1. Abstract #LBA7511
Results of a Randomized, Phase III Trial of nab-Paclitaxel and Carboplatin Compared With Cremophor-based Paclitaxel and Carboplatin as First-line Therapy in Advanced Non-small Cell Lung Cancer
MA Socinski,1 I Bondarenko,2 NA Karaseva,3 AM Makhson,4 IO Vynnychenko,5 I Okamoto,6 J Hon,7 V Hirsh,8 P Bhar,9 J Iglesias9
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA; 2City Hosp #4, Dnepropetrovsk, Ukraine; 3City Oncology Center, St. Petersburg, Russia; 4City Oncology Hospital #62, Moscow, Russia; 5Regional Oncology Center, Sumy, Ukraine; 6Kinki University School of Medicine, Osaka-Sayama, Japan; 7Clearview Cancer Inst Onc Specialties, P.C, Huntsville, AL, USA; 8McGill University, Montreal, Quebec, Canada; 9Abraxis BioScience, Los Angeles, CA

2. Study Rationale
Platinum-based doublets have reached a therapeutic plateau in advanced NSCLC
Paclitaxel plus carboplatin produces overall response rates of 15-25% (Kelly 2001; Sandler 2006; Schiller 2002) and survival outcomes comparable to all other doublets
The solvent polyoxyethylated castor oil (cremophor) may decrease efficacy and contribute to the toxicities observed with paclitaxel including hypersensitivity reactions and neuropathy
Nanoparticle albumin-bound (nab) paclitaxel has been shown to be more efficacious than solvent-based paclitaxel in MBC (Gradishar 2005)

3. Biologic Rationale for nab-P
nab-P leverages the gp60 / caveolin-1 / SPARC transcytosis pathway to establish a portal to the tumor microenvironment resulting in high intra-tumoral drug concentration (Desai 2008)
Overexpression of caveolin-1 and SPARC occurs in NSCLC and is associated with poor prognosis (Yoo, 2002; Chin 2005; Koukorakis, 2003)

4. nab-Paclitaxel With Carboplatin (nab-P/C) in Advanced NSCLC: A Dose-finding Nonrandomized Phase II
A 7 arm trial investigated the safety and efficacy of nab-P/C at both weekly and q3w dosing schedules (Socinski, JTO 5:852-61, 2010)
Weekly nab-paclitaxel (100 mg/m2 d1, 8, 15) plus carbo AUC 6 q3w demonstrated optimal therapeutic index
RR = 48%, median PFS = 6.2 months, median OS = 11.3 months
Grade 3/4 toxicity: neutropenia 64%, neuropathy 8%, thrombocytopenia 20%, anemia 16%
Based on the phase II results, a phase III trial was designed to investigate the efficacy / safety of nab-P/C vs P/C as first-line therapy in advanced NSCLC

5. Phase III nab-P/C vs P/C Dexamethasone + Antihistamines
Study Design
nab-Paclitaxel 100 mg/m2 d1,8,15
Carboplatin AUC 6 d1
No Premedication
n = 525
Chemo-naive
PS 0-1
Stage IIIb/IV NSCLC
N = 1,050
1:1
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
With Premedication of
Dexamethasone + Antihistamines
n = 525
Stratification factors:
Stage (IIIb vs IV)
Age (<70 vs >70)
Sex
Histology (squamous vs nonsquamous)
Geographic region

6. Study Endpoints Primary endpoint:
Objective response rate by independent radiologic review based on RECIST
complete + partial response (CR, PR)
Secondary endpoints:
Progression-free and overall survival
Disease control rate: CR + PR + stable disease (SD) ≥16 weeks
Safety (NCI CTCAE v3)

7. Study Endpoints Primary endpoint:
Objective response rate by independent radiologic review based on RECIST
complete + partial response (CR, PR)
Secondary endpoints:
Progression-free and overall survival
Disease control rate: CR + PR + stable disease (SD) ≥16 weeks
Safety (NCI CTCAE v3)

8. Patient Eligibility Major Inclusion
Histologically/cytologically confirmed adult patients with stage IIIb/IV NSCLC
ECOG performance status of 0 or 1
Measurable disease by RECIST
Adequate hematologic, hepatic, and renal function
No prior treatment for metastatic disease (adjuvant therapy allowed if it was >1 year prior to study entry)
Major Exclusion
Active brain metastases (treated, controlled mets allowed)
Baseline peripheral neuropathy > grade 2

9. Statistical Considerations Primary Endpoint
Objective response rate of P/C in ECOG 1594 = 17%
Based on the activity of nab-P in MBC, a relative improvement of ~40% for nab-P/C over P/C was assumed (corresponding to an ORR = 24%)
Based on this assumption, 525 patients on each arm provides 80% power with a two-sided Type I error of to reject the null hypothesis

10. Patient Accrual Russia 45% (29 sites) Canada 4% (6 sites) Ukraine
Japan
14%
(21 sites) US
12% (25 sites)
Australia 1%
(5 sites)
Planned enrollment: from Dec to Aug 1, 2009
Actual enrollment: from Dec to July 14, 2009
Planned follow-up: 18 months
# of patients enrolled: 1052
# of patients evaluable for efficacy: 1052
# of patients evaluable for toxicity: 1038

11. Results: Baseline Demographics
nab-P/C
(n = 521)
P/C
(n = 531)
All Patients
(N = 1052)
Age, median (range) years
60 (28, 81)
60 (24, 84)
<70 years, n (%)
≥70 years, n (%)
448 (86)
73 (14)
449 (85)
82 (15)
897 (85)
155 (15)
Female, n (%)
129 (25)
134 (25)
263 (25)
ECOG, n (%)
133 (26)
113 (21)
246 (23) 1
385 (74)
416 (78)
801 (76)
Histology of Primary Diagnosis, n (%)*
Adenocarcinoma
254 (49)
264 (50)
518 (49)
Squamous Cell Carcinoma
228 (44)
221 (42)
449 (43)
Large Cell Carcinoma
9 (2)
13 (2)
22 (2)
Other
29 (6)
33 (6)
62 (6)
Stage at Current Diagnosis, n (%)*
Stage III
99 (19)
107 (20)
206 (20)
Stage IV
421 (81)
424 (80)
845 (80)
Prior Chemotherapy, n (%)
12 (2)
8 (2)
20 (2)
Smoking Status, n (%)
513
521
1034
Never Smoked
138 (27)
144 (28)
282 (27)
Smoked and Quit
165 (32)
146 (28)
311 (30)
Smoked and Still Smokes
210 (41)
231 (44)
441 (43)
* Data was missing for 1 pt at the time of this analysis

12. Dose Intensity and Administered Cycles
nab-P/C
(n = 514)
P/C
(n = 524)
Taxane Dose Intensity (mg/m2/wk)
Median (min, max)
83 (26.7, 102.9)
66 (32.9, 88.9)
Cycles Administered
6 (1, 17)
6 (1, 22)
There was no limitation on the # of cycles

13. Primary Endpoint Results Objective Responses – All Histologies
Response Ratio = 1.31
(1.082 – 1.593)
P = 0.005
Percent Responses
nab-P/C response rate was superior to P/C both by independent review (31% improvement) and by investigator review (26% improvement)

14. Primary Endpoint Results Objective Responses – All Histologies
Response Ratio = 1.31
(1.082 – 1.593)
P = 0.005
Response Ratio = 1.26
(1.060 – 1.496)
P = 0.008
(n = 521)
Percent Responses
(n = 531)
nab-P/C response rate was superior to P/C both by independent review (31% improvement) and by investigator review (26% improvement)

15. Objective Responses by Histology*
Squamous
P < 0.001
P = 0.060
Percent Responses
Histologic analysis showed a 67% improvement in response rate for nab-P/C in squamous patients
nab-P/C was as effective as P/C in patients with non-squamous histology
n = 228
n = 221
* Not a pre-specified endpoint

16. Objective Responses by Histology*
Squamous
Nonsquamous
P < 0.001
P = 0.060
P = 0.808
P = 0.069
Percent Responses
Histologic analysis showed a 67% improvement in response rate for nab-P/C in squamous patients
nab-P/C was as effective as P/C in patients with non-squamous histology
n = 228
n = 221
n = 292
n = 310
* Not a pre-specified endpoint

17. * Favors nab-P/C; ** Favors P/C
Safety
nab-P/C
(n = 514)
P/C
(n = 524)
Adverse Events, %
Grade 3
Grade 4
P-values for grade 3/4
Hematologic
Neutropenia 33 12 23
0.009*
Thrombocytopenia 13 4 6 2
<0.001**
Anemia 22 5
<1
Febrile Neutropenia 1 NS
Nonhematologic
Fatigue
Sensory Neuropathy 3 10
<0.001*
Anorexia
Nausea
Myalgia
0.011*
There was a 70% reduction in high-grade neuropathy with nab-P
* Favors nab-P/C; ** Favors P/C
No hypersensitivity reaction occurred in the nab-P/C arm without prophylactic premedication, while 3 occurred in the P/C arm (grade 1, 2, and 3, respectively).

18. * Favors nab-P/C; ** Favors P/C
Safety
nab-P/C
(n = 514)
P/C
(n = 524)
Adverse Events, %
Grade 3
Grade 4
P-values for grade 3/4
Hematologic
Neutropenia 33 12 23
0.009*
Thrombocytopenia 13 4 6 2
<0.001**
Anemia 22 5
<1
Febrile Neutropenia 1 NS
Nonhematologic
Fatigue
Sensory Neuropathy 3 10
<0.001*
Anorexia
Nausea
Myalgia
0.011*
There was a 70% reduction in high-grade neuropathy with nab-P
* Favors nab-P/C; ** Favors P/C
No hypersensitivity reaction occurred in the nab-P/C arm without prophylactic premedication, while 3 occurred in the P/C arm (grade 1, 2, and 3, respectively).

19. * Favors nab-P/C; ** Favors P/C
Safety
nab-P/C
(n = 514)
P/C
(n = 524)
Adverse Events, %
Grade 3
Grade 4
P-values for grade 3/4
Hematologic
Neutropenia 33 12 23
0.009*
Thrombocytopenia 13 4 6 2
<0.001**
Anemia 22 5
<1
Febrile Neutropenia 1 NS
Nonhematologic
Fatigue
Sensory Neuropathy 3 10
<0.001*
Anorexia
Nausea
Myalgia
0.011*
There was a 70% reduction in high-grade neuropathy with nab-P
* Favors nab-P/C; ** Favors P/C
No hypersensitivity reaction occurred in the nab-P/C arm without prophylactic premedication, while 3 occurred in the P/C arm (grade 1, 2, and 3, respectively).

20. Conclusions
In this phase III randomized trial, nab-P/C demonstrated a statistically significant higher response rate than P/C (33% vs 25 %, P < 0.001).
The response rate in the squamous cell subset was 41% in the nab-P/C arm vs 24% in the P/C arm (P < 0.001).
nab-P/C was well tolerated and associated with less sensory neuropathy, myalgia, and neutropenia than P/C.
nab-P/C was associated with more anemia and thrombocytopenia than P/C.
Progression-free survival analysis is planned for later this year.

21. Acknowledgments
We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff.

22. Thank you Acknowledgments
We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff.
Thank you