1. Fighting a Smarter War On Colon Cancer: John L. Marshall, MD Angiogenesis inhibition through all lines of therapy Tel: (202) 444-0275 Fax: (202) 444-1229 http://lombardi.georgetown.edu/GI

2. Stakeholder Motivation Stakeholders FDA CMS/Payers NCI/CTEP PhRMA Community Onc Academic Onc PatientsPriority/Agenda Safety and Efficacy Cost Control/Value Cure Cancer Markets, ROI Efficient/Quality Care Clinical Trial Accrual Cure/Benefit/Altruism

3. 2012 ESMO Guidelines: Sequence of Treatment by Line Schmoll et al. Ann Oncol. 2012;23:2479-2516.

4. 4 A. Friedman and N. Perrimon, Cell 128, January 26, 2007 Pathway vs. Network signaling Network “Chaotic” Pathway “Newtonian”

5. The Nature of the Disease

6. Multiple signaling pathways activated in CRC Multiple pathways implicated in CRC, including: 1–3 –EGF / EGFR –VEGF / VEGFR –PDGF / PDGFR –FGF / FGFR –Downstream pathways: RAS–RAF–MEK–ERK PI3K–PTEN–AKT–mTOR Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI 3 Provides rationale for using a multitargeted agent following progression 1.Macarulla T et al. Clin Colorectal Cancer 2006 2.Siena S et al. J Natl Cancer Inst 2009 3.Kopetz S et al. J Clin Oncol 2010 Figure adapted from Siena S et al 2009 2

7. CORRECT study design Multicenter, randomized, double-blind, placebo-controlled, phase III –2:1 randomization –Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region Global trial: 16 countries, 114 active centers –1,052 patients screened, 760 patients randomized within 10 months Secondary endpoints: PFS, ORR, DCR Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers mCRC after standard therapy RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Placebo + BSC 3 weeks on, 1 week off 2 : 1 Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall  =0.025 Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall  =0.025

8. CORRECT Primary Endpoint: Overall Survival 1.00 0.50 0.25 0 0.75 200100500150300250400350450 Days From Randomization Survival Distribution Function Placebo (n = 255) Regorafenib (n = 505) Median 6.4 months 5.0 months 95% CI 5.9-7.3 4.4-5.8 Hazard ratio: 0.77 (95% CI, 0.64-0.94) 1-sided P = 0.0052 Placebo Primary endpoint met prespecified stopping criteria at interim analysis. (1-sided P<0.009279 at approximately 74% of events required for final analysis). Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier. Regorafenib

9. 1.00 0.50 0.25 0 0.75 200100500150300250350 Days From Randomization Survival Distribution Function Placebo (n = 255) Regorafenib (n = 505) RegorafenibPlacebo Median 1.9 months 1.7 months 95% CI 1.9-2.1 1.7-1.7 Hazard ratio: 0.49 (95% CI, 0.42-0.58) 1-sided P<0.000001 Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier. CORRECT Secondary Endpoint: Progression-Free Survival

10. CORRECT: Common Adverse Events 1.Grothey A, et al. Lancet. 2012. [epub]. Treatment-related adverse events occurring in >10% of patients in either group from start of treatment to 30 days after end of treatment Regorafanib (n=500)Placebo (n=253) Any GrGr 3Gr 4Any GrGr 3Gr 4 Fatigue, n (%) 237 (47)46 (9)2 (<1)71 (28)12 (5)1 (<1) Hand-foot skin reaction, n (%) 233 (47)83 (17)019 (8)1 (<1)0 Diarrhea, n (%) 169 (34)35 (7)1 (<1)21 (8)2 (1)0 Anorexia, n (%) 152 (30)16 (3)039 (15)7 (3)0 Voice changes, n (%) 147 (29)1 (<1)014 (6)00 Hypertension, n (%) 139 (28)36 (7)015 (6)2 (1)0 Oral mucositis, n (%) 136 (27)15 (3)09 (4)00 Rash or desquamation, n (%) 130 (26)29 (6)010 (4)00 Nausea, n (%) 72 (14)2 (<1)028 (11)00 Weight loss, n (%) 69 (14)006 (2)00 Thrombocytopenia, n (%) 63 (13)13 (3)1 (<1)5 (2)1 (<1)0

11. First LineSecond Line Continued Beyond First Progression Trial AVF2107 1,2 (n=411 vs 402) E3200 3 (n=285 vs 287) ML18147 4 (n=410 vs 409) TreatmentIFL vs IFL + Bev FOLFOX4 vs FOLFOX4 + Bev CT* vs CT* + Bev OS, mos P value HR 15.6 vs 20.3 <0.001 0.66 10.0 vs 12.9 0.001 0.75 9.8 vs 11.2 0.0057 Unstratified HR: 0.81 PFS, mos P value HR 6.2 vs 10.6 <0.001 0.54 4.7 vs 7.3 <0.0001 0.61 4.4 vs 5.7 <0.0001 Unstratified HR: 0.68 Summary of Survival From Pivotal Phase III Bevacizumab Studies Data represent a summary of reported data and are not intended for cross-trial comparisons. 1. Hurwitz, et al. N Engl J Med. 2004;350:2335-2342. 2. Hurwitz, et al. Oncologist. 2009;14:22-28. 3. Giantonio, et al. J Clin Oncol. 2007;25:1539-1544. 4. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1. *CT= Fluoropyrimidine + oxaliplatin-containing chemotherapy or Fluoropyrimidine + irinotecan-containing chemotherapy.

12. ML18147: Randomized, Open-Label, Phase III Study of Bevacizumab + Chemotherapy Beyond Progression in Bevacizumab-Treated mCRC Stratification: –First-line chemotherapy (oxaliplatin-based, irinotecan-based), first-line PFS (≤ or >9 months), time from last dose of bevacizumab (≤ or > 42 days), and ECOG PS (0, ≥1) Primary endpoint: OS post progression Secondary endpoints: PFS post progression, ORR post progression Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1. PD Fluoropyrimidine-based chemotherapy until PD Bevacizumab 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks + Fluoropyrimidine-based chemotherapy until PD mCRC treated with Bev + standard first-line chemotherapy (n=820) Randomization – switch chemotherapy: Oxaliplatin  irinotecan Irinotecan  oxaliplatin Chemotherapy options: Fluoropyrimidine + oxaliplatin-containing chemotherapy Fluoropyrimidine + Irinotecan-containing chemotherapy

13. ML18147: Demographic and Baseline Characteristics – Well Balanced CharacteristicFluoropyrimidine- based chemotherapy alone (n=411) Bev + Fluoropyrimidine- based chemotherapy (n=409) Sex, male, %6365 Age, median years63 ECOG status, % 04344 15251 255 First-line PFS, % ≤9 months5654 >9 months4446 Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

14. Fluoropyrimidine- based chemotherapy alone (n=411) Bev + Fluoropyrimidine- based chemotherapy (n=409) First-line chemo, % Irinotecan based5859 Oxaliplatin based4241 Duration from last bevacizumab dose to randomization, % ≤42 days77 >42 days23 Liver metastasis only, % No7173 Yes2927 Number of organs with metastasis, % 13936 >16164 ML18147: Demographic and Baseline Characteristics – Well Balanced (Cont.)

15. ML18147: Second-line Chemotherapy During Study – Physician’s Choice Second-line Chemotherapy Regimen, % Fluoropyrimidine-based chemotherapy alone (n=407) Bevacizumab + Fluoropyrimidine-based chemotherapy (n=407) sFOLFIRI1416 XELIRI12 LV5FU2 + CPT11 7 7 FOLFOX499 sFOLFOX499 FOLFOX61316 FUFOX 9 6 XELOX 11 14 Other regimens16 12 sFOLFIRI=simplified fluorouracil 400 mg/m 2 intravenous bolus and 2400 mg/m 2 over 46 h, folinate 400 mg/m 2 intravenously, and irinotecan 180 mg/m 2 intravenously on day 1 every 2 weeks. LV5FU2 CPT11=fluorouracil 400 mg/m 2 intravenous bolus and 600 mg/m 2 (central venous line) over 22 h on days 1, 2, 15, and 16, folinate 200 mg/m 2 intravenously on days 1, 2, 15, and 16, and irinotecan 180 mg/m 2 intravenously on days 1 and 15 every 4 weeks. FOLFOX4=fluorouracil 400 mg/m 2 intravenous bolus and 600 mg/m 2 intravenously over 22 h on days 1 and 2, folinate 200 mg/m 2 intravenously on days 1 and 2, and oxaliplatin 85 mg/m 2 intravenously on day 1 every 2 weeks. sFOLFOX4=simplified folinate 400 mg/m 2, fluorouracil 400 mg/m 2 intravenous bolus, fluorouracil 2400 mg/m 2 continuous infusion (over 46 h), and oxaliplatin 85 mg/m 2 on day 1 every 2 weeks. FOLFOX6=fluorouracil 400 mg/m 2 intravenous bolus and 2400 mg/m 2 intravenously over 46 h on days 1 and 15, folinate 400 mg/m 2 intravenously on days 1 and 15, and oxaliplatin 100 mg/m 2 intravenously on days 1 and 15 every 4 weeks. FUFOX=fluorouracil 2000 mg/m2 over 22 h (central venous line) on days 1, 8, 15, and 22, folinate 500 mg/m 2 intravenously on days 1, 8, 15, and 22, and oxaliplatin 50 mg/ m 2 intravenously on days 1, 8, 15, and 22 every 5 weeks. XELIRI=capecitabine 800 mg/m 2 orally twice daily on days 1–14 and 22–35, and irinotecan 200 mg/m 2 intravenously on days 1 and 22 every 6 weeks. XELOX=capecitabine 1000 mg/m 2 orally twice daily on days 1–14 and 22–35, and oxaliplatin 130 mg/m 2 intravenously on days 1 and 22 every 6 weeks. *Six of 409 patients in the bevacizumab and chemotherapy group and four of 411 in the chemotherapy group were not given any treatment; however, four patients in the Bevacizumab and chemotherapy group were misreported as having been given chemotherapy. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

16. ML18147: Overall Survival (OS) a – ITT Population OS Estimate Time, Months 1.0 0.8 0.6 0.4 0.2 0 0612182430384248 Fluoropyrimidine-based chemotherapy alone (n=410) Bev + Fluoropyrimidine-based chemotherapy (n=409) 9.811.2 Unstratified b HR: 0.81 (95% CI: 0.69-0.94) P=0.0057 (log-rank test) a From randomization. b Primary analysis method. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1. 410 409 293 328 162 189 51 64 24 29 7 13 3434 2121 0000 Number at risk Fluoropyrimidine-based Chemotherapy alone Bev+Fluoropyrimidine-based Chemotherapy

17. ML18147: Secondary Endpoints PFS Estimate Time, Months 1.0 0.8 0.6 0.4 0.2 0 06121824303842 4.15.7 a From randomization. b Primary analysis method. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1. Unstratified b HR: 0.68 (95% CI: 0.59-0.78) P<0.0001 (log-rank test) 410 409 119 169 20 45 6 12 4545 0202 0202 0000 PFS a – ITT Population There was no significant difference in response rate. Fluoropyrimidine-based chemotherapy alone (n=410) Bev + Fluoropyrimidine-based chemotherapy (n=409) Number at risk Fluoropyrimidine-based Chemotherapy alone Bev+Fluoropyrimidine-based Chemotherapy

18. 18 What about VEGF + EGFR?  Bond-2 vs CAIRO 2 and PACCE 18

19. “Bond-2” C225 Alone C225 + Bev PValue C225 + CPT-11 C225 + CPT-11 + Bev P Value PR11%23%0.0523%38%0.03 TTP 1.5 mo 5.6 mo >0.01 4.1 mo 7.9 mo >0.01 OS 6.9 mo NR- 8.6 mo NR-

20. Kaplan-Meier estimates of time to tumor progression: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab). Saltz L B et al. JCO 2007;25:4557-4561 ©2007 by American Society of Clinical Oncology

21. Kaplan-Meier estimates of survival: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab). Saltz L B et al. JCO 2007;25:4557-4561 ©2007 by American Society of Clinical Oncology

22. 22 Colon Cancer is more than one disease kRAS Wild Type kRAS mutant MSI-High MSS + EGFR Agents - EGFR Agents ? No 5FU 50-60% 40-50% 15-20% 80-85% And of course it is very many more than the 4 sub-groups above

23. Clinical Research 2.0

24. AgentHR$ Cost/Month (÷100) Toxicity (G1+2) * (G3+4) # Patients QOL/UtilityScore Pass/Fail Imatinib vs IFN CML 0.17 55.900.67 Nilotinib vs Imat CML 0.8 76.400.17 Imatinib GIST 0.4 55.901.22 Erlotinib vs Chemo Mut NSCL 0.75 52.800.71 Erlotinib Pancreas 0.82 52.8011.9 Bevacizumab 2 nd line CRC 0.74 22.900.8 Aflibercept 2 nd line CRC 0.79 ????-3.0 Value Metric

25. Finding Value Come together Listen to each other Respect what we hear Find the common threads Weave a new fabric - provide global healthcare with value

27. Engaging the 97% Better education/information Incentives for patients and providers – No added incentives for delivering SOC – Honor our “soldiers” in the war on cancer Recognized the shared investment in research – Docs, hospitals, NCI, Industry, Payers, Patients Target “substantial therapeutic benefit” – “Breakthrough Designation” Reduce concept to approval time line Embrace the emerging markets

28. Fundamental Shifts In Cancer Care Yesterday Consumption Individual Practices Rich Countries Microscope Safety and Efficacy Large trials 1.4 months QOL Patient as a “Subject” Chaotic Data Collection Institutional IRBs National ApprovalsTomorrow Outcomes Healthcare Systems All Countries Gene Profile Value Small trials “Substantial Improvement” Patient Reported Outcomes Patient as a “Partner” Standard Data Collection Central/National IRBs Global Approvals