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

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):852-861.

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 76-100 340 mg/m2 on day 1 q3w weekly AB-paclitaxel dosing Cohort 5 Patients 101-125 140 mg/m2 on day 1, 8 q3w Cohort 6 Patients 126-150 100 mg/m2 on day 1, 8, 15 q3w Cohort 7 Patients 151-175 125 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):852-861.

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) 20.8-59.2 6 (24) 7.3-40.7 8 (32) 13.7-50.3 14 (56) 36.5-75.5 12 (48) 28.4-67.6 9 (36) 17.2-54.8 CR, n (%) 1 (4) PR, n (%) 5 (20) 11 (44) SD ≥ 16 wks, 3 (12) 2 (8) DCRb 15 (60) 40.8-79.2 16 (64) 45.2-82.8 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 4.2-9.6 6.5 4.3-9.1 5.3 2.2-8.5 4.8 3.9-7.8 5.6 3.9-7.7 6.2 4.2-9.7 6.4 4.2-7.9 Median OS, 10.7 8.7-17.0 12.2 8.5-21.9 8.3 4.2-15.4 14.6 7.6-17.2 12.0 6.5-17.1 11.3 7.8- >20.1 15.0 10- >18.4

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):852-861.

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):852-861.

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

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 28 - 81 448 (86) 73 (14) 24 - 84 449 (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. 2010 [abstract LBA7511]. NSCLC, non-small cell lung cancer.

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. 2011 [Abstract 7551].

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. 2011 [Abstract 7551]. * Not a pre-specified endpoint

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. 2011 [Abstract 7551]. * Not a pre-specified endpoint

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. 2011 [Abstract 7551]. * Not a pre-specified endpoint

Subgroups analyses

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

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.

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.

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.

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.

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.

Approved FDA Oct 12, 2012

Approved EMA Jan 23, 2015

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 2013. [abstract 3438].

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 2013. [abstract 3438].

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

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. 2011 [Abstract 7046].

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Study Design Dose-escalating 3 + 3 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. 2011 [Abstract 7046].

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. 2011 [Abstract 7046].

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. 2011 [Abstract 7046].