1. Nab-paclitaxel nel NSCLC avanzato
Cesare Gridelli
Division of Medical Oncology
“S.G. Moscati” Hospital – Avellino (Italy)
Nab-paclitaxel nel NSCLC avanzato

2. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
A Dose Finding Study of Weekly and Every 3 Week Albumin-Bound Paclitaxel Followed by Carboplatin as First-Line Therapy in Patients with Advanced Non-Small Cell Lung Cancer
M.A. Socinski, G.M. Manikhas, D.L. Stroyakovsky, A.N. Makhson, S.V. Cheporov, S.V. Orlov, P.K. Yablonsky, P.H. Bhar, and J. Iglesias
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

3. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Study Design
Open-label, multicenter, phase II study
AB-paclitaxel dosing schedule shown below
All patients also received q3w carboplatin AUC = 6
q3w AB-paclitaxel dosing
Cohort 1
Patients 1-25
225 mg/m2 on day 1 q3w
Cohort 2
Patients 26-50
260 mg/m2 on day 1 q3w
Cohort 3
Patients 51-75
300 mg/m2 on day 1 q3w
Cohort 4
Patients
340 mg/m2 on day 1 q3w
weekly AB-paclitaxel dosing
Cohort 5
Patients
140 mg/m2 on day 1, 8 q3w
Cohort 6
Patients
100 mg/m2 on day 1, 8, 15 q3w
Cohort 7
Patients
125 mg/m2 on day 1, 8, 15 q3w
Key Points:
Patients were sequentially enrolled in four q3w cohorts (25 patients per cohort).
After the emergence of promising weekly data (presumably from other trials), three additional cohorts were added, in which patients sequentially enrolled in weekly regimens of ab-paclitaxel.
Patients continued receiving treatment in the absence of disease progression or unacceptable toxicity.
AB-paclitaxel, albumin-bound paclitaxel; AUC, area under the curve; NSCLC, non-small cell lung cancer; q3w, every 3 weeks.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

4. First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC :Results
Clinical response (N = 175)
q3w
Weekly (days 1, 8)
Weekly (days 1, 8, 15)
Cohortsa
225 mg/m2
260 mg/m2
300 mg/m2
340 mg/m2
140
mg/m2
100
125
ORR,
n (%)
95% CI
10 (40)
6 (24)
8 (32)
14 (56)
12 (48)
9 (36)
CR, n (%)
1 (4)
PR, n (%)
5 (20)
11 (44)
SD ≥ 16 wks,
3 (12)
2 (8)
DCRb
15 (60)
16 (64)
Key Points:
All patients who received at least one dose of ab-paclitaxel and carboplatin (treated population) were evaluated for efficacy.
Response assessments were performed every third cycle, that is, every 9 weeks. All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, were identified as target lesions and measured and recorded at baseline.
In general, there was a trend for improved RR in the weekly cohorts compared with the q3w cohorts
There was no apparent direct dose proportional relationship observed in ORR across the q3w or weekly cohorts in terms of ab-paclitaxel dose.
Similar to ORR, DCR showed a wide range among the seven dose cohorts spanning from 32 to 64%, but there was no difference between weekly (48–64%) and q3w treatments (32–60%).
Clinical response (N = 175)
q3w
Weekly
(days 1, 8)
(days 1, 8, 15)
Cohortsa
225 mg/m2
260 mg/m2
300 mg/m2
340 mg/m2
140
mg/m2
100
125
Median PFS,
months
95% CI
6.9
6.5
5.3
4.8
5.6
6.4
Median OS,
10.7
12.2
8.3
14.6
12.0
11.3
7.8- >20.1
15.0
10- >18.4

5. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Treatment-Related Non-Hematologic ≥ Grade 3 AEs in ≥ 5% of Patients
Adverse event,
n (%) (N = 175)
q3w
Weekly (days 1, 8)
Weekly
(days 1, 8, 15)
Cohortsa
225 mg/m2
260 mg/m2
300 mg/m2
340 mg/m2
140
mg/m2
100
125
Peripheral neuropathy
Grade 3
Grade 4
3 (12)
0 (0)
4 (16)
6 (24)
12 (48)
2 (8)
Fatigue
3(12)
1 (4)
Myalgia Grade 3 Grade 4
0 0
1 (4) 0
6 (24) 0
Arthralgia Grade 3 Grade 4
Key Points:
In general, all seven cohorts showed comparable safety results, with the least severe AEs occurring in the 100 mg/m2 weekly cohort.
Seven probably or possibly treatment-related deaths occurred: six in the q3w cohorts and one in the weekly cohorts.
The most common treatment-related nonhematologic grade 3 AE was peripheral neuropathy (19%), and no grade 4 event occurred.
Seven (21%) and four (13%) patients with nonsquamous cell carcinoma in the q3w and weekly cohorts, respectively, had grade 3 peripheral neuropathy.
In patients with squamous cell carcinoma, 16 (27%) in the q3w and 4 (10%) in the weekly cohorts had grade 3 peripheral neuropathy.
AUC, area under the curve; q3w, every 3 weeks.
a 25 patients per cohort, all patients received carboplatin AUC = 6.
AE, adverse event; NSCLC, non-small cell lung cancer.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

6. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):852-861.
First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Conclusions
Albumin-bound paclitaxel + carboplatin demonstrated antitumor activity in all cohorts and was well tolerated
100 mg/m2 dose of albumin-bound paclitaxel, although not showing the highest DCR of all doses tested, provided the best clinical benefit-risk ratio
Weekly vs q3w albumin-bound paclitaxel was associated with improved clinical outcomes and less serious AEs
100 mg/m2 weekly albumin-bound paclitaxel + carboplatin AUC = 6 q3w is an optimal dose and schedule for treating NSCLC
Based on the these results, a phase III study comparing 100 mg/m2 albumin-bound paclitaxel + carboplatin AUC = 6 q3w with standard dose Cremophor® EL paclitaxel + carboplatin for NSCLC was initiated
AE, adverse event; AUC, area under the curve; DCR, disease control rate; NSCLC, non-small cell lung cancer; q3w, every 3 weeks.
Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

8. Albumin-Bound Paclitaxel + Carboplatin vs
Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor-Paclitaxel + Carboplatin in Advanced NSCLC Study Design
Albumin-bound 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 Randomization
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
With Premedication of
Dexamethasone + Antihistamines
n = 525
Key points:
The study was stratified by stage, age, sex, histology, and geographic region
The targeted enrollment is over 1000 patients, divided 1:1 into the two treatment groups
Stratification factors:
Stage (IIIb vs IV)
Age (< 70 vs > 70)
Sex
Histology (squamous vs nonsquamous)
Geographic region
NSCLC, non-small cell lung cancer; PS, Eastern Cooperative Oncology Group performance status; AUC, area under the curve
Socinski MA et al, J Clin Oncol 2012

9. Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Baseline Patient Characteristics
Baseline characteristic
AB-paclitaxel + carboplatin (n = 521)
CrEL paclitaxel + carboplatin (n = 531)
Age, years
Median
Range
< 70 years, n (%)
≥ 70 years, n (%) 60
448 (86)
73 (14)
449 (85)
82 (15)
Sex, n (%)
Male
Female
392 (75)
129 (25)
397 (75)
134 (25)
Stage, n (%)a
III IV
99 (19)
421 (81)
107 (20)
424 (80)
Histology, n (%)a
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other
254 (49)
228 (44)
9 (2)
29 (6)
264 (50)
221 (42)
13 (2)
33 (6)
ECOG PS, n (%) 1
133 (26)
385 (74)
113 (21)
416 (78)
Prior chemotherapy, n (%)
12 (2)
8 (2)
Smoking status, n (%)
Never smoked
Smoked and quit
Smoked and still smokes
138 (27)
165 (32)
210 (41)
144 (28)
146 (28)
231 (44)
AB, albumin-bound; CrEL, Cremophor EL ; ECOG PS, Eastern Cooperative Oncology Group performance status.
a Data were missing for 1 patient at the time of this analysis.
Socinski MA, et al. ASCO [abstract LBA7511].
NSCLC, non-small cell lung cancer.

10. Socinski MA et al. ASCO. 2011 [Abstract 7551].
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Primary Endpoint: Objective Responses -ITT
AUC, area under the curve; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer.
Socinski MA et al. ASCO [Abstract 7551].

11. Socinski MA et al. ASCO. 2011 [Abstract 7551].
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Results: ORR, Stratified by Histology
Key Points:
AB-pac + carboplatin, squamous histology, n=228
CrEL-pac + carboplatin, squamous histology, n=221
a Not a pre-specified endpoint.
AB, albumin-bound; CrEL Cremophor EL; NSCLC, non-small cell lung cancer; ORR, objective response rate.
Socinski MA et al. ASCO [Abstract 7551].
* Not a pre-specified endpoint

12. Socinski MA et al. ASCO. 2011 [Abstract 7551].
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Results: Progression-Free Survival
Key Points:
AB-pac + carboplatin, squamous histology, n=228
CrEL-pac + carboplatin, squamous histology, n=221
AB, albumin-bound; AUC, area under the curve; CI, confidence interval; CrEL, Cremophor EL; HR, hazard ratio; PFS, progression-free survival.
Socinski MA et al. ASCO [Abstract 7551].
* Not a pre-specified endpoint

13. Socinski MA et al. ASCO. 2011 [Abstract 7551].
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Results: Overall Survival
Key Points:
AB-pac + carboplatin, squamous histology, n=228
CrEL-pac + carboplatin, squamous histology, n=221
AB, albumin-bound; AUC, area under the curve; CI, confidence interval; CrEL, Cremophor EL; HR, hazard ratio; OS, overall survival.
Socinski MA et al. ASCO [Abstract 7551].
* Not a pre-specified endpoint

15. Subgroups analyses

16. Overall Survival 19.9 months with nab-P/C vs 10.4 mos with sb-P/C

19. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
Phase II Trial of Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in First-Line Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer
C. Reynolds, D. Barrera, R. Jotte, A. I. Spira, C. Weissman, K. A. Boehm, S. Pritchard,
L. Asmar
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

20. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Response After Treatment
Response (N = 48)
Value
ORR, % 31
Clinical benefit rate (CR + PR + [SD ≥ 6 months]), % 54
CR, n
PR, n (%)
15 (31)
SD, n (%)
≥ 6 months, n
< 6 months, n
26 (54) 11 15
PD, n (%)
2 (4)
Key Points:
Reasons for discontinuation (N = 50)
Normal study completion, n=17, 34%
Adverse event, n=16, 32%
Progressive disease, n=11, 22%
CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Median time to response: 1.3 months (range, 1.2 – 2.6)
Median duration of response: 8.9 months (range, 2.9 – 19.1)
NSCLC, non-small cell lung cancer.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

21. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Progression-Free Survival
NSCLC, non-small cell lung cancer; PFS, progression-free survival.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

22. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Overall Survival
Survival at 1- and 2-years was 62% and 30% respectively.
NSCLC, non-small cell lung cancer; OS, overall survival.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

23. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Safety
Treatment-related AEs occurring in > 1 patient (N = 48)
Grade 3
Grade 4
Hematologic, n (%)
Leukopenia
Neutropenia
Thrombocytopenia
2 (4)
8 (17)
4 (8)
18 (38)
1 (2)
Nonhematologic, n (%)
Anorexia
Constipation
Diarrhea
Fatigue
Febrile neutropenia
Neuropathy
Peripheral neuropathy
3 (6)
6 (13)
5 (10)
Key Points:
Although treatment could be delayed for up to 3 weeks to allow for recovery from adverse events, 34% of patients discontinued study treatment due to adverse events
Grade 3-4 neutropenia occurred in 26/48 (5%) patients
Grade 3 neuropathy in 5/28 (10%) patients; No grade 4 neuropathy occurred
1 fatal pulmonary hemorrhage occurred
1 pt died of complications associated with COPD unrelated to study treatment.
AE, adverse event.
Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.
NSCLC, non-small cell lung cancer.

24. Approved FDA
Oct 12, 2012

26. Approved EMA
Jan 23, 2015

27. Subanalysis in the Maintenance Setting of the Phase III CA031 Trial Objective and Patient Population
Objective: This exploratory analysis examined outcomes in patients with squamous cell carcinoma (SCC) histology receiving > 4 cycles of nab-P/C
229 patients with SCC NSCLC received nab-P/C in induction phase (first 4 cycles)
138 of 229 patients (60.3%) treated with nab-P/C were progression free at cycle 4 and entered cycle 5; median PFS and OS were evaluated for these patients and expressed from day 1 of cycle 5
NSCLC, non-small cell lung cancer; OS, overall survival; P/C, paclitaxel + carboplatin; PFS, progression-free survival.
Socinski MA, et al. Oral presented at: IASLC [abstract 3438].

28. Subanalysis in the Maintenance Setting of the Phase III CA031 Trial Efficacy From Day 1, Cycle 5
a As assessed by the investigator.
Socinski MA, et al. Oral presented at: IASLC [abstract 3438].

29. ABOUND: Phase III Trial of nab-Paclitaxel in Patients With Squamous NSCLC in the Maintenance Setting
ENDPOINTS
Primary : PFS (per investigator assessment) from randomization into maintenance phase until disease progression
Secondary: OS, ORR, safety and tolerability
Exploratory: QoL, correlative biomarkers

30. Keedy VL et al. ASCO. 2011 [Abstract 7046].
A Phase I Study of Albumin-Bound Paclitaxel With Carboplatin and Thoracic Radiation in Patients With Locally Advanced NSCLC
V. L. Keedy, B. Lu, L. Horn, Y. Shyr, W. Conkright, D.P. Carbone, A. Sandler
Keedy VL et al. ASCO [Abstract 7046].

31. Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Study Design
Dose-escalating phase I trial of inoperable, stage III NSCLC patients receiving albumin-bound paclitaxel plus carboplatin plus XRT
DLT period: 7 weeks
Consolidation period: 21-day cycle Χ 2
Albumin-bound paclitaxel 40 – 60 mg/m2 qw
Albumin-bound paclitaxel 100 mg/m2 qw
21 days rest
Carboplatin
AUC = 2 qw
Carboplatin
AUC = 6 Day 1
Restaging
Concurrent radiation therapy
2 Gy
qd Χ 33 days
Key Points:
The DLT period in this study was defined as the concurrent chemoradiation period.
8 patients were treated at 2 dose levels of albumin-bound paclitaxel:
40 mg/m2
60 mg/m2
1 patient gave their consent and then withdrew it, so 7 patients completed all cycles of therapy
AUC, area under the curve; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; qd, daily; qw, weekly; XRT, radiation therapy.
Keedy VL et al. ASCO [Abstract 7046].

32. Keedy VL et al. ASCO. 2011 [Abstract 7046].
Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Results: Antitumor Activity
Best response, n
n = 9a
Partial response 9
Stable disease
a Of the 11 enrolled patients, 1 withdrew and 1 was not evaluable for response
Two dose-limiting toxicities occurred in the 60 mg/m2 arm
40 mg/m2 determined to be the MTD of albumin-bound paclitaxel
Seven patients have progressed
At 3, 5, 6 (2 patients), 7, 8, and 20 months after enrollment
Two patients remain progression-free at 10 and 34 months
Key Points:
Three patients progressed at 5, 7, and 8 months after enrollment
Four patients remained stable at 5, 7, 13, and 18 months
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO [Abstract 7046].

33. Keedy VL et al. ASCO. 2011 [Abstract 7046].
Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Conclusions
The recommended phase II dose of weekly albumin-bound paclitaxel + weekly carboplatin AUC = 2 + radiation therapy for patients with stage III NSCLC is 40 mg/m2
Key Points:
The 40 mg/m2 cohort was expanded and 1 patient remains on concurrent treatment
NSCLC, non-small cell lung cancer.
Keedy VL et al. ASCO [Abstract 7046].