140) 1.0 0.8 0.6 0.4 0.2 0.0 HR=0.53 (95% CI: 0.41–0.69) P<0.001 PFS estimate 5.1 mo 9.1 mo 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (months) Number at risk Cape + BEV 140 121 99 80 68 55 41 28 23 16 13 9 8 3 2 1 Cape 140 109 82 56 38 25 13 9 6 4 2 1 Cunningham et al, ASCO GI 2013

CAIRO-3 R N=558 MT CFI PFS1 PFS2 TT2PD XELOXx6 CTX-BEV PFS2 11.5 10.5 Mos MT CFI HR P PFS1 8.5 4.1 0.44 <0.00001 PFS2 11.5 10.5 0.81 0.028 TT2PD 19.8 15.0 0.67 <0.00001 OS 21.7 18.2 0.87 0.16 MT R PD1 PD2 CFI XELOXx6 CTX-BEV N=558 PFS1 MT: LD-Cape (625 mg/m2 BID daily) + BEV (7.5 mg/KG every 3 wks) PFS2 TT2PD PFS2: time from R until PD upon re-introduction of XELOX-B TT2PD: time from R until PD upon any treatment after PFS1 Koopman, M et al. ASCO 2013

CAIRO-3 R PFS from start 1st line: N=558 4 + 11.5 mos = 15.5 mos XELOXx6 CTX-BEV Mos MT CFI HR P PFS2 11.5 10.5 0.81 0.028 MT R PD2 CFI XELOXx6 CTX-BEV PFS from start 1st line: 4 + 11.5 mos = 15.5 mos First-line PFS ΔOS 3.5 months! N=558 PFS2 PFS2: time from R until PD upon re-introduction of XELOX-B Koopman, M et al. ASCO 2013

ML18147 study design (phase III) Standard 2nd-line CT (oxaliplatin or irinotecan-based) until PD BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomize 1:1 BEV (2.5 mg/kg/wk) + standard 2nd-line CT (oxali or irino-based) until PD CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin Primary endpoint Overall survival (OS) from randomization Secondary endpoints included Progression-free survival (PFS) Best overall response rate Safety Stratification factors First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS (≤9 months, >9 months) Time from last BEV dose (≤42 days, >42 days) ECOG PS at baseline (0/1, 2) Bennouna et al., Lancet Oncol 2012

Bennouna et al., Lancet Oncol 2012 OS: ITT population CT (n=410) BEV + CT (n=409) 1.0 0.8 0.6 0.4 0.2 Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) OS estimate Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) 9.8 mo 11.2 mo 0 6 12 18 24 30 36 42 No. at risk CT 410 293 162 51 24 7 3 2 BEV + CT 409 328 188 64 29 13 4 1 Time (months) Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0) aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1) Bennouna et al., Lancet Oncol 2012

Bennouna et al., Lancet Oncol 2012 PFS: ITT population CT (n=410) BEV + CT (n=409) 1.0 0.8 0.6 0.4 0.2 Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test) PFS estimate Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test) 4.1 mo 5.7 mo 0 6 12 18 24 36 Time (months) No. at risk CT 410 119 20 6 4 0 BEV + CT 409 189 45 12 5 2 aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1) Bennouna et al., Lancet Oncol 2012

Large molecule VEGF inhibitors VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Permeability PlGF VEGF-B VEGF-C, VEGF-D Functions Y Bevacizumab Y Ramucirumab Aflibercept (VEGF Trap)

16 EFC10262: VELOUR Phase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks 600 pts mCRC after failure of an oxaliplatin based regimen R 1:1 SPEAKER NOTES The large, phase III randomized trial, VELOUR, has enrolled 1226 patients with previously treated metastatic CRC whose disease progressed on an oxaliplatin-based regimen. Patients are randomized to receive either aflibercept plus FOLFIRI or FOLFIRI alone. An important stratification in this trial is patients who have received prior bevacizumab-containing therapy in the front-line setting. In the United States, the majority of patients receive bevacizumab-containing therapy as treatment for their newly diagnosed mCRC. VELOUR has completed accrual of patients. The primary endpoint in this trial is median OS. An interim analysis of the data from VELOUR determined that the trial should continue to final analysis of OS. Final results are expected in late 2011. More details on this trial are available at clinicaltrials.gov (NCT00561470). Placebo + FOLFIRI q 2 weeks Stratification factors: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) 600 pts 30% of patients had prior BEV PIs: Allegra, Van Cutsem 16

VELOUR Study OS PFS HR 0.82 HR 0.76 Van Cutsem et al., JCO 2012 17

Progression-Free Survival Aflibercept: VELOUR Phase III: OS and PFS Stratified by Prior Bevacizumab Overall Survival Strata (as per UVRS) N HR (95.34% CI) HR Interaction P All patients 1,226 0.82 (0.713-0.937) Prior BEV No Yes 853 373 0.79 (0.669-0.927) 0.86 (0.673-1.104) .5668 1 2 3 Favors aflibercept Favors placebo Progression-Free Survival Strata (as per UVRS) N HR (95% CI) HR Interaction P All patients 1,226 0.76 (0.661-0.869) Prior BEV No Yes 853 373 0.80 (0.679-0.936) 0.66 (0.512-0.852) .1958 1 2 3 Favors aflibercept Favors placebo Adapted from Van Cutsem E, et al. J Clin Oncol. 2012 Sep 4. [Epub ahead of print].

VELOUR Response Rates Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.

Safety – Most frequent AEs, with ≥5% difference in incidence between treatment arms, excluding anti-VEGF class events Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611 All Grades Grade 3-4 Diarrhea 56.5 7.8 69.2 19.3 Neutropenia** Complicated neutropenia 56.3 29.5 2.8 67.8 36.7 5.7 Asthenic conditions (HLT) 50.2 10.6 60.4 16.9 Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7 Thrombocytopenia** 33.8 1.7 47.4 3.3 Infections (SOC) 32.7 6.9 46.2 12.3 Decrease appetite 23.8 1.8 31.9 3.4 Weight decreased 14.4 0.8 2.6 Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 Skin hyperpigmentation 8.2 Dehydration 3.0 1.3 9.0 AEs leading to treatment discontinuation: AFL: 26.6% PL: 12.1% Van Cutsem E, et al. J Clin Oncol. 2012;30(28):3499-3506.

Conclusion anti-VEGF Therapy Duration of VEGF-inhibition matters Treatment to progression Maintenance strategies Treatment beyond progression Clinical synergism between FP + bevacizumab Positive distinguishing factors for aflibercept vs BEV in 2nd line Tx not clear Head-to-head comparison warranted (Efficacy? Toxicity?) BEV combinable with FOLFOXIRI (TRIBE)

EGFR Monoclonal antibodies

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

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 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: 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 = 0.0479 8.0 vs 8.9 mos PFS estimate N=1217 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

CRYSTAL: 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 0.70 [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

PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS WT mCRC 0.7 Cetuximab Panitumumab 0.6 0.5 0.4 0.3 1‒HR 0.2 NORDIC VII3 0.1 COIN4 CRYSTAL6 PICCOLO7 PRIME5 Amado9 CO.1710 1818 –0.1 If we look at the PFS/DFS data from studies of EGFR inhibitors, we can see that they improve with later lines of therapy; offering their greatest efficacy values in 3L It therefore makes sense to use these in 3L if possible N01471 –0.2 PETACC-82* –0.3 Adjuvant 1L 2L 3L (single agent) 1. Alberts, et al. JAMA 2012; 2. Salazar, et al. ESMO 2012; 3. Tveit, et al. JCO 2012; 4. Maughan, et al. Lancet 2011 5. Douillard, et al. JCO 2010; 6. Van Cutsem, et al. JCO 2011; 7. Seymour, et al. ASCO 2011 8. Peeters, et al. JCO 2010; 9. Amado, et al. JCO 2008; 10. Karapetis, et al. NEJM 2008 *KRAS mutant CRC

Updated Analysis of PRIME study KRAS exon 2 codon 12/13 40% KRAS exon 3 codon 61 4% KRAS exon 4 codon 117/146 6% NRAS exon 2 codon 12/13 3% NRAS exon 3 codon 61 BRAF exon 15 codon 600 8% 17% Oliner et al., ASCO 2013

OS HR 0.83 (KRAS wt cod 12/13) Detriment! HR 0.78 (all RAS wt) Oliner et al., ASCO 2013

Satore-Bianchi et al., PLoS 2009 Outcome to EGFR mAb therapy based on KRAS, BRAF, PIK3CA and PTEN (n=132) Satore-Bianchi et al., PLoS 2009

FIRE-3 Phase III study design 1st-line therapy KRAS wild-type 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. 30-90min 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., ASCO 2013

Assessable for response 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 0.85-1.64 0.183 Assessable for response (N= 526) 1.52 1.05-2.19 72.2 66.2 – 77.6 63.1 57.1 – 68.9 0.017 p = Fisher´s exact test (one-sided) Heinemann et al., ASCO 2013

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 0.25 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 100 99 19 15 10 6 5 4 3 at risk 295 Heinemann et al., ASCO 2013

FIRE-3 Overall survival Events n/N (%) Median (months) 28.7 95% CI 1.0 ― FOLFIRI + Cetuximab 158/297 24.0 – 36.6 (53.2%) 0.75 ― FOLFIRI + Bevacizumab 185/295 25.0 22.7 – 27.6 Probability of survival (62.7%) HR 0.77 (95% CI: 0.62 – 0.96) Log-rank p= 0.017 0.50 0.25 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 218 214 111 60 47 29 18 9 2 Heinemann et al., ASCO 2013 at risk 295

FIRE-3 Overall survival Events n/N (%) Median (months) 28.7 95% CI 1.0 PFS ― FOLFIRI + Cetuximab 158/297 24.0 – 36.6 (53.2%) 0.75 ― FOLFIRI + Bevacizumab 185/295 25.0 22.7 – 27.6 Probability of survival (62.7%) HR 0.77 (95% CI: 0.62 – 0.96) Log-rank p= 0.017 0.50 Split of curves 0.25 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 218 214 111 60 47 29 18 9 2 Heinemann et al., ASCO 2013 at risk 295

Potential reasons for OS difference with same PFS Imbalance in post-progression therapy First-line therapy affects sensitivity of cancer cells to subsequent treatments Early clonal selection Is there an optimal sequence of treatment options? First-line therapy is highly effective in a subpopulation of CRC with long-lasting treatment benefit

FIRE-3 Overall survival Who are these pts? Analysis of RAS, PIK3CA, BRAF, PTEN, EGFR ligands 1.0 ― FOLFIRI + Cetuximab 0.75 ― FOLFIRI + Bevacizumab Probability of survival 0.50 0.25 0.0 12 24 36 48 60 72 months since start of treatment numbers 297 218 214 111 60 47 29 18 9 2 Heinemann et al., ASCO 2013 at risk 295

Conclusions EGFR mAbs (1) Efficacy in KRAS wt CRC well established Cetuximab and panitumumab likely interchangeable 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 More data on H2H cetuximab vs BEV will come from 80405 (RAS wt analysis!)

Conclusions EGFR mAbs (2) All-RAS wild-type CRC = 40-45% of CRC Further molecular refinements in future (PTEN, EGFR ligands, PIK3CA…) could cut the patient population suitable for EGFR mAbs down to 30-35% This refined patient population could sustain a marked benefit from use of first-line EGFR mAbs! EGFR mAbs could turn into the trastuzumab of CRC after all

regorafenib

Confidential • Advisory Board • 30 Sept 2012 Regorafenib (BAY 73-4506), an Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways Biochemical Activity Regorafenib IC50 mean ± SD nmol/l (n) VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAFV600E 19 ± 6 (6) F Cl O N H Regorafenib Questions and Probes for Facilitator: How would you interpret regorafenib’s multi-kinase inhibitor properties in its ability to prolong OS in patients with mCRC? How should regorafenib be positioned given its multi-kinase inhibitor properties? Inhibition of proliferation Inhibition of tumor microenvironment signaling Inhibition of neoangiogenesis KIT PDGFR RET PDGFR-β FGFR VEGFR1-3 TIE2 Wilhelm SM, et al. Int J Cancer. 2011;129(1):245-255. Mross K, et al. Clin Cancer Res. 2012;18(9):2658-2667. Strumberg D, et al. Expert Opin Invest Drugs. 2012;21(6):879-889.

CORRECT study design PS 0-1 Life expectancy 3 months! RANDOM I ZAT I ON Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025 mCRC after standard therapy 2 : 1 Placebo + BSC 3 weeks on, 1 week off Multicenter, randomized, double-blind, placebo-controlled, phase III 2:1 randomization Strat. factors: time from diagnosis of mCRC, geographical region Global trial: 16 countries, 114 active centers 1,052 patients screened, 760 patients randomized within 10 months PS 0-1 Life expectancy 3 months! Grothey, Van Custem et al., Lancet 2012

Overall survival (primary endpoint) Median 6.4 mos 5.0 mos 95% CI 5.9–7.3 4.4–5.8 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 Regorafenib Placebo 1.00 0.75 Survival distribution function 0.50 0.25 Placebo N=255 Regorafenib N=505 50 100 150 200 250 300 350 400 450 Days from randomization Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) Grothey, Van Custem et al., Lancet 2012

Progression-free survival (secondary endpoint) Pts beyond the “point of return”? 1.00 Regorafenib Placebo Median 1.9 mos 1.7 mos 95% CI 1.9–2.1 1.7–1.7 Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001 0.75 Survival distribution function 0.50 Placebo N=255 0.25 Regorafenib N=505 50 100 150 200 250 300 350 Days from randomization Grothey, Van Custem et al., Lancet 2012

Summary and Conclusions Biologics play an important role in the treatment of mCRC to optimize outcome Identification of patient population benefitting from one specific sequence of intervention is emerging All-RAS wild-type (+ other factors?) could favor EGFR mAbs in first-line mCRC At this point however, at least until 80405 results are available, BEV first-line is an appropriate option in KRAS wt mCRC Duration of therapy and access to all available treatment options essential Even in recent studies (CAIRO/FIRE) only a minority of pts received all agents

Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 2010 2015 median overall survival BSC 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab Aflibercept Regorafenib BBP