1. Understanding the Costs and Benefits of Colon Cancer Treatment Colorectal Cancer Poster Discussion 2006 Neal J. Meropol, M.D. Director, Gastrointestinal Cancer Program Divisions of Medical Science and Population Science Fox Chase Cancer Center

2. “Costs” and “Benefits” Some Costs Severe toxicity Symptomatic vs. laboratory toxicity Hospitalization Irreversible toxicity Quality of life Death Dollars, euros, and yen Some Benefits Response Progression free survival Relapse free survival Overall survival Surgical resection Cure Quality of life

3. Deriving a Treatment Valuation V = Σ (W n pB n ) - Σ (W n pC n ) Implications There are different types of benefits There are different types of costs Various stakeholders evaluate costs/benefits differently Individual patients may weigh each cost and benefit differently, e.g. based upon goals of therapy, decision making “calculus”

4. What have we learned today?

5. The triplet combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) vs the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.) A. Falcone, G. Masi, I. Brunetti, G. Benedetti, O. Bertetto, V. Picone, S. Chiara, M. Merlano, S. Vitello, S. Ricci

6. Falcone et al: Is more better? Abstract #3513 Randomized phase III trial Unresectable metastatic CRC Age 18-75 First-line therapy FOLFIRI vs. FOLFOXIRI N = 244 Primary endpoint = response rate

7. FOLFOX vs. FOLFOXIRI: Benefits FOLFIRIFOLFOXIRIp Response rate34%60%<0.0001 Resection of mets all (n=244)6%15%0.03 liver (n=81)12%36%0.02 Median PFS6.9 mo.9.8 mo.0.0006 Median S16.7 mo.22.6 mo.0.032 67% in FOLFIRI arm received subsequent FOLFOX 48% in FOLFOXIRI arm received same drugs subsequently

8. FOLFIRI vs. FOLFOXIRI: Costs FOLFIRIFOLFOXIRIp Diarrhea G3-412%20%0.08 Vomiting G3-42% 7%0.10 Neurotox G2-30% 20%<0.0001 Neutropenia G3-428%50%0.0006 Neutropenia G411% 17% Febrile neutropenia3% 5% Toxic death0%0% 60-day mortality1.6%1.6% Hospitalization??

9. FOLFIRI vs. FOLFOXIRI: Conclusions Higher response rate = higher toxicity Note: EGFR/VEGF antibodies not routinely available Resection of mets may account for improvements in long-term outcome Identify which patients have the potential for long- term survival and CURE with aggressive surgical management. In this setting, benefits are more likely to trump costs

10. Tolerability of fluoropyrimidines appears to differ by region D. G. Haller, J. Cassidy, S. Clarke, D. Cunningham, E. Van Cutsem, P. Hoff, M. Rothenberg, L. Saltz, H. J. Schmoll, C. Twelves

11. Haller et al: Are there regional variations in fluoropyrimidine toxicity? Abstract #3514 Industry databases from phase III studies, international enrollment Metastatic –2 studies, N=1189, capecitabine vs. daily x 5 FU/LV Adjuvant –1 study, N=1861, CAPOX vs. FU/LV Endpoints: adverse events vs. country

12. Fluoropyrimidine Toxicity (Grade 3-4) Adjusted Relative Risk (95% CI) GI ToxicityNeutropenia Metastatic US/RoW1.72 (1.25-2.36)1.51 (1.01-2.25) Adjuvant US/Asia3.62 (2.11-6.20)0.96 (0.53-1.73) RoW/Asia2.38 (1.50-3.77)0.63 (0.41-0.95)

13. Potential Causes for Regional Variation in Toxicity Patient selection (clinical) Reporting bias Regional biologic differences Regional environmental differences Host-environment interactions Drug interactions

14. Host-Environment Interactions DHFR 5,10-MTHF DHFTHF 5-MTHF MTHFR Folinic Acid Host Environ- ment

15. Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): A comparative analysis of N9741 and AVF2107 A. Grothey, E. E. Hedrick, R. D. Mass, S. Sarkar, R. K. Ramanathan, H. Hurwitz, R. M. Goldberg, D. J. Sargent

16. Grothey et al: Does benefit require response? Abstract #3516 Retrospective analysis of AVF2107g (N=813) and N9741 (N=768) Response criteria: RECIST (AVF) and WHO (N9741) Hypothesis: Non-responders as well as responders benefit from the superior therapy

17. PFS: IFL/Bev vs. IFL Responders Non Responders

18. PFS: FOLFOX vs. IFL Responders Non Responders

19. Response Rate is Merely a Surrogate Clinical response is not a categorical variable as RECIST/WHO criteria imply Grothey et al analysis supports use of other endpoints in randomized trials Choice of surrogate should depend on clinical context, goal of study, and treatment mechanism of action (RR, non-progression rate, PFS, tumor marker, in vivo pharmacodynamics…..) Endpoints must be validated Endpoints must permit discrimination of activity from background; “go – no go” decision

20. A pooled safety and efficacy analysis of the FOLFOX4 regimen (bi-monthly oxaliplatin plus fluorouracil/leucovorin) in elderly compared to younger patients with colorectal cancer D. J. Sargent, R. M. Goldberg, H. Bleiberg, A. De Gramont, C. Tournigand, T. Andre, M. L. Rothenberg, I. M. Tabah-Fisch

21. Sargent et al: Does age impact efficacy or toxicity with FOLFOX4? Abstract #3517 Pooled efficacy and toxicity analysis of 4 studies with FOLFOX4 (3 metastatic, 1 adjuvant) N=3743, 614 at least 70 years old Analyses: age <>70 (3 studies excluded patients >75 years old) Greater G3-4 neutropenia (49 vs. 43%, p=0.04), thrombocytopenia (5% vs. 2%) in older age group No differences in response, survival, dose intensity, neurotox, GI tox, 60 day mortality (2.3 vs. 1.1%, p=0.2)

22. Questions Remain….. Other key clinical endpoints: –What was hospitalization rate? –What was grade 4 neutropenia rate? –What was dehydration rate? What was the age distribution in these studies? How many patients were old old (e.g. >80)? How representative are these study populations of the general population? These data highlight the importance of better characterizing key differences in clinical trial and off- study populations, and maximizing the representativeness of clinical trial populations

23. Direct cost-survival analysis of therapies for metastatic colorectal cancer Y. Wong, N. J. Meropol, D. Sargent, R. Goldberg, J. R. Beck

24. Wong et al: What is the cost- effectiveness of CRC treatment? Abstract #3515 Markov Model comparing cost and effectiveness of up to 3 lines of treatment to base cases of 5-FU/LV or FOLFOX Cost = total drug costs (average sales price, 70 kg, BSA 1.7 sq.m.) Effectiveness = life expectancy Aggregate data on progression, survival, and toxicity from phase II and III published reports, and N9741 unpublished data

25. CE Compared to 5-FU/LV Example: FOLFOX/Bev – Irinotecan -- Cetuximab/Irinotecan $2700/wk compared to 5FU (survival 117 vs. 55 weeks)

26. Why does this matter? New agents for treatment of metastatic colorectal cancer result in meaningful improvements in survival Cost is largely driven by drug price These observations challenge traditional healthcare cost-effectiveness thresholds Cost already limits access to care ASCO must work to ensure: –development of new cancer therapies (innovation) –access to high quality care for all cancer patients –appropriate and optimal use of cancer treatments

27. Expanding Our Understanding of “Costs” and “Benefits” Goals of treatment impact valuation of costs and benefits Biologic and/or environmental factors may influence treatment toxicity Clinical benefit is not restricted to patients who achieve an objective “response” Among clinical trial participants <75 years old, age alone does not confer substantially greater risk of certain toxicities with FOLFOX Drugs are expensive. We will ultimately need to address what is an “acceptable” CE ratio, and work with all stakeholders to ensure access of high quality care for all patients