Ruolo di carboplatino + nab-paclitaxel nel trattamento di I linea nel carcinoma polmonare non a piccole cellule         P.Bidoli S.C. Oncologia Medica Ospedale San Gerardo ASST Monza Roma 29/10/2017

nab® -paclitaxel is the first tumour-targeted nanomedicine to leverage the natural transport properties of albumin1 A single molecule of albumin can bind up to 6 or 7 molecules of paclitaxel6 nab® -paclitaxel individual molecule nab® -paclitaxel complex 4–14 nm in size3–5 Albumin Paclitaxel It is important to note the sizes of the nab®-paclitaxel complex (130 nm) and individual molecules (4–14 nm).1–4 Modelling and in vivo studies have shown that drug penetration by nanomedicines depends on the size of pores within vasculature.1 Tumour vasculature is leaky and contains large pores of heterogeneous size.1 Smaller nanomedicines demonstrate the most rapid penetration across a range of pore sizes.5 As such, the small size of individual nab®-paclitaxel molecules has the potential to facilitate effective drug delivery to tumours. References Kratz F, et al. J Control Release 2008;132:171–83. Desai N, et al. Clin Cancer Res 2006;12:1317–24. Abraxane [Summary of Product Characteristics]. EU: Celgene Corporation; 2013. Peters T, Jr. Adv Protein Chem 1985;37:161–245. Chauhan VP, et al. Nat Nanotechnol 2012;7:383–8. 130 nm in size1–3 Desai N. Drug Delivery Report 2007. Kratz F, et al. J Control Release 2008;132:171–83. Desai N, et al. Clin Can Res 2006;12:1317–24. Abraxane [Summary of Product Characteristics]. EU: Celgene Corporation; 2013. Peters T, Jr. Adv Protein Chem 1985;37:161–245. Paal K, et al. Eur J Biochem 2001;268:2187-–91. 2

Key milestones in the development of systemic chemotherapy for NSCLC FDA Approvals

CA031: nab-P/C vs sb-P/C in NSCLC Study Design and Objectives Stage IIIb/IV NSCLC No prior therapy for metastatic disease ECOG PS 0-1 N = 1052 nab-Paclitaxel 100 mg/m2 d1, 8, 15 (30-min infusion) Carboplatin AUC 6 d1 21-day cycles No premedication sb-Paclitaxel 200 mg/m2 d1 (3-h infusion) Carboplatin AUC 6 d1 21-day cycles with premedication of dexamethasone + antihistamines Stratification factors: Stage (IIIb vs IV); age; (< 70 vs ≥ 70); sex; histology (adenocarcinoma vs squamous cell vs other); geographic region Objective: To compare the efficacy and safety of nab-paclitaxel plus carboplatin vs sb-paclitaxel plus carboplatin in advanced NSCLC Primary endpoint: ORR by independent radiological review (CR + PR) Secondary endpoints: PFS, OS, DCR (CR + PR + SD), and safety AUC, area under the curve; CR, complete response; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; NSCLC, non–small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PS, performance status; sb, solvent-based; SD, stable disease. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 4

CA031: nab-P/C vs sb-P/C in NSCLC Baseline Patient Demographics (cont’d) Characteristic nab-P/C (n = 521) sb-P/C (n = 531) Histology, n (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Other   254 (49) 229 (44) 9 (2) 29 (6) 264 (50) 221 (42) 13 (2) 33 (6) ECOG, n (%) 1 2 133 (26) 385 (74) 3 (< 1) 113 (21) 416 (78) 2 (< 1) Stage at randomization, n (%) Stage IIIB Stage IV 108 (21) 413 (79) 110 (21) 421 (79) Prior therapy, n (%) Radiation therapy Chemotherapy 39 (7) 14 (3) 50 (9) Smoking status, n (%) Never smoked Smoked and quit Smoked and still smokes 519a 137 (26) 168 (32) 214 (41) 526a 144 (27) 148 (28) 234 (44) a Few missing values. ECOG, Eastern Cooperative Oncology Group; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 5

CA031: nab-P/C vs sb-P/C in NSCLC Primary Endpoint: Objective Response – ITT CI, confidence interval; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 6

CA031: nab-P/C vs sb-P/C in NSCLC Secondary Endpoint: OS (ITT) Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved. CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 7

CA031: nab-P/C vs sb-P/C in NSCLC OS by Stratification Factor Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved. HR, hazard ratio; OS, overall survival; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 8

CA031: nab-P/C vs sb-P/C in NSCLC Objective Response By Histology CI, confidence interval; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 9

CA031 (Socinski): Analysis of Elderly Patients With NSCLC in a Phase III Trial of nab-P/C vs sb-P/C Overall Survival In elderly patients, a significant improvement in median OS with nab-P/C vs sb-P/C was observed; no difference in median OS in patients < 70 years was observed HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA, et al. Ann Oncol. 2013;24:314-321, by permission of the European Society for Medical Oncology. © 2013 European Society for Medical Oncology. 10

CA031: nab-P/C vs sb-P/C in NSCLC Most Common Treatment-Related ≥ Grade 3 Hematologic Adverse Events nab-P/C n = 514 NCI CTCAE Grade 3 Grade 4 Hematologic AEs, % Neutropenia Thrombocytopenia Anemia Febrile neutropenia 33 13 22 < 1 14 5 32 7 6 1 26 2 < 0.001a < 0.001b ns sb-P/C n = 524 a P < 0.05 in favor of nab-P/C b P < 0.05 in favor of sb-P/C Compared with sb-P/C, treatment with nab-P/C resulted in significantly less grade 3/4 neutropenia An increased incidence of thrombocytopenia and anemia with the nab-P/C regimen was observed, and these toxicities were readily manageable Most anemia was corrected with a single blood transfusion; thrombocytopenia did not lead to increased rates of hemorrhage  AE, adverse event; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; ns, not statistically significant; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 11

CA031: nab-P/C vs sb-P/C in NSCLC Most Common Treatment-Related ≥ Grade 3 Nonhematologic Adverse Events nab-P/C n = 514 NCI CTCAE Grade 3 Grade 4 Nonhematologic AEs, % Fatigue Sensory neuropathy Anorexia Nausea Myalgia Arthralgia 4 3 2 < 1 6 11 <1 ns < 0.001a = 0.011a = 0.008a sb-P/C n = 524 a P < 0.05 in favor of nab-P/C b P < 0.05 in favor of sb-P/C Median time to improvement of grade ≥ 3 sensory neuropathy to grade 1 (nab-P/C vs sb-P/C): 38 vs 104 days Sensory neuropathy (all grades) with nab-P/C vs sb-P/C: 46% vs 62%, P < 0.001 Significantly higher percentage of patients did not develop neuropathy with nab-P/C vs sb-P/C: 54% vs 38%, P < 0.001 AE, adverse event; NCI-CTCAE, National Cancer Institute -Common Terminology Criteria for Adverse Events; ns, not statistically significant; P/C, paclitaxel + carboplatin; sb, solvent-based. Socinski MA et al. J Clin Oncol. 2012;30:2055-62. 12

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]. 13

nab-Paclitaxel + Carboplatin in Higher-Risk Pt Populations With Advanced NSCLC Elderly pts and pts with ECOG PS 2 have poorer prognosis than younger pts or those with better PS Both subgroups underrepresented in randomized clinical trials due to concerns about tolerability and comorbidities ABOUND.PS2 evaluated safety, efficacy of nab-paclitaxel + carboplatin followed by nab-paclitaxel in chemotherapy-naive pts with advanced NSCLC and PS 2[1] ABOUND.70+ evaluated safety, efficacy of nab-paclitaxel + carboplatin in chemotherapy-naive pts aged 70 yrs or older with advanced NSCLC[2] ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status. 1. Gajra A, et al. ASCO 2017. Abstract 9058. 2. Langer CJ, et al. ASCO 2017. Abstract 9059. 14