1. Alessandra Gennari, MD PhD
SNAP A randomized phase II study evaluating three different schedules of nab-paclitaxel as maintenance therapy
Alessandra Gennari, MD PhD
S.C. Oncologia Medica
E.O. Ospedali Galliera
Genova

2. SNAP Background
Longer first-line chemotherapy (CT) duration is associated with modest, but significant improvement in PFS and OS in MBC.
Prolonging CT until progressive disease (PD) must be weighed against the detrimental effects of continuous delivery.

3. Why SNAP?
SNAP seeks to improve the tolerability of prolonged CT administration strategy by studying alternative treatment schedules, while preserving treatment efficacy.
SNAP randomized phase II trial evaluates 3 schedules of nab-Paclitaxel as prolonged CT administration strategy.

4. SNAP: Objectives
Primary: To evaluate the efficacy of 3 different schedules of nab-paclitaxel, in terms of PFS, using the historical reference of PFS (7 mos.) of docetaxel for first-line MBC.
Secondary: Tolerability, Feasibility, ORR, OS, QoL.

5. SNAP: Study Design A B C nab-Pac 150 mg/m2 days 1,15 nab-Paclitaxel
RANDOM I ZE A
nab-Pac 150 mg/m2 days 1,15
nab-Paclitaxel
150 or 125* mg/m2
days 1,8,15
3 cycles (28-day) B
nab-Pac 100 mg/m2 days 1,8,15 C
nab-Pac 75 mg/m2 Q8
*30 June 2014, induction dose reduced to 125 mg/m² after a planned safety review.
Continue treatment until PD or unacceptable toxicity
Tumor evaluations required every 3 mos.

6. SNAP: Objectives
Primary: To evaluate the efficacy of 3 different schedules of nab-paclitaxel, in terms of PFS, using the historical reference of PFS (7 mos.) of docetaxel for first-line MBC.
Secondary: Tolerability, Feasibility, ORR, OS, QoL.

7. SNAP Endpoints Primary endpoint Progression-free survival (PFS)
Secondary endpoints
Adverse events according to CTCAE v4
Feasibility: completing treatment according to the protocol for at least 24 weeks
Disease control: stable disease for ≥24 weeks or confirmed overall partial response or complete response
Overall survival
Quality of life

8. SNAP Inclusion/Exclusion Criteria
Inclusion Criteria
Histologically/cytologically confirmed HER2-negative MBC
Measurable/non-measurable, evaluable disease
ECOG PS 0 or 1
ER-/ER+ (fail prior ET or candidates for 1st line CT)
Prior adjuvant CT allowed, provided DFS >12 months
Exclusion criteria
Any prior CT for MBC, CNS metastasis, peripheral neuropathy grade 2 or higher (CTCAE version 4)

9. SNAP Statistical Considerations
Sample Size
Efficacy measured by PFS (from randomization to PD or death).
88% power to detect 3 months improvement using one- sided log-rank test vs. null of 7 mos. median PFS at alpha error of 0.05.
Target accrual 258
Target events per arm 63
Analysis population 255 (2 pts did not start CT; 1 did not have metastatic breast cancer)

10. SNAP: Accrual Country/Group Enrollment IBCSG Belgium (3 centers) 33
Italy (8 centers) 40
Slovenia (1 center) 7
Switzerland (9 centers) 75
IBCSG Total
155
SOLTI Spain
SOLTI (5 centers) 42
ICORG Ireland
ICORG (9 centers) 61
Total
258
SNAP enrolled 258 patients from April 2013 to August 2015.

11. Patient Characteristics
nab-P Maintenance Dose
150 mg/m2
(n = 83)
100 mg/m2
(n = 86)
75 mg/m2
Age, median, years 58
55.5 60
Age > 70 years, % 11 14 16
ECOG PS 0, % 59 69 63
ER positive, % 87 80
Measurable disease, % 82 85
Visceral disease, % 64 77 76
Number of metastatic sites ≤ 3, % 89 83 81
Prior adjuvant chemotherapy, % 53 62 48
Prior taxanes, % 31 33 30
Prior endocrine therapy for MBC, % 36 35 38
Gennari A, et al. Poster at SABCS 2016 [abstract P ].

12. Induction Treatment Summary
Starting Dose
150mg/m²
125mg/m²
Analysis population (N=255)
122
133
Completed induction
108
119
Permanently discontinued during induction 14
Completed induction without dose adjustment 26 41
Dose adjustment/discontinuation due to toxicity 87 78
Dose adjustment/discontinuation not toxicity 9

13. Maintenance Treatment Summary
Arm A
Arm B
Arm C
Entered maintenance phase (N=199) 66 72 61
Receiving maintenance treatment 5 8 3
Permanently discontinued maintenance 64 58
Dose adjustment/discont due to toxicity 42 41
Dose adjustment/discont not toxicity 24 28 20
Continuing without dose adjustments 2
Maintenance cycles received thus far
Median (range) 
Patients permanently discont
3 (1, 17)
4 (1, 18)
5 (1, 14)
Patients receiving maintenance
13 (11,23)
15 (4,30)
15 (15, 28)
All patients
3 (1, 23)
4 (1, 30)
5 (1, 28)

14. Adverse Events Induction Therapy
AE, %
nab-P 150 mg/m2
n = 122
nab-P 125 mg/m2
n = 133
Max AE grade 2 3 4 5
Peripheral sensory neuropathy 12 – 8
Decreased neutrophils 46 21 20 18
Decreased platelets 1
Febrile neutropenia
Anemia 22 26
Nausea 7
Vomiting
Diarrhea
Other grade 3-5 adverse event 23
Patients experiencing ≥ 1 AE 98 93

15. Adverse Events Maintenance Phase
AE, %a
A n = 66
150 Q14
B n = 72
100 d 1,8,15 Q28
C n = 61
75 Q8
Max AE grade 2 3 4
Peripheral neuropathy 29 9 – 31 6 25 7
Decreased neutrophils 15 5 24 8 21
Febrile neutropenia 1
Anemia 18 10
Nausea
Vomiting
Diarrhea
Patients’ maximum AE grade 40 44 28 41
Patients experiencing ≥ 1 AE 96 97
a Only reporting events grade ≥ 3.
Gennari A, et al. Poster at SABCS 2016 [abstract P ].

16. nab-P Maintenance Dose
SNAP Efficacy PFS
Outcome
nab-P Maintenance Dose
150 mg/m2
(n = 83)
100 mg/m2
(n = 86)
75 mg/m2
PFS, median (90% CI)
7.9 ( )
9.0 ( )
8.5 ( )
P valuea
0.12
0.03
0.20
Feasibilityb, %
48.2
50.0
51.2
Disease control ratesc, %
65.1
68.6
60.5
At a median follow-up of 18.2 months, 182 PFS events occurred
a Compared with the historical reference PFS. b Defined as percentage of patients who completed treatment according to the protocol for at ≥ 24 weeks. c Defined as SD ≥ 24 weeks or PR or CR.
Gennari A, et al. Poster at SABCS 2016 [abstract P ].

17. Progression Free Survival

18. Progression Free Survival by ER status
ER positive
ER negative

19. Progression Free Survival by prior adjuvant taxanes
Tax yes
Tax no

20. SNAP Conclusions
Alternative maintenance CT schedules with reduced doses after a short induction phase at conventional doses are feasible for first line treatment of MBC, and all resulted in a median PFS greater than the historical reference of 7.0 months
One maintenance schedule, 100 mg/m2 on days 1, 8, 15a (Arm B), had significantly longer median PFS of 9.0 months
The higher induction dose (150 mg/m2) was not tolerable
No new safety signals were observed
a Authors’ conclusions had “days 1, 8, and 12;” however, the study design had days 1, 8, and 15.
Gennari A, et al. Poster at SABCS 2016 [abstract P ].