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 1

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

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

Pathway vs. Network signaling In recent years the view of signaling had shifted from the canonical pathway signaling towards a concept of NETWORK SIGNALING. The latter takes into account a tremendous degree of overlap and cross-talk between the pathways. This network signaling concept came to existence as a result of studies based on Y2H and RNAi technologies. Pathway “Newtonian” Network “Chaotic” A. Friedman and N. Perrimon, Cell 128, January 26, 2007

The Nature of the Disease

Multiple signaling pathways activated in CRC Figure adapted from Siena S et al 20092 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 + FOLFIRI3 Provides rationale for using a multitargeted agent following progression Macarulla T et al. Clin Colorectal Cancer 2006 Siena S et al. J Natl Cancer Inst 2009 Kopetz S et al. J Clin Oncol 2010

CORRECT study design Primary Endpoint: OS mCRC after standard therapy 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: 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

CORRECT Primary Endpoint: Overall Survival 1.00 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 Regorafenib 0.75 0.50 Survival Distribution Function 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 A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier.

CORRECT Secondary Endpoint: Progression-Free Survival 1.00 0.50 0.25 0.75 200 100 50 150 300 250 350 Regorafenib Placebo 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 Survival Distribution Function Placebo (n = 255) Regorafenib (n = 505) Days From Randomization Grothey A et al. Lancet. 2013;381:303-312. Reprinted with permission from Elsevier.

CORRECT: Common Adverse Events 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 Gr Gr 3 Gr 4 Fatigue, n (%) 237 (47) 46 (9) 2 (<1) 71 (28) 12 (5) 1 (<1) Hand-foot skin reaction, n (%) 233 (47) 83 (17) 19 (8) Diarrhea, n (%) 169 (34) 35 (7) 21 (8) 2 (1) Anorexia, n (%) 152 (30) 16 (3) 39 (15) 7 (3) Voice changes, n (%) 147 (29) 14 (6) Hypertension, n (%) 139 (28) 36 (7) 15 (6) Oral mucositis, n (%) 136 (27) 15 (3) 9 (4) Rash or desquamation, n (%) 130 (26) 29 (6) 10 (4) Nausea, n (%) 72 (14) 28 (11) Weight loss, n (%) 69 (14) 6 (2) Thrombocytopenia, n (%) 63 (13) 13 (3) 5 (2) This slide details the most common adverse drug reactions seen with STIVARGA. Grothey A, et al. Lancet. 2012. [epub].

Summary of Survival From Pivotal Phase III Bevacizumab Studies First Line Second Line Continued Beyond First Progression Trial AVF21071,2 (n=411 vs 402) E32003 (n=285 vs 287) ML181474 (n=410 vs 409) Treatment IFL 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 6.2 vs 10.6 0.54 4.7 vs 7.3 <0.0001 0.61 4.4 vs 5.7 Unstratified HR: 0.68 *CT= Fluoropyrimidine + oxaliplatin-containing chemotherapy or Fluoropyrimidine + irinotecan-containing chemotherapy. 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. 11

ML18147: Randomized, Open-Label, Phase III Study of Bevacizumab + Chemotherapy Beyond Progression in Bevacizumab-Treated mCRC 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 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 ADDITIONAL INFORMATION The ML18147 is a randomized, open label, phase III study The ML18147 excluded patients who had progressed on first-line Avastin in <3 months and allowed patients to have up to a 3-month treatment break prior to randomization. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1. Reference: Bennouna J, et al. Lancet Oncol. 2012;pii:S1470-2045(12)70477-1. 12

ML18147: Demographic and Baseline Characteristics – Well Balanced Fluoropyrimidine-based chemotherapy alone (n=411) Bev + Fluoropyrimidine-based chemotherapy (n=409) Sex, male, % 63 65 Age, median years ECOG status, % 43 44 1 52 51 2 5 First-line PFS, % ≤9 months 56 54 >9 months 46 Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

ML18147: Demographic and Baseline Characteristics – Well Balanced (Cont.) Fluoropyrimidine-based chemotherapy alone (n=411) Bev + Fluoropyrimidine-based chemotherapy (n=409) First-line chemo, % Irinotecan based 58 59 Oxaliplatin based 42 41 Duration from last bevacizumab dose to randomization, % ≤42 days 77 >42 days 23 Liver metastasis only, % No 71 73 Yes 29 27 Number of organs with metastasis, % 1 39 36 >1 61 64 Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

ML18147: Second-line Chemotherapy During Study – Physician’s Choice Second-line Chemotherapy Regimen, % Fluoropyrimidine-based chemotherapy alone (n=407) Bevacizumab + Fluoropyrimidine-based chemotherapy sFOLFIRI 14 16 XELIRI 12 LV5FU2 + CPT11 7 FOLFOX4 9 sFOLFOX4 FOLFOX6 13 FUFOX 6 XELOX 11 Other regimens Second-line Chemo During Study: Many Regimens—Physician’s Choice sFOLFIRI=simplified fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 over 46 h, folinate 400 mg/m2 intravenously, and irinotecan 180 mg/m2 intravenously on day 1 every 2 weeks. LV5FU2 CPT11=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 (central venous line) over 22 h on days 1, 2, 15, and 16, folinate 200 mg/m2 intravenously on days 1, 2, 15, and 16, and irinotecan 180 mg/m2 intravenously on days 1 and 15 every 4 weeks. FOLFOX4=fluorouracil 400 mg/m2 intravenous bolus and 600 mg/m2 intravenously over 22 h on days 1 and 2, folinate 200 mg/m2 intravenously on days 1 and 2, and oxaliplatin 85 mg/m2 intravenously on day 1 every 2 weeks. sFOLFOX4=simplified folinate 400 mg/m2, fluorouracil 400 mg/m2 intravenous bolus, fluorouracil 2400 mg/m2 continuous infusion (over 46 h), and oxaliplatin 85 mg/m2 on day 1 every 2 weeks. FOLFOX6=fluorouracil 400 mg/m2 intravenous bolus and 2400 mg/m2 intravenously over 46 h on days 1 and 15, folinate 400 mg/m2 intravenously on days 1 and 15, and oxaliplatin 100 mg/m2 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/m2 intravenously on days 1, 8, 15, and 22, and oxaliplatin 50 mg/ m2 intravenously on days 1, 8, 15, and 22 every 5 weeks. XELIRI=capecitabine 800 mg/m2 orally twice daily on days 1–14 and 22–35, and irinotecan 200 mg/m2 intravenously on days 1 and 22 every 6 weeks. XELOX=capecitabine 1000 mg/m2 orally twice daily on days 1–14 and 22–35, and oxaliplatin 130 mg/m2 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.

ML18147: Overall Survival (OS)a – ITT Population 1.0 0.8 0.6 0.4 0.2 Fluoropyrimidine-based chemotherapy alone (n=410) Bev + Fluoropyrimidine-based chemotherapy (n=409) Unstratifiedb HR: 0.81 (95% CI: 0.69-0.94) P=0.0057 (log-rank test) OS Estimate 9.8 11.2 0 6 12 18 24 30 38 42 48 Time, Months Number at risk Fluoropyrimidine-based Chemotherapy alone Bev+Fluoropyrimidine-based Chemotherapy 410 409 293 328 162 189 51 64 24 29 7 13 3 4 2 1 aFrom randomization. bPrimary analysis method. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

ML18147: Secondary Endpoints PFSa – ITT Population 1.0 0.8 0.6 0.4 0.2 Fluoropyrimidine-based chemotherapy alone (n=410) Bev + Fluoropyrimidine-based chemotherapy (n=409) Unstratifiedb HR: 0.68 (95% CI: 0.59-0.78) P<0.0001 (log-rank test) PFS Estimate 4.1 5.7 0 6 12 18 24 30 38 42 Time, Months Number at risk Fluoropyrimidine-based Chemotherapy alone Bev+Fluoropyrimidine-based Chemotherapy 410 409 119 169 20 45 6 12 4 5 2 There was no significant difference in response rate. aFrom randomization. bPrimary analysis method. Bennouna J, et al. Lancet Oncol. 2012;pii: S1470-2045(12)70477-1.

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

“Bond-2” PR TTP OS 11% 23% 0.05 38% 0.03 1.5 mo 5.6 mo >0.01 4.1 mo C225 Alone C225 + Bev P Value C225 + CPT-11 C225 + CPT-11 + Bev P Value PR 11% 23% 0.05 38% 0.03 TTP 1.5 mo 5.6 mo >0.01 4.1 mo 7.9 mo OS 6.9 mo NR - 8.6 mo

Kaplan-Meier estimates of time to tumor progression: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab). 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

Kaplan-Meier estimates of survival: arm A (cetuximab, bevacizumab, irinotecan) versus arm B (cetuximab, bevacizumab). 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

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

Clinical Research 2.0

Value Metric Agent HR $ Cost/Month (÷100) Toxicity (G1+2) * (G3+4) # Patients QOL/Utility Score Pass/Fail Imatinib vs IFN CML 0.17 55.90 0.67 Nilotinib vs Imat 0.8 76.40 Imatinib GIST 0.4 1.22 Erlotinib vs Chemo Mut NSCL 0.75 52.80 0.71 Erlotinib Pancreas 0.82 11.9 Bevacizumab 2nd line CRC 0.74 22.90 Aflibercept 2nd line CRC 0.79 ????- 3.0

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

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

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 Approvals Tomorrow 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