1. Istituto Oncologico Veneto IRCCS
tnAcity trial: Nab-paclitaxel in combination with gemcitabine or carboplatin vs gemcitabine/carboplatin as first lile treatment in TNMBC
Maria Vittoria Dieci
Department of Surgery, Oncology and Gastroenterology – University of Padova
Istituto Oncologico Veneto IRCCS

2. Rationale mTNBC has a poor prognosis and an aggressive clinical course
Although there is no standard of care for mTNBC, chemotherapy (including taxane-based regimens) is recommended by the NCCN
nab-P has demonstrated greater efficacy and favorable safety vs paclitaxel in a phase III trial of metastatic breast cancer1
nab-P–based regimens have also shown activity as first-line treatment of mTNBC in phase II trials2-4
nab-P in combination with carbo and bevacizumab resulted in an ORR of 85% and a median PFS of 9.2 months3
nab-P in combination with Gem resulted in an ORR of 77%4
tnAcity is a phase II/III study designed to evaluate the efficacy and safety of nab-P doublet chemotherapy regimens in mTNBC (NCT )
1. Gradishar WJ, et al. J Clin Oncol. 2005;23: Lobo C, et al. Breast Cancer Res Treat. 2010;123: Hamilton E, et al. Clin Breast Cancer. 2013;13: Roy V, et al. Ann Oncol. 2009;20:

3. tnAcity - Study Design
N = 730 subjects (Phase 2 = 180 (240) ; Phase 3 = 550), 150 sites
First Line TNMBC
nab-Paclitaxel +
Gemcitabine
N = 60
Gemcitabine +
Carboplatin
RANDOMIZE
nab-Paclitaxel arm selected by combination of efficacy + safety
Winner of the 2 nab-Paclitaxel arms
N = 275
Phase 2
Phase 3
End Points
Primary – PFS (central)
Secondary – ORR, OS, DCR, DOR, Safety
Stratification
Disease free interval ≤ 1 year vs > 1 year
Prior taxane neo/adjuvant therapy (Ph 3 only)
End Points
Primary – PFS (investigator)
Secondary – ORR, % of patients initiating cycle 6, OS, Safety
Abraxane 125mg/m2,
Gemcitabine 1000mg/m2 D1,8 q21d
Carboplatin AUC2
Due to the changing treatment landscape, this study was stopped after the phase 2 portion was concluded
Ph2 Patients will not be included in Ph3 analysis

4. ABI-007-MBC-001 nab®-Paclitaxel + Carboplatin or Gemcitabine vs Gemcitabine + Carboplatin as First-Line Treatment for Patients With Triple-Negative Metastatic Breast Cancer: Results From the Randomized Phase II Portion of the tnAcity Trial
Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O’Shaughnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N, on behalf of the tnAcity investigators
Yardley D et al, Poster at SABCS 2016 [abstract 874].

5. Objective
To report the phase II portion of the tnAcity trial, which evaluated the safety and efficacy of 3 common chemotherapy regimens as first-line treatment for patients with mTNBC.

6. Endpoints - Phase 2 Primary Endpoint: Secondary Endpoints:
PFS (investigator assessment of response -RECIST 1.1)
Secondary Endpoints:
Efficacy
ORR, investigator-determined,
Percentage of subjects who initiated Cycle 6 OS
Safety
Incidence/Grade of treatment-emergent adverse events (TEAEs), SAEs, laboratory abnormalities
Incidence of subjects experiencing dose modifications (dose interruptions and reductions)
Percentage of subjects who discontinued for adverse event
Biomarkers:
Tumor sample (paraffin block and/or slides) will be collected to evaluate molecular profiles (protein, tumor cell mutations and gene expression) and identify potential predictive markers of clinical response and to determine possible correlation with efficacy outcomes. The most recently obtained tumor sample will be submitted for receptor/biomarker assessment . Blood samples will be collected at the beginning of cycle 1 and of cycle 3 to assess treatment efficacy vs. subject pharmacogenomic characteristics, tumor DNA and miRNA characteristics, and tumor-derived exosome characteristics.
Exploratory analysis of CTCs will be performed to assess any significant correlation of CTC levels with relevant clinical benefits. Sample collection for this exploratory analysis may be limited to selected clinical centers.

7. Key Inclusion Criteria
Female, age ≥ 18 years, no prior chemotherapy for metastatic disease
Prior use of neo/adjuvant anthracycline or medically unfit for anthracycline use.
Pathologically confirmed TNMBC as per ASCO guidelines
ECOG 0-1
Measurable disease (RECIST 1.1)
Bone cannot be the only site of metastatic disease
No brain metastasis
Adequate hematology and organ function
Prior immunotherapy/MAB therapy, or neo/adjuvant chemo/RT acceptable
Prior treatments must have been discontinued ≥ 30 d prior to start of study
Toxicities must have resolved to ≤ Grade 1.
Prior RT must have completed ≥ 2 w before randomization, with full recovery.
Target lesions must be outside radiation portal or there must be unequivocal progressive disease within the radiation portal

8. Exclusion Criteria Male patients with breast cancer
Concurrent chemotherapy or any other antitumor therapy for BC
History of or known current evidence of brain metastasis
Patients with bone as the only site of metastatic disease
History of other primary malignancy in the last 5 years
Baseline peripheral neuropathy grade ≥ 2 by NCI CTCAE v4.0

9. Statistical plan
An algorithm ranking 5 key efficacy and safety endpoint parameters was used to identify the «winning» nab-P experimental arm based on the rank sum of: - HR of PFS (nab-P/G vs nab-P/C) - ratio of ORR - percentage of patients initiating cycle 6 receiving a doublet - percentage of patients with myelosuppression-related events - percentage of patients who discontinued from all study treatment due to Aes PFS and ORR carried twice the weight as the remaining 3 endpoints

10. tnAcity: Baseline Characteristics
Characteristic (N = 191 in Phase II)
nab-P/C
(n = 64)
nab-P/G
(n = 61)
G/C
(n = 66)
Age, median (min - max), years
< 65, n (%)
55 ( )
48 (75)
53 ( )
43 (71)
59 ( )
49 (74)
ECOG PS, n (%)a 1
38 (59)
26 (41)
34 (56)
25 (41)
42 (64)
22 (33)
Race, n (%)
White
Black or African American
Not collected or reported
55 (86)
6 (9)
3 (5)
50 (82)
9 (15)
2 (3)
54 (82)
8 (12)
4 (6)
Region, n (%)
North America
Western Europe
South America
Australia
31 (48)
24 (38)
9 (14)
29 (48)
26 (43)
6 (10)
31 (47)
30 (46)
1 (2)
Yardley D et al, Poster at SABCS 2016 [abstract 874].

11. tnAcity: Baseline Characteristics 2
Characteristic (N = 191 in Phase II)
nab-P/C
(n = 64)
nab-P/G
(n = 61)
G/C
(n = 66)
Disease-free interval, n (%)
≤ 1 year
> 1 year
Missing
17 (27)
47 (73)
17 (28)
43 (71)
1 (2)
20 (30)
45 (68)
Triple negative at primary diagnosis, n (%)
53 (83)
51 (84)
48 (73)
Site of metastasis, n (%)
Lymph node(s)
Lung/thoracic
Bone
Liver
50 (78)
42 (66)
20 (31)
16 (25)
38 (62)
42 (69)
23 (38)
51 (77)
41 (62)
24 (36)
23 (35)
Prior neoadjuvant/adjuvant therapy, n (%)
Anthracyclinesa
Taxanes
43 (67)
36 (56)
37 (61)
41 (67)
42 (64)
Yardley D et al, Poster at SABCS 2016 [abstract 874].

12. tnAcity Phase II: PFS (Primary End-point)
nab-P/C
nab-P/G
G/C
Median PFS, months
7.4
5.4
6.0
HR (95% CI)
P value –
0.60 ( )
0.02a
0.61 ( )
0.03a
12-month PFS rate, % 27 13 11
a Compared with nab-P/C.
Yardley D et al, Poster at SABCS 2016 [abstract 874].

13. tnAcity Phase II: Overall Survival
nab-P/C
nab-P/G
G/C
Median OS, months
16.4
12.1
12.6
HR (95% CI)
P value –
0.66 ( )
0.07a
0.74 ( )
0.18a
a Compared with nab-P/C.
Yardley D et al, Poster at SABCS 2016 [abstract 874].

14. tnAcity Phase II: Response Rates
Response, n (%)
nab-P/C
n = 64
nab-P/G
n = 61
G/C
n = 66
ORR CR PR
46 (72)
7 (11)
39 (61)
24 (39)
5 (8)
19 (31)
29 (44)
24 (36)
SD >16 weeks
14 (22)
27 (44)
21 (32)
Yardley D et al, Poster at SABCS 2016 [abstract 874].

15. tnAcity Phase II - Safety
Selected Grade ≥ 3 TEAEs
Yardley D et al, Poster at SABCS 2016 [abstract 874].

16. tnAcity Phase II – Ranking Algorithm
Safety and Efficacy Endpoints
nab-P/C
nab-P/G
Value
Rank
HR of PFS (nab-P/G/nab-P/C) — 2
1.68
ORR ratio (nab-P/G/nab-P/C)
0.55
Patients initiating cycle 6 with a doublet, % 64 1 56
Patients with myelosuppression-related events, %b 53 42
Patients discontinuing all study treatment due to AEs, % 27 22
Rank sum 5
Rank sum of the algorithm for key efficacy and safety endpoints favored nab-P/C
Yardley D et al, Poster at SABCS 2016 [abstract 874].

17. tnAcity Phase II - Conclusions
nab-P/C demonstrated a significantly longer PFS and a better risk-benefit profile than nab-P/G or G/C as first-line treatment of patients with mTNBC
Treatment duration and exposure were greater with nab-P/C than with nab-P/G or G/C
The combination of nab-P/C is active in mTNBC and may be considered a therapeutic option in this patient population
Due to the evolving landscape including ongoing phase III trials with immunotherapy and other novel agents, this trial is not progressing to phase III. However, nab-P is being used as a backbone chemotherapy with novel agents in both mTNBC and the neoadjuvant setting (NCT , NCT , NCT )