Nab-paclitaxel: lo stato dell’arte III Sessione - Il carcinoma del pancreas Chair: C. Pinto - Moderatori: F. de Braud, A. Falcone Nab-paclitaxel: lo stato dell’arte Alberto Sobrero IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova

“Raising the bar for antineoplastic agents: how to choose threshold values for superiority trials in advanced solid tumors”   A F. Sobrero1, A Pastorino1 , D. J. Sargent.2 and P Bruzzi.1 Clin Ca Res 2015

Probability of Survival (%) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 HR (Cox model) 2. Gain in median OS (a b) 3. Absolute increase in OS (c d) at 2-3 years a b 4. Proportional increase in OS (ce/de) at 2-3 years c d e Time

NUMBER OF POSITIVE TRIALS N. of rials meeting the low required benefit for mCMO out of 43 pivotal randomized studies analyzed.   CRITERIA NUMBER OF POSITIVE TRIALS Prognosis N of Hazard gain "either" "both" in control trials Ratio in OS parameter prameters < 9 mo 9 0,70 2 mo 4 5 9-12 mo 8 0,75 2,5 mo 12-18 mo 3 mo 6 3 >18 mo 17 0,80 3,5 mo 7 TOT 43 21 23 15

MCWE for the low required benefit for “LARGE” at 2 or 3 yrs in poor or good prognosis groups: N of trials meeting these criteria for success among the 18 trials analyzed   CRITERIA NUMBER OF POSITIVE TRIALS TRIALS Absolute Proportional 2 YEARS 3 YEARS Prognosis increase A P "either" "both" < 9 mo 4 5% 25% 3 9-12 mo 7 5 12-18 mo >18 mo 1 TOT 18 8 Sunitinib GIST ((3 yrs) Nab-paclitaxel- pancreas Temsirolimus kidney Bevacizumab NSCLC Bevacizumab colon Ipilimumab melanoma Radium223 prostate Erlotinib NSCLC trastuzumab gastric

MCWE for the high required benefit for “LARGE” at 2 or 3 yrs in poor or good prognosis groups: number of trials meeting these criteria for success among the 18 trials analyzed   CRITERIA NUMBER OF POSITIVE TRIALS TRIALS Absolute Proportional 2 YEARS 3 YEARS Prognosis increase A P "either" "both" < 9 mo 4 15% 100% 1 9-12 mo 7 12-18 mo >18 mo TOT 18 Sunitinib –GIST Nab-paclitaxel- pancreas

N Engl J Med 2013; 369:1691-1703

Disegno dello Studio Primary endpoint OS Secondary endpoints PFS and ORR by independent review (RECIST v1.0) Safety and tolerability By NCI CTCAE v3.0 With 608 events, 90% power to detect OS HR = 0.769 (2-sided α = 0.049) Treat until progression or unacceptable toxicity Spiral CT or MRI scans every 8 weeks CA19-9 measurements at baseline and every 8 weeks Von Hoff DD, et al. N Engl J Med. 2013 Oct 16

Proportion of Survival Overall Survival: dati aggiornati OS, months Events/n Median (95% CI) 75th Percentile 380/431 8.7 (7.89 - 9.69) 14.8 394/430 6.6 (6.01 - 7.20) 11.1 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion of Survival nab-P + Gem Gem HR 0.72 95% CI, 0.620 - 0.825 P < 0.0001 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Patients at Risk nab-P + Gem: Gem: Time (months) 431 357 284 208 144 84 48 34 25 16 10 6 5 2 1 430 340 231 149 90 47 27 19 14 8 4 2 Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 9

OS—Prespecified Subgroups nab-P + Gem Events/n Gem HR 333/431 359/430 0.72 188/254 209/242 0.65 145/177 150/188 0.81 138/186 141/173 195/245 218/257 142/179 146/161 0.61 187/248 212/268 0.75 142/191 155/180 0.59 188/237 201/246 0.80 290/365 309/360 0.69 43/66 50/70 0.86 21/33 16/21 0.41 159/202 163/206 104/136 121/140 0.79 49/60 59/63 0.50 47/60 43/56 1.07 96/122 95/120 0.83 151/197 171/195 50/61 53/59 0.67 62/64 59/62 0.84 14/38 17/38 207/268 230/271 0.68 Group HR All patients Age < 65 years Age ≥ 65 years Female Male KPS 70-80 KPS 90-100 Primary tumor location: head Primary tumor location: other No liver metastases Liver metastases Normal CA19-9 CA19-9 ULN to < 59 x ULN CA19-9 ≥ 59 x ULN > 3 metastatic sites 1 metastatic site 3 metastatic sites 2 metastatic sites Will be redone with log scale Australia Western Europe North America Eastern Europe 0.125 0.25 0.5 1.0 2.0 Favors nab-P + Gem Favors Gem Von Hoff et al. ASCO 2013. 10

Tassi di sopravvivenza e terapie successive Variable nab-P + Gem n = 431 Gem n = 430 HR (nab-P + Gem/Gem) P Value Patients who received subsequent therapy, % 38 42 — Median OS censored at time of secondary therapy, months 9.4 6.8 0.68 < 0.001 Von Hoff DD, et al. N Engl J Med. 2013 Oct 16

PFS: valutazione indipendente Median PFS by investigator assessment was also significantly longer with nab-P + Gem vs Gem (median 5.3 vs 3.5 months; HR 0.61; 95% CI, 0.52 - 0.71; P < 0.001) Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; PFS, progression-free survival; Pts, patients. Von Hoff DD, et al. N Engl J Med. 2013 Oct 16

23% 4.3 27% Deltas not due to under or over performing of control 17% 1.8 13%

RANKING OF CT EFFICACY IN METASTATIC PANCREATIC CA Folfirinox GEM-nab Paclitaxel GEM Are the patients populations similar ? Trial characteristics Patients characteristics

Worse population in GEM nab-paclitaxel

Treatment-related determinants of medical choices Efficacy Toxicity Convenience

GEM-nab paclitaxel closer to GEM 24% 1% 12% 8% 20% 0% FOLFIRINOX most toxic GEM least toxic GEM-nab paclitaxel closer to GEM

Safety Grade ≥ 3 neuropathy nab-P + Gem (n = 421) Gem (n = 402) Time to onset, median days Time to improvement by 1 grade, median days Time to improvement to grade ≤ 1, median days Pts who resumed nab-P, % 140 21 29 44 113 -- Hematologic values: table. 14.3.4.1.1 Nonhematologic: table 14.3.2.3.5 Febrile neutropenia: 14.3.2.9.1 AE leading to death: 14.3.2.1 Neuropathy time: table 14.3.3.4 a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term. Von Hoff et al. ASCO 2013. 19

CONCLUSIONS CT impact on natural hx III generation CT better than single agents Good to have several options Expected tox is the main driver of our choice Folfirinox most efficacious Gem-nab paclitaxel best in most conditions GEM , still an option, sometimes