1. 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

2. “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

3. 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

4. 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

5. 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 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

6. 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 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

7. N Engl J Med 2013; 369:

8. 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 = (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 Oct 16

9. Proportion of Survival
Overall Survival: dati aggiornati
OS, months
Events/n
Median (95% CI)
75th Percentile
380/431
8.7 ( )
14.8
394/430
6.6 ( )
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,
P <
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

10. 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
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

11. 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 Oct 16

12. 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, ; 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 Oct 16

13. 23% %
Deltas not due to under or over performing of control
17% %

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

16. Worse population in GEM nab-paclitaxel

17. Treatment-related determinants of medical choices
Efficacy
Toxicity
Convenience

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

19. 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
Nonhematologic: table
Febrile neutropenia:
AE leading to death:
Neuropathy time: table
a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term.
Von Hoff et al. ASCO 2013. 19

22. 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