1. FOLFIRINOX: The Obvious Choice Jordan D. Berlin, M.D. Ingram Professor of Cancer Research Co-director, GI Oncology Director, Phase I Research Vanderbilt-Ingram Cancer Center

2. Disclosures Advisory Boards here and there in last year –Genentech/Roche –Karyopharm –Amgen –Astra Zeneca –BMS –Lilly/Imclone –Symphogen –Celgene –Vertex –Ipsen Current Research Support –Amgen, Lilly/Imclone, Pfizer, Novartis, Abbvie, Immunomedics, Otsuka, Merrimack, Oncomed, Genentech/Roche, Taiho

3. CA046 Randomized Phase III Study of Weekly nab- Paclitaxel Plus Gemcitabine vs Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas (MPACT) DD Von Hoff, T Ervin, FP Arena, EG Chiorean, J Infante, M Moore, T Seay, SA Tjulandin, W Ma, MN Saleh, M Harris, M Reni, RK Ramanathan, J Tabernero, M Hidalgo, E Van Cutsem, D Goldstein, X Wei, J Iglesias, MF Renschler ® nab is a registered trademark of Celgene Corporation. Von Hoff DD, Ervin T, Arena FP, et al. Randomized Phase III Study of Weekly nab-Paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) [abstract LBA148]. Oral presentation at: The Gastrointestinal Cancers Symposium 2013; January 24-26; San Francisco, CA. Published n engl j med 369;18 nejm.org october 31, 2013 by Von Hoff, et al:

4. Study Design Planned N = 842 Stage IV No prior treatment for metastatic disease Karnofsky PS ≥70 Measurable disease Total bilirubin ≤ULN Planned N = 842 Stage IV No prior treatment for metastatic disease Karnofsky PS ≥70 Measurable disease Total bilirubin ≤ULN nab-Paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks nab-Paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks Gemcitabine 1000 mg/m 2 IV qw for 7 weeks then qw 3/4 weeks Gemcitabine 1000 mg/m 2 IV qw for 7 weeks then qw 3/4 weeks Von Hoff

5. IMPACT: Efficacy Response Rate is 29% for gemcitabine + nab-paclitaxel by investigator review

6. FOLFIRINOX A phase II-III randomized study comparing Folfirinox regimen to gemcitabine alone was launched –Please note: Robust randomized phase II with strong signal for going forward –This is the best-supported go-forward in pancreas cancer history Results of phase II randomized study step (n=88) were presented during ASCO 2007: –31.8% RR in the Folfirinox arm vs –11.4% in the gemcitabine arm Due to these encouraging interim results, the trial continued as a phase III study Conroy T et al. J Clin Oncol 2005;23:1228-36 Ychou M et al. J Clin Oncol 2007;25:18S:201s

7. Objective Response Rate Folfirinox N=171 Gemcitabine N=171 p Complete response0.6% 0% Partial response31%9.4% 0.0001 CR/PR 95% CI[24.7-39.1][5.9-15.4] Stable disease38.6%41.5% Disease control CR+PR+SD 70.2%50.9%0.0003 Progression15.2%34.5% Not assessed14.6% Median duration of response 5.9 mo. 4 mo.ns

8. Progression-Free Survival Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

9. Overall Survival Med Survival: 11.1 vs 6.8 months

10. Safety: hematological AEs AE, % per patient Folfirinox N=167 Gemcitabine N=169 p AllGrade 3/4AllGrade 3/4 Neutropenia79.945.754.818.70.0001 Febrile Neutropenia 7.2 2.40.60.009 Anemia90.47.894.65.4NS Thrombocytopenia75.29.154.82.40.008 5.4 42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm AE, adverse event

11. Safety: main non-hematological AEs AE, % per patient Folfirinox N=167Gemcitabine N=169 p AllGrade 3/4AllGrade 3/4 Infection without neutropenia 61.27.11.8NS Peripheral neuropathy70.590.600.0001 Vomiting61.414.543.24.70.002 Fatigue87.323.278.714.20.036 Diarrhea73.312.730.81.20.0001 Alopecia (grade 2)32.5(11.4)3.0(0.6)0.0001 ALT64.87.383.80.0022 18.6 Conroy et al, NEJM, 364:1817-1825, 2011

12. FOLFIRINOX Conclusions Clearly the most robust phase III results in metastatic pancreatic cancer Limited patient subset –PS 0 or 1 only –Age <76 Includes a platinum which is likely a key element in treating the BRCA2/Fanconi/PALB2 subset of patients Largely being used in modified form –Most common modification is dropping the bolus 5FU

13. FOLFIRINOX vs Gem-nab-paclitaxel Similarities in population –Median age –Gender –100% stage IV –Site of primary –% with liver involvement Differences in population –MPACT allowed PS 2 (KPS 70%) patients though <10% of population –MPACT was worldwide, PRODIGE in France only –Age >75 allowed on MPACT though only 5% –Median # of sites of mets 3 in MPACT 2 in PRODIGE

14. Tolerability: Select Grade 3+ Toxicities, % nab-pacli + GEM FOLFIRINOX Fatigue1723.6 Diarrhea612.7 Neuropathy179 Neutropenia3845.7 Neutropenic fever35.4 Thrombocytopenia139.1 Conroy et al, NEJM, 364:1817-1825, 2011 Von Hoff, et al GI ASCO 2013 and ASCO 2013 Neuropathy appears to resolve faster with nab-paclitaxel

15. Differences in efficacy OS for FOLFIRINOX was 11.1 months vs 8.7 months for gemcitabine + nab-paclitaxel HR was 0.57 for FOLFIRINOX vs 0.72 for gem- nab-paclitaxel –Comparison is limited by differences in study design/population, etc –However control arm was the same gemcitabine for both (FOLFIRINOX 6.8 months and Gem-nab-paclitxel 6.7 monhts) Response Rate –Really similar: By investigator assessment 29% for gem-nab-paclitaxel vs 31.6% for FOLFIRINOX

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17. Conclusions FOLFIRINOX –Rumors of its toxicity are greatly exaggerated –Some of this can be modulated by removing bolus 5FU Preliminary reports suggest this does not impact on efficacy Gem-nab-Paclitaxel –Rumors of its tolerability will be exaggerated –There is concern about lowering either of the two drug doses Hazard ratio means that at any point along the curve if you were supposed to be dead on gemcitabine, then for gem- nab-paclitaxel you only have a 72% chance of being dead, and only a 57% chance of being dead on FOLFIRINOX –And it took half the number of patients to prove the point with FOLFIRINOX

18. 2 nd to last slide Let your patients be 43% less dead rather than only 28% less dead, favor FOLFIRINOX

19. Friends don’t let friends conduct mindless clinical trials RANDOMIZERANDOMIZE Gemcitabine + nab-paclitaxel Gemcitabine + nab-paclitaxel + Your Drug Here Your Drug = some new nibs mabs pibs and despite all evidence this is incredibly stupid, probably something that blocks VEGF Prevent this and make sure there is real science before you sign up for these trials

20. Slides Provided By Thierry Conroy Philip Dan Von Hoff