Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer 51 5 ESA 1217 00004853 2007 05 14 - 04:33:17 PM 5 ESA 1255 2007 09 27 - 02:06:42.

Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer
51 5 ESA 1217 :33:17 PM 5 ESA 1255 :06:42 PM 52 Clinical data 1

Albumin-Bound Paclitaxel Trials in NSCLC: Monotherapy
Trial Description Phase AB-paclitaxel dosed every-3-weeks as first-line therapy for patients with advanced NSCLC1 II AB-paclitaxel dosed weekly as initial chemotherapy for patients with stage IV NSCLC2 I/II Green MR, et al. Ann Oncol. 2006;17: Rizvi NA, et al. J Clin Oncol. 2008;26: AB, albumin-bound; NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Trials in NSCLC: Combination Therapy
Trial Description Phase Combination Therapy with Carboplatin Weekly AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC1 II Dose-finding study of weekly and q3w AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC2 AB-paclitaxel + carboplatin vs CrEL paclitaxela + carboplatin as first-line therapy for advanced NSCLC3,4 III AB-Paclitaxel + carboplatin for patients at risk of bleeding from VEGF-directed therapies5 AB-paclitaxel + carboplatin in 2 different schedules for patients with ES-SCLC6 Combination Therapy with Carboplatin and Bevacizumab AB-paclitaxel + carboplatin + bevacizumab as first-line therapy for advanced nonsquamous NSCLC7 In vivo assessment of the effects of bevacizumab in advanced NSCLC8 Combination with Carboplatin and Radiotherapy AB-paclitaxel + carboplatin + thoracic radiation in locally advanced NSCLC9 I Inclusion of the small cell lung cancer trial in the NSCLC modules per client request. Allerton JP, et al. ASCO [Abstract 7127]. Socinski MA, et al. J Thoracic Oncol. 2010;5(5): Socinski MA, et al. ASCO [Abstract LBA7511]. Socinski MA et al. ASCO [Abstract 7551]. Otterson GA et al. IASLC [Abstract 2230]. Grilley-Olson JE et al. IASLC [Abstract 2221]. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7. Heist RS, et al. ASCO [Abstract 7612]. Keedy VL et al. ASCO [Abstract 7046]. ® Cremophor is a registered trademark of BASF. AB, albumin-bound; CrEL, Cremophor® EL; ES-SCLC, extensive stage small cell lung cancer; NSCLC, non-small cell lung cancer; q3w, every 3 weeks; VEGF, vascular endothelial growth factor.

Albumin-Bound Paclitaxel as First-line Treatment for Non-Small Cell Lung Cancer
Monotherapy Studies

Summary of Albumin-Bound Paclitaxel Monotherapy Studies in Non-Small Cell Lung Cancer
Trial Description Phase Albumin-bound paclitaxel as first-line treatment in advanced NSCLC1 II Albumin-bound paclitaxel as first-line treatment in stage IV NSCLC2 I/II NSCLC, non-small cell lung cancer. Green MR, et al. Ann Oncol. 2006;17(8): Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Summary of Albumin-Bound Paclitaxel Monotherapy Studies in Non-Small Cell Lung Cancer
Trial Description Phase Main Idea Albumin-bound paclitaxel as first-line treatment in advanced NSCLC1 II q3w albumin-bound paclitaxel at 260 mg/m2 showed considerable activity and a favorable therapeutic index in advanced NSCLC Albumin-bound paclitaxel as first-line treatment in stage IV NSCLC2 I/II qw 3/4 albumin-bound paclitaxel at 125 mg/m2 demonstrated encouraging clinical efficacy in stage IV NSCLC NSCLC, non-small cell lung cancer; q3w, every 3 weeks; qw 3/4, first 3 of 4 weeks. Green MR, et al. Ann Oncol. 2006;17(8): Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Green MR, et al. Ann Oncol. 2006;17(8):1263-1268.
nab-paclitaxel®, a Novel, Cremophor® EL-Free Albumin-Bound Particle Form of Paclitaxel for the Treatment of Advanced Non-Small Cell Lung Cancer M.R. Green, G.M. Manikhas, S. Orlov, B. Afanasyev, A.M. Makhson, P. Bhar, M.J. Hawkins Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Background
Cremophor® ELa paclitaxel plays a role in first-line therapy for advanced NSCLC1 Cremophor EL, the solvent vehicle2, is associated with severe hypersensitivity reactions2,3 To prevent severe hypersensitivity reactions, all patients should be premedicated prior to administration of Cremophor EL paclitaxel2 Albumin-bound paclitaxel is a solvent-free formulation4 Use of albumin as a vehicle eliminates solvent-related toxicities5 No premedication to prevent hypersensitivity reactions is required prior to administration4 Due to the limitations of treatments for NSCLC, Green et al. explored efficacy/safety of albumin-bound paclitaxel for NSCLC5 NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor is a registered trademark of BASF; NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Objective Objective Evaluate the efficacy and safety of albumin-bound paclitaxel 260 mg/m2 q3w as first-line treatment for patients with advanced NSCLC Primary efficacy endpoint ORR Secondary endpoints TTP OS Toxicity Other endpoints assessed Overall disease control rate (confirmed responders + patients with SD ≥ 16 weeks) NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; q3w, every 3 weeks; SD, stable disease; TTP, time to tumor progression. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Key Eligibility Criteria Key inclusion criteria Men and non-pregnant women ≥ 18 years of age Histologically or cytologically confirmed advanced NSCLC (at least 1 measurable stage IIIB or IV lesion) Evidence of inoperable local recurrence or metastasis, but no other active malignancy No prior therapy for metastatic disease Expected survival of > 12 weeks Adequate hematologic, hepatic, and renal function Green MR, et al. Ann Oncol. 2006;17(8): NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Key Eligibility Criteria (cont.) Key exclusion criteria Clinical evidence of brain metastasis Serious concurrent illness ECOG PS of ≥ 2 Peripheral neuropathy ≥ grade 2 Prior radiotherapy ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-bound paclitaxel
Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Phase II Study Design Albumin-bound paclitaxel 260 mg/m2 IV over 30 minutes Treatment repeated q3w until disease progression or unacceptable toxicity Dose reduction (from 260 to 200 mg/m2) was permitted for: Grade 4 hematologic toxicity Neutropenic fever or sepsis Grade 3 or 4 non-hematologic toxicity Dose reduction (to 130 mg/m2) was recommended for all subsequent cycles if: Adverse events listed above recurred after the initial resolution and reinitiation of albumin-bound paclitaxel dosing IV, intravenous; NSCLC, non-small cell lung cancer; q3w, every 3 weeks. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Baseline Patient Characteristics Baseline characteristic (N = 43) Value Sex, n (%) Men Women 33 (77) 10 (23) Age, years Median Range < 65, n (%) ≥ 65, n (%) 58 34 (79) 9 (21) ECOG PS, n (%) 0 1 Dominant lesion site, n (%) Visceral Nonvisceral 36 (84) 7 (16) Total number of lesions, n (%) 1 2 - 3 > 3 5 (12) 13 (30) 25 (58) Stage at primary diagnosis I II III IV Unknown 1 (2) 2 (5) 14 (33) 24 (56) Key points: Two patients (5%) had pre-existing grade 1 peripheral neuropathy All patients in this study were Caucasian ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Results: Overall Response and Response by Histology Subgroup/variable Baseline, n Confirmed ORR, n (%) Disease control,a Death, Overall responseb Response by histology Carcinoma/adenocarcinoma Squamous cell carcinoma Otherc 43 11 29 3 7 (16) 1 (9) 5 (17) 1 (33) 21 (49) 5 (45) 14 (48) 2 (67) 23 (53) 16 (55) ORR, overall response rate. a Includes responders + patients with stable disease ≥ 16 weeks. b Includes all partial responses. c Other categories of NSCLC include large-cell carcinoma, undifferentiated NSCLC, and mixed squamous and adenocarcinoma. Key points: The ORR was 16% (n = 7) All responses were complete The disease control rates were similar between patients with squamous (48%) and non-squamous (45%) disease Green MR, et al. Ann Oncol. 2006;17(8): NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Results: Time to Disease Progression (treated population) Median TTP: 6 months (95% CI: ) Probability of not having progressed: 50% at 6 months,13% at 1 year CI, confidence interval; NSCLC, non-small cell lung cancer; q3w, every 3 weeks; TTP, time to tumor progression. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Results: Overall Survival (treated population) Median survival was 11 months (95% CI: ) Probability of surviving 1 year was 45% CI, confidence interval; NSCLC, non-small cell lung cancer; q3w, every 3 weeks. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Results: Dose Adjustments and Discontinuations Due to AEs Dose adjustments and discontinuations due to treatment-related AEs (N = 43) n (%) Dose reductiona 2 (5) Dose interruption Discontinuation of therapy AE, adverse event. aTwo dose reductions were permitted: from 260 to 200 mg/m2 and from 200 to 130 mg/m2. Other points: 2 patients (5%) discontinued therapy because of treatment-related toxicities; 1 had grade 3 sensory neuropathy after 7 cycles, and 1 had grade 3 fatigue after 2 cycles but received 4 more cycles of nab-paclitaxel after onset of the event. 2 patients (5%) had dose reductions due to AEs (elevated liver-function test value after cycle 4 and peripheral neuropathy after cycle 6 [1 each]). Treatment was well-tolerated 95% of patients received albumin-bound paclitaxel at the protocol-specified dose 98% of all cycles were administered at the full dose Patients received a median of 6 treatment cycles 63% of patients received ≥ 6 treatment cycles AE, adverse event; NSCLC, non-small cell lung cancer. Green MR, et al. Ann Oncol. 2006;17(8):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Results: Treatment-Related Toxicities/Adverse Events Toxicity/AEa Maximum grade, n (%) of patients All 1 2 3 4 Patients with ≥ 1 treatment-related AE 40 (93) 7 (16) 24 (56) 9 (21) Hematologicb Anemia Neutropenia Leukopenia Thrombocytopenia 32 (74) 21 (49) 10 (23) 6 (14) 8 (19) 3 (7) 4 (9) Non-hematologic Alopecia Sensory neuropathy Arthralgia Fatigue Myalgia Fever 33 (77) 28 (65) 15 (35) 14 (33) 5 (12) 2 (5) 29 (67) NA 1 (2) AE, adverse event; NA, not applicable. aReported in ≥ 10% of patients (N = 43). bBased on central laboratory values. Key points: If a patient reported the same toxicity more than once, that patient was counted only once for that toxicity, using the highest grade. No patients suffered grade 4 adverse events Grade 3 neutropenia occurred in 4 patients (9%) Two patients (5%) experienced grade 3 sensory neuropathy Each patient was counted only once for a given toxicity (counted at the highest grade of that toxicity suffered for each patient) Green MR, et al. Ann Oncol. 2006;17(8): NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Conclusions Albumin-bound paclitaxel 260 mg/m2 administered IV over 30 minutes without premedication was well tolerated Significant tumor responses and prolonged disease control were documented in these patients with NSCLC Exploration of higher doses of albumin-bound paclitaxel alone and in combination with other drugs in NSCLC is warranted IV, intravenous; NSCLC, non-small cell lung cancer. Green MR, et al. Ann Oncol. 2006;17(8):

Rizvi NA, et al. J Clin Oncol. 2008;26(4):639-643.
Phase I/II Trial of Weekly Intravenous Albumin-Bound Paclitaxel as Initial Chemotherapy in Patients with Stage IV Non-Small Cell Lung Cancer N.A. Rizvi, G.J. Riely, C.G. Azzoli, V.A. Miller, K.K. Ng, J. Fiore, G. Chia, M. Brower, R. Heelan, M.J. Hawkins, M.G. Kris Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Advanced NSCLC Background
Cremophor® ELa paclitaxel plays a role in first-line therapy for advanced NSCLC1 Cremophor EL, the solvent vehicle2, is associated with severe hypersensitivity reactions2,3 To prevent severe hypersensitivity reactions, all patients should be premedicated prior to administration of Cremophor EL paclitaxel2 Albumin-bound paclitaxel is a solvent-free formulation4 Use of albumin as a vehicle eliminates solvent-related toxicities5 No premedication to prevent hypersensitivity reactions is required prior to administration4 NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): aCremophor EL is a registered trademark of BASF; NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Background (cont.)
In a phase II study of albumin-bound paclitaxel 260 mg/m2 IV q3w as first-line therapy for advanced NSCLC1: ORR 16%; median TTP 6 months; median survival 11 months No severe hypersensitivity reactions reported In a phase I/PK dose-ranging study of weekly albumin-bound paclitaxel in patients with solid tumors2: MTD in lightly pretreated patients was 150 mg/m2 DLTs were grade 3 peripheral neuropathy and grade 4 neutropenia PR in 1 patient with lung cancer previously treated with Cremophor® EL paclitaxel Rizvi et al. explored the MTD of weekly albumin-bound paclitaxel in patients with untreated stage IV NSCLC3 DLT, dose-limiting toxicity; IV, intravenous; MTD, maximum-tolerated dose; NSCLC, non-small cell lung cancer; ORR, overall response rate; PK, pharmacokinetics; PR, partial response; q3w, every 3 weeks; TTP, time to tumor progression. Green MR, et al. Ann Oncol. 2006;17(8): Nyman DW, et al. J Clin Oncol. 2005; 23(31): Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Objective Objective Determine MTD and single-agent activity of albumin-bound paclitaxel administered weekly as first-line therapy for patients with stage IV NSCLC Primary endpoints ORR* (CR and PR determined using RECIST) Safety Secondary efficacy endpoints TTP OS *Responses had to be confirmed at least 4 weeks after initial documentation; CR, complete response; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to tumor progression. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Key Eligibility Criteria Key inclusion criteria Stage IV or recurrent NSCLC Laboratory requirements AST and ALT ≤ 2.5X the upper limit of normal range Total bilirubin within the normal range Creatinine ≤ 1.5 mg/dL ANC ≥ 1.5  109 cells/L Platelets ≥ 100  109 cells/L Hemoglobin ≥ 9 g/dL Key exclusion criteria Prior chemotherapy for advanced NSCLC Peripheral neuropathy > grade 1 Radiotherapy received ≤ 3 weeks before study entry Key points: Chemotherapy in the adjuvant or neoadjuvant setting was allowed Prior treatment with gefitinib or erlotinib for advanced disease was allowed ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; NSCLC, non-small cell lung cancer. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Study Design Open-label, single-arm, phase I/II trial Albumin-bound paclitaxel 125 mg/m2 IV qw 3/4 Phase II (N = 40) 100 → 125 → 150 mg/m2 IV Phase I (N =15) Radiologic tumor assessment q8w Phase I serial dose escalations 100 mg/m2 (n = 3), 125 mg/m2 (n = 6), 150 mg/m2 (n = 6) Phase II MTD determined to be 125 mg/m2 Based on toxicities observed in phase 1 at 150 mg/m2 Key points: Three patients were enrolled at each dose level starting at dose level 1. If no DLT was observed in cycle 1, three patients were enrolled at the next dose level. If one DLT was observed, the dose level was expanded to six patients. If two DLTs were observed, the MTD was exceeded and the previous dose level was expanded to six patients. The recommended phase II dose was the highest dose level at which one of six patients experienced a DLT. Four dose levels were planned (100, 125, 150, and 175mg/m2). No intrapatient dose escalations were allowed. Dose reductions for toxicities were allowed with a reduction by 25 mg/m2 to a minimum dose of 100 mg/m2. Dose reductions were allowed for grade 3 or 4 thrombocytopenia or any grade 3 or 4 non-hematologic toxicity. The use of filgrastim and pegfilgrastim was encouraged for neutropenic fever and as prophylaxis in patients who had neutropenic fever in previous cycles of treatment or delay of previous treatments. Because of the toxicities observed in patients at the 150 mg/m2 dose, no patients were administered the 175 mg/m2 dose The phase I portion of the trial determined the MTD of intravenous AB-paclitaxel administered weekly. Three patients treated at the 100 mg/m2 dose level had no DLT. Three patients were treated in the initial cohort of patients at the 125 mg/m2 dose level without DLT. Six patients were treated at the 150 mg/m2 dose level; one patient experienced febrile neutropenia and one patient experienced grade 3 sensory neuropathy during the first cycle of treatment. Dose escalation was discontinued, and after the 125mg/m2 dose level was expanded to six patients without DLT, a total of 40 patients were enrolled onto the phase II portion of the study IV, intravenous; NSCLC, non-small cell lung cancer; q8w, every 8 weeks; qw 3/4, first 3 of 4 weeks. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Baseline Characteristics of Patients in Phase II Portion Baseline characteristic (N = 40) Value Sex, n (%) Men Women 19 (47) 21 (53) Age, years Median Range 70 Karnovsky PS, n (%) 90%-100% 70%-80% 10 (25) 30 (75) Prior chemotherapy, n (%) Neoadjuvant Adjuvant Prior gefitinib or erlotinib 3 (8) 6 (15) 5 (13) Histology, n (%) Adenocarcinoma Squamous cell carcinoma 32 (80) 8 (20) EGFR TKI—epidermal growth factor tyrosine kinase inhibitor NSCLC, non-small cell lung cancer; PS, performance status. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Results: Phase II Outcome (N = 40) Value ORR (PR + CR)* % 95% CI 30 SD ≥ 16 weeks n % 8 20 Median TTP months 95% CI 5 3 - 8 Median OS 11 7 - NR One-year OS 41 *Responses had to be confirmed at least 4 weeks after initial documentation. CI, confidence interval; CR, complete response; NR, not reached; ORR, overall response rate; OS, overall survival; PR, partial response; SD, stable disease; TTP, time to tumor progression. NSCLC, non-small cell lung cancer. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Results: Treatment-Related Adverse Events AE* (N = 40) Maximum grade, % All 1 2 3 4 Hematologic Anemia Leukopenia Neutropenia 92 62 60 63 23 13 20 28 8 15 5 Non-hematologic Fatigue Neuropathy Alopecia Constipation Diarrhea Nausea Rash Edema Myalgia Anorexia Hypersensitivity 75 73 70 58 48 45 40 30 35 10 38 25 18 Other points: The median number of cycles administered was four (range, one to 14). Most patients (85%) did not require dose reduction, although 18 patients (45%) discontinued study drug because of cumulative toxicity, primarily sensory neuropathy and fatigue. One patient died within 30 days of receiving NAB-paclitaxel. This patient died 27 days after receiving NAB-paclitaxel (cycle 3, week 2) with progressive liver metastases. This death was not treatment related. The most common grade ¾ toxicities were neutropenia (grade 3 in 15% and grade 4 in 5%), leukopenia (grade 3 in 20%), sensory neuropathy (grade 3 in 15%), fatigue (grade 3 in 18%), diarrhea (grade 3 in 13%),andanemia (grade 3 in 8%). Resolution of sensory neuropathy was not assessed formally in this trial. Follow-up schedules for individual patients depended on subsequent treatment regimen, if any. Of the patients in this trial who developed grade 3 sensory neuropathy, one patient was lost to follow up. The remaining patients all had improvement of neuropathy to grade 1 (three patients) or grade 2 (two patients) generally within 60 days. Most patients continued to have some symptoms of neuropathy. *Most frequent treatment-related AEs in patients treated with albumin-bound paclitaxel 125 mg/m2. AE, adverse event. NSCLC, non-small cell lung cancer. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Albumin-Bound Paclitaxel Monotherapy as First-Line Treatment for Stage IV NSCLC Conclusions Albumin-bound paclitaxel 125 mg/m2 administered qw 3/4 was well tolerated No corticosteroid premedication was administered and no hypersensitivity reactions were seen Albumin-bound paclitaxel 125 mg/m2 demonstrated encouraging single-agent activity Additional studies of single-agent albumin-bound paclitaxel as well as platinum-based combinations are warranted NSCLC, non-small cell lung cancer; qw 3/4, first 3 of 4 weeks. Rizvi NA, et al. J Clin Oncol. 2008;26(4):

Combination Therapy Studies
Albumin-Bound Paclitaxel for the Treatment of Non-Small Cell Lung Cancer Combination Therapy Studies

Summary of Albumin-Bound Paclitaxel Combination Therapy Studies in NSCLC
Trial Description Phase Combination Therapy with Carboplatin Weekly AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC1 II Dose-finding study of weekly and q3w AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC2 AB-paclitaxel + carboplatin vs CrEL paclitaxel + carboplatin as first-line therapy for advanced NSCLC3,4 III AB-Paclitaxel + carboplatin for patients at risk of bleeding from VEGF-directed therapies5 Combination Therapy with Carboplatin and Bevacizumab AB-paclitaxel + carboplatin + bevacizumab as first-line therapy for advanced nonsquamous NSCLC6 In vivo assessment of the effects of bevacizumab in advanced NSCLC7 Combination with Carboplatin and Radiotherapy AB-paclitaxel + carboplatin + thoracic radiation in locally advanced NSCLC8 I Combination Therapy in SCLC AB-paclitaxel + carboplatin in 2 different schedules for patients with ES-SCLC9 AB, albumin-bound; CrEL, Cremophor® EL; ES-SCLC, extensive stage small cell lung cancer; NSCLC, non-small cell lung cancer; q3w, every 3 weeks; VEGF, vascular endothelial growth factor. Allerton JP, et al. ASCO [Abstract 7127]. Socinski MA, et al. J Thoracic Oncol. 2010;5(5): Socinski MA, et al. ASCO [Abstract LBA7511]. Socinski MA et al. ASCO [Abstract 7551]. Otterson GA et al. IASLC [Abstract P3.183]. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7. Heist RS, et al. ASCO [Abstract 7612]. Keedy VL et al. ASCO [Abstract 7046]. Grilley-Olson JE et al. IASLC [Abstract P3.272]. ® Cremophor is a registered trademark of BASF. References in slide notes.

Summary of Albumin-Bound Paclitaxel Combination Therapy Studies in NSCLC
Trial Description Phase Main Idea Combination Therapy with Carboplatin Weekly AB-paclitaxel + carboplatin as first-line therapy for advanced NSCLC1 II AB-paclitaxel + carboplatin has a high degree of antitumor activity and an acceptable safety profile1 Dose-finding study of weekly and q3w ab-pac + carboplatin as first-line therapy for advanced NSCLC2 AB-paclitaxel 100 mg/m2 weekly + carboplatin AUC = 6 q3w is an optimal dose and schedule for treating NSCLC2 AB-paclitaxel + carboplatin vs CrEL paclitaxel + carboplatin as first-line therapy for advanced NSCLC3,4 III AB-paclitaxel + carboplatin demonstrated a higher response rate than CrEL paclitaxel + carboplatin3,4 AB-paclitaxel + carboplatin for NSCLC patients at risk of bleeding from VEGF directed therapies5 AB-paclitaxel + carboplatin showed a high ORR in NSCLC patients ineligible for VEGF directed therapies5 Combination Therapy with Carboplatin and Bevacizumab AB-paclitaxel + carboplatin + bevacizumab as first-line therapy for advanced nonsquamous NSCLC6 PFS and OS were higher than previously reported in patients with advanced nonsquamous NSCLC and toxicity was generally acceptable5 In vivo assessment of the effects of bevacizumab in advanced NSCLC7 PD and imaging biomarker studies in bevacizumab-treated NSCLC patients are feasible and may predict tumor response6 Combination with Carboplatin and Radiotherapy AB-paclitaxel + carboplatin + thoracic radiation in locally advanced NSCLC8 I Weekly AB-paclitaxel at 40 mg/m2 + carboplatin + thoracic radiation appears to be safe and well tolerated7 Combination Therapy in SCLC AB-paclitaxel + carboplatin in 2 different schedules for patients with ES-SCLC9 qw and q3w schedules of AB-paclitaxel + carboplatin produced high ORRs in patients with ES-SCLC6 AB, albumin-bound; AUC, area under the curve; CrEL, Cremophor® EL; ES-SCLC, extensive stage small cell lung cancer; NSCLC, non-small cell lung cancer; OS, overall survival; PD, pharmacodynamic; PFS, progression-free survival; q3w, every 3 weeks; qw, weekly. Allerton JP, et al. ASCO [Abstract 7127]. Socinski MA, et al. J Thoracic Oncol. 2010;5(5): Socinski MA, et al. ASCO [Abstract LBA7511]. Socinski MA et al. ASCO [Abstract 7551]. Otterson GA et al. IASLC [Abstract 2230]. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7. Heist RS, et al. ASCO [Abstract 7612]. Keedy VL et al. ASCO [Abstract 7046]. Grilley-Olson JE et al. IASLC [Abstract P3.272]. References in slide notes.

Combination Therapy with Carboplatin
Albumin-Bound Paclitaxel for the First-Line Treatment of Non-Small Cell Lung Cancer Combination Therapy with Carboplatin

Allerton JP, et al. ASCO. 2006 [abstract 7127].
A Phase II Evaluation of the Combination of Albumin-Bound Paclitaxel + Carboplatin in the First-Line Treatment of Advanced Non-Small Cell Lung Cancer J.P. Allerton, C.T. Hagenstad, T.R. Webb, G.B. Smith, R. Birch, T.F. Goggins, S.B. Katakkar, W. Khan, N.D. Mehta, F.A. Greco, Online Collaborative Oncology Group Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Background
Cremophor® EL paclitaxela + platinum agents are recommended as first-line chemotherapy for advanced NSCLC1 In phase III trials, CrEL paclitaxel + carboplatin showed efficacy Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4 CrEL use is associated with severe hypersensitivity reactions6 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions5 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7 Use of albumin as a vehicle eliminates solvent-related toxicities8 No premedication to prevent hypersensitivity reactions is required prior to administration7 Key Points: Taxanes are used in combination with platinum agents for treatment of patients with advanced NSCLC. However, the Cremophor EL excipient in solvent-based paclitaxel raises safety concerns. Cremophor EL contributes to severe toxicities, including hypersensitivity reactions and peripheral neuropathy. Lung cancer is still the leading cause of cancer death in the US and the 5-year relative survival rate for stage IV NSCLC is only 2%. Because of the safety and efficacy limitations of current therapy options, there is a critical need for safe chemotherapy agents with improved antitumor activity. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Kelly K, et al. J Clin Oncol. 2001;19: Scagliotti GV, et al. J Clin Oncol. 2002;20: Lilenbaum RC, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor® EL is a registered trademark of BASF; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; RR, response rates.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Background (cont.)
Belani et al. studied weekly Cremophor® EL paclitaxel 100 mg/m2 qw 3/4 + carboplatin for advanced NSCLC1 ORR 32% Median TTP 30 weeks Median survival time 49 weeks 1-year survival rate 47% Allerton et al. examined whether substituting albumin-bound paclitaxel for Cremophor® EL paclitaxel at an identical dose would improve ORR2 NSCLC, non-small cell lung cancer; ORR, objective response rate; qw3/4, weekly for 3 of 4 weeks; TTP, time to tumor progression. Belani CP, et al. J Clin Oncol. 2003;21(15): Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Objective Objective Determine efficacy and safety of albumin-bound paclitaxel + carboplatin as first-line therapy for advanced NSCLC Efficacy endpoints Response rate Response duration TTP Safety endpoints Toxicities NSCLC, non-small cell lung cancer ; TTP, time to tumor progression. Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Key Eligibility Criteria Key inclusion criteria Inoperable stage IIIB or IV NSCLC ≥ 1 measurable indicator lesion > 4 weeks from previous radiation therapy ECOG PS of 0, 1, or 2 at screening and on first day of treatment Life expectancy > 12 weeks Key exclusion criteria Previous treatment with chemotherapy Peripheral neuropathy ≥ grade 2 Key Points: Other inclusion criteria: Previous radiation therapy had to involve no more than 30% of the marrow-containing skeleton Blood counts Neutrophils > 1,500/mm3 Platelets > 100,000/mm3 Clinical chemistry/liver function tests (normal limit defined by institution) Serum creatinine < upper limit of normal Calculated creatinine clearance > 50 mL/min Aspartate aminotransferase < 1.5 times the upper limit of normal Total bilirubin < the upper limit of normal Alkaline phosphatase < 5 times the upper limit of normal ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Study Design Open-label, phase II study Albumin-bound paclitaxel 100 mg/m2 IV on days 1, 8, and 15 q28 days Carboplatin AUC = 6 IV on day 1 AUC, area under the curve; IV, intravenous; NSCLC, non-small cell lung cancer; q28, every 28 days. Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Baseline Patient Characteristics Baseline characteristic (N = 56) Value Age, years Median Range 66 Sex, n (%) Men Women 39 (70) 17 (30) Disease stage, n (%) Stage IIIB 14 (25) Stage IV with metastasis to, n Bone Liver Brain Lymph nodes 17 7 2 ECOG PS 0, n 1, n 2, n 1 18 33 ECOG, Eastern Cooperative Oncology Group; PS, performance status. NSCLC, non-small cell lung cancer. Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Response Rate Patients Response rate, n (%) CR PR SD > 12 weeks All evaluable patients (N = 50) 1 (2) 24 (48) 18 (36) Stage IIIB (n = 12) 4 (33) Stage IV (n = 38) 1 (3) 20 (53) 14 (37) CR, complete response; PR, partial response; SD, stable disease. Total of 6 patients removed from study after less than 2 cycles of treatment: Death from progressive disease, n=3; Toxicities, n=2 (Thrombocytopenia, n=1; Neutropenia, n=1), Refusal of Therapy, n=1 Of 18 patients with SD Stable at weeks, n = 14 Progressed at 20, 21, 23, and 28 weeks, n = 4 Allerton JP, et al. ASCO [abstract 7127]. NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Time to Tumor Progression Median TTP, 28 weeks; maximum follow-up, 39 weeks a Albumin-bound paclitaxel 100 mg/m2 was administered IV qw 3/4 and carboplatin AUC = 6 was administered on day 1 only of a 28-day cycle. AUC, area under the curve; NSCLC, non-small cell lung cancer; qw 3/4 weekly on 3 of 4 weeks; TTP, time to tumor progression. Allerton JP, et al. ASCO [abstract 7127].

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Toxicities Grade 3 or 4 toxicitiesa n (%) Neutropenia 24 (44) Thrombocytopenia 14 (25) Anemia 5 (9) Neuropathy Arthralgia Myalgia Nausea 1 (2) Vomiting Diarrhea Key Points: No grade 3 or 4 neuropathy Grade 1 neuropathy, n = 10 patients (18%) Grade 2 neuropathy, n = 3 patients (5%) Note: the taxane-associated toxicities listed in the table arose from the combination albumin-bound paclitaxel + carboplatin treatment. The table title reflects what is given in the poster. It may reflect only a subset of toxicities, but this is not clear from the poster. a Toxicities associated with albumin-bound paclitaxel followed by carboplatin. Allerton JP, et al. ASCO [abstract 7127]. NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Conclusions Efficacy conclusions In first-line treatment of advanced NSCLC, albumin-bound paclitaxel + carboplatin had a high degree of objectively-defined antitumor activity ORR 50% Median TTP 28 weeks Safety conclusions Acceptable safety profile Neutropenia was the most common severe toxicity No patients had grade 3/4 peripheral neuropathy Note to client: these slides previously included follow-up data from a Greco Chemotherapy reference that could not be obtained. Thus, these slides were cut from this deck. NSCLC, non-small cell lung cancer; ORR, overall response rate; TTP, time to tumor progression. Allerton JP, et al. ASCO [abstract 7127].

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):

Cremophor® EL paclitaxela + platinum agents are recommended as first-line chemotherapy for advanced NSCLC1 In phase III trials, CrEL paclitaxel + carboplatin showed efficacy: Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4 CrEL use is associated with severe hypersensitivity reactions6 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions5 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7 Use of albumin as a vehicle eliminates solvent-related toxicities8 No premedication to prevent hypersensitivity reactions is required prior to administration7 Key Points: Taxanes are used in combination with platinum agents for treatment of patients with advanced NSCLC. However, the Cremophor EL excipient in solvent-based paclitaxel raises safety concerns. Cremophor EL contributes to severe toxicities, including hypersensitivity reactions and peripheral neuropathy. Lung cancer is still the leading cause of cancer death in the US and the 5-year relative survival rate for stage IV NSCLC is only 2%. Because of the safety and efficacy limitations of current therapy options, there is a critical need for safe chemotherapy agents with improved antitumor activity. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Kelly K, et al. J Clin Oncol. 2001;19: Scagliotti GV, et al. J Clin Oncol. 2002;20: Lilenbaum RC, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor® EL is a registered trademark of BASF; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; RR, response rates.

NSCLC treatment studied Phase Patients, n ORR, % Median TTP, months Median OS, months CrEL paclitaxel monotherapy1 III 157 16 4 6.8 CrEL paclitaxel + carboplatin2 NA 290 17 3.1 8.1 q3w AB-paclitaxel monotherapy3 II 43 6 11 weekly AB-paclitaxel monotherapy4 40 30 5 weekly AB-paclitaxel + carboplatin5 50 7 AB, albumin-bound; CrEL, Cremophor EL; NA, not available; ORR overall response rate; OS, overall survival; q3w, every 3 weeks; TTP, time to tumor progression. Based on the efficacy of ab-paclitaxel vs CrEL paclitaxel, Socinski et al. aimed to identify the optimal dose of ab-paclitaxel + carboplatin as first-line therapy in advanced NSCLC6 Ranson M, et al. J Natl Cancer Inst. 2000;92: Schiller JH, et al. N Engl J Med. 2002;346:92-98. Green MR, et al. Ann Oncol. 2006;17: Rizvi NA, et al. J Clin Oncol. 2008;26: Allerton JP, et al. ASCO [abstract 7127]. Socinski MA, et al. J Thoracic Oncol. 2010;5(5): NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Objective Objective Identify optimal dose and schedule of albumin-bound paclitaxel + carboplatin as first-line therapy for advanced NSCLC Primary efficacy endpoints CR or PR based on RECIST Secondary efficacy endpoints SD ≥ 16 weeks PFS OS Safety endpoints Serious AEs Treatment-related AEs Laboratory abnormalities Dose modifications, dose interruptions, premature discontinuation of study drug AE, adverse event; CR, complete response; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Key Eligibility Criteria Key inclusion criteria Men and nonpregnant, nonlactating women ≥ 18 years of age Stage IIIB or IV NSCLC Histologically or cytologically confirmed Pleural effusion or evidence of inoperable local recurrence or metastasis Measurable disease as defined by RECIST guidelines No previous treatment for metastatic disease Life expectancy > 12 weeks ECOG PS of 0 or 1 Adequate hematologic, hepatic and renal function ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Key Eligibility Criteria Key exclusion criteria Evidence of active brain metastasis Any other clinically serious concurrent illness Radiotherapy or chemotherapy in the previous 4 weeks Peripheral neuropathy > grade 1 History of allergy or hypersensitivity to either of the study drugs NSCLC, non-small cell lung cancer. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

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):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Baseline Patient Characteristics Baseline characteristic (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 Age, years Mean 59.7 63.1 60.1 61.3 61.6 59.9 58.8 Sex, n (%) Men 23 (92) 18 (72) 17 (68) 20 (80) 22 (88) 21 (84) Stage, n (%) IIIB IV 10 (40) 15 (60) 8 (32) 4 (16) 3 (12) 7 (28) Histology, n (%) Nonsquamous Squamous Otherb 9 (36) 11 (44) 5 (20) 14 (56) 2 (8) 16 (64) 0 (0) 13 (52) ECOG PS, n (%) 1 1 (4) 24 (96) 25 (100) Preexisting peripheral neuropathy, n (%) Grade 0 Grade 1 Key Points: 100 (57%) received albumin-bound paclitaxel q3w Only patients in the q3w cohorts received prior chemotherapy; two (2%) patients had neoadjuvant, and one patient had adjuvant therapy. No patients received prior therapy for metastatic disease AUC, area under the curve; ECOG PS, Eastern Cooperative Oncology Group performance status; q3w, every 3 weeks. a 25 patients per cohort; all patients received carboplatin AUC = 6. b Poorly differentiated or non-differentiated NSCLC. Socinski MA, et al. J Thoracic Oncol. 2010;5(6): NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Response Rates and DCR for All Treated Patients 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%). AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PR, partial response; q3w, every 3 weeks; SD, stable disease. a 25 patients per cohort, all patients received carboplatin at AUC = 6.. b DCR = CR + PR + SD ≥ 16 weeks. NSCLC, non-small cell lung cancer. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: PFS and OS for All Treated Patients 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 AUC, area under the curve; CI, confidence interval; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks. a 25 patients per cohort, all patiente received carboplatin AUC = 6. 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. PFS was evaluated based on RECIST. Median PFS and OS was similar between q3w and weekly treatments. Socinski MA, et al. J Thoracic Oncol. 2010;5(6): NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Progression-Free Survival 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. PFS was evaluated based on RECIST. Median PFS was similar between q3w and weekly treatments. AUC, area under the curve; NSCLC, non-small cell lung cancer; q3w, every 3 weeks. Note: all patients received carboplatin AUC = 6. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Overall Survival 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. Median OS was similar between the q3w and weekly cohorts. AUC, area under the curve; NSCLC, non-small cell lung cancer; q3w, every 3 weeks. Note: all patients received carboplatin AUC = 6. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Efficacy Results by Histologic Subtype, SCC Clinical response q3w Weekly (days 1, 8) (days 1, 8, 15) Cohortsa 225 mg/m2 (n = 11 ) 260 mg/m2 (n = 18) 300 mg/m2 (n = 14) 340 mg/m2 (n = 16) 140 mg/m2 (n = 15) 100 (n= 16) 125 (n = 10) ORR, n (%) 95% CI 5 (45) 5 (28) 5 (36) 6 (38) 8 (53) 5 (31) 3 (30) CR, n (%) 1 (6) PR, n (%) 4 (22) SD ≥ 16 weeks, n (%) 2 (18) 6 (33) 1 (7) 1 (10) DCRb n (%) 7 (64) 11 (61) 6 (43) 6 (37) 9 (60) 4 (40) Median PFS, months 8.1 8.4 5.3 6.0 5.0 4.5 4.2 Median OS, months 13.2 12.2 8.0 15.1 9.4 12.6 5.3->18.8 10.9 Key Points: Of the 59 (total) patients in the q3w cohorts with squamous cell carcinoma, 1 (2%) patient had CR, 20 (34%) patients had a PR, and 9 (15%) patients had SD for 16 weeks. In the weekly cohorts of patients with squamous cell carcinoma (41 total), 16 (39%) patients had PR (no CR occurred) and 3 (7%) patients had SD for ≥16 weeks. AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; SCC, squamous cell carcinoma; SD, stable disease. a All patients received carboplatin AUC = 6. b DCR = CR + PR + SD ≥ 16 weeks. Socinski MA, et al. J Thoracic Oncol. 2010;5(6): NSCLC, non-small cell lung cancer.

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Efficacy Results by Histologic Subtype, Non-SCC Clinical response q3w Weekly (days 1, 8) (days 1, 8, 15) Cohorts 225 mg/m2 (n = 9) 260 mg/m2 (n = 7) 300 mg/m2 340 mg/m2 140 (n = 10) 100 125 (n = 13) ORR, n (%) 95% CI 4 (44) 1 (14) 1 (11) 2 (22) 6 (60) 7 (78) 6 (46) CR, n (%) 1 (8) PR, n (%) 6 (67) 5 (38) SD ≥ 16 weeks, 2 (29) 1 (10) DCRa 5 (56) 3 (43) 3 (33) 7 (70) 8 (89) 7 (54) PFS in months, median 5.8 5.5 5.3 4.4 7.7 6.6 18.3 OS in months, 12.4 10.7 7.3->22.0 10.5 7.3->25.1 11.9 4.4->22.3 13.1 4.8->18.4 9.8 >18.4 15.0->18.4 Key Points: Of the 34 (total) patients in the q3w cohorts with nonsquamous cell carcinoma, 8 (24%) patients had PR (no CR occurred) and 5 (15%) patients had SD for 16 weeks. In the weekly cohorts of patients with nonsquamous cell carcinoma (32 total), 2 (6%) patients had CR, 17 (53%) patients had PR, and 3 (9%) patients had SD for 16 weeks. AUC, area under the curve; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; SD, stable disease. a All patients received carboplatin AUC = 6. b DCR = CR + PR + SD ≥ 16 weeks. Non-SCC, nonsquamous cell carcinoma; NSCLC, non-small cell lung cancer; Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: ORR and DCR by Histologic Subtype Key Points: Patients with histologic confirmation of nonsquamous cell carcinoma receiving weekly ab-paclitaxel (all adenocarcinoma cases) achieved better efficacy compared with the q3w schedule (mostly 91% adenocarcinoma cases) (ORR: 59.4% vs. 23.5%, respectively, p ) In patients with squamous cell carcinoma receiving q3w versus weekly ab-paclitaxel, there was no difference in ORR between dosing groups. DCR, disease control rate; Non-SCC, nonsquamous cell carcinoma; NS, not statistically significant; NSCLC, non-small cell lung cancer; ORR, overall response rate; q3w, every 3 weeks; SCC, squamous cell carcinoma. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: PFS and OS by Histologic Subtype Key Points: Patients with histologic confirmation of nonsquamous cell carcinoma receiving weekly ab-paclitaxel (all adenocarcinoma cases) achieved >2 months longer PFS and OS compared with the q3w schedule. In patients with squamous cell carcinoma receiving q3w versus weekly ab-paclitaxel, PFS significantly increased by 3 months (p ) and OS increased by >2 months. Non-SCC, nonsquamous cell carcinoma; NS, not statistically significant; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks; SCC, squamous cell carcinoma. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Treatment-Related 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 Neutropenia Grade 3 Grade 4 8 (32) 9 (36) 6 (24) 3 (12) 7 (28) 5 (20) 11 (44) Leukopenia 1 (4) 0 (0) 12 (48) Thrombocytopenia 2 (8) 4 (16) Anemia 10 (40) 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. Treatment-related hematologic ≥ grade 3 AEs were neutropenia (60%), leukopenia (32%), thrombocytopenia (29%), and anemia (22%). In particular, with q3w treatment grade 3 and 4 neutropenia occurred in 33 and 22% of patients, respectively. With weekly treatment grade 3 and 4 neutropenia occurred in 32 and 35% of patients, respectively. No febrile neutropenia occurred. 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):

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):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Time to Improvement of Peripheral Neuropathy Improvement of peripheral neuropathy q3w Weekly (days 1, 8) Weekly (days 1, 8, 15) Cohortsa 225 mg/m2 (n = 3) 260 mg/m2 (n = 4) 300 mg/m2 (n = 6) 340 mg/m2 (n = 12) 140 mg/m2 (n = 2) 100 125 Improved to grade ≤ 2, n (%) 2 (67) 4 (100) 2 (33) 7 (58) 1 (50) 2 (100) 1 (25) Time to improvement, Median daysa 95% CI 15.0 9.0-> 21.0 14.5 > 48.0 6.0-> 48.0 23.0 17.0-> 66.0 8.0 --- 15.5 > 24.0 8.0-> 24.0 AUC, area under the curve; CI, confidence interval; q3w, every 3 weeks. a All patients received carboplatin AUC = 6. b Time to improvement was defined as the time from first occurrence of grade 3 peripheral neuropathy to improvement of at least to grade 2. Key Points: The most common treatment-related nonhematologic grade 3 AE was peripheral neuropathy (19%), and no grade 4 event occurred. Nineteen of 33 patients (58%) with grade 3 peripheral neuropathy improved to grade 2 or better: 15 of 25 (60%) patients in the q3w cohorts and four of eight (50%) in the weekly cohorts. Both q3w and weekly ab-paclitaxel dosing produced a median time to peripheral neuropathy recovery of 18 days (q3w: 95% CI, 15–34 days; weekly: 95% CI, 8–24 days) NSCLC, non-small cell lung cancer. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

First-Line Albumin-Bound Paclitaxel + Carboplatin in Advanced NSCLC Results: Dose Modifications and Dose Interruptions Dose modifications Albumin-bound paclitaxel: In the q3w cohorts, 40% of patients had ≥ 1 dose reduction In the weekly cohorts, 51% of patients had ≥ 1 dose reduction Hematologic toxicity was the most common reason for dose reductions Carboplatin: In the q3w cohorts, 6% of patients had a dose reduction In the weekly cohorts, 16% of patients had a dose reduction Dose interruptions None In the q3w cohorts, 2 patients had a dose interruption because of a hypersensitivity reaction NSCLC, non-small cell lung cancer. q3w, every 3 weeks. Socinski MA, et al. J Thoracic Oncol. 2010;5(6):

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):

Socinski MA et al. ASCO. 2011 [Abstract 7551].
Survival Results of a Randomized, Phase III Trial of Albumin-Bound Paclitaxel and Carboplatin Compared With Cremophor-Based Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non-Small Cell Lung Cancer M.A. Socinski, I. Bondarenko, N.A. Karaseva, A.M. Makhson, I.O. Vynnychenko, I. Okamoto, J. Hon, V. Hirsh, P. Bhar, G.I. Berks, J.L. Iglesias aCremophor is a registered trademark of BASF. Socinski MA et al. ASCO [Abstract 7551].

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Background Cremophor® EL paclitaxela + platinum agents are recommended as first-line chemotherapy for advanced NSCLC1 In phase III trials, CrEL paclitaxel + carboplatin showed efficacy: Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4 CrEL use is associated with severe hypersensitivity reactions6 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions5 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7 Use of albumin as a vehicle eliminates solvent-related toxicities8 No premedication to prevent hypersensitivity reactions is required prior to administration7 Key Points: Taxanes are used in combination with platinum agents for treatment of patients with advanced NSCLC. However, the Cremophor EL excipient in solvent-based paclitaxel raises safety concerns. Cremophor EL contributes to severe toxicities, including hypersensitivity reactions and peripheral neuropathy. Lung cancer is still the leading cause of cancer death in the US and the 5-year relative survival rate for stage IV NSCLC is only 2%. Because of the safety and efficacy limitations of current therapy options, there is a critical need for safe chemotherapy agents with improved antitumor activity. NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Kelly K, et al. J Clin Oncol. 2001;19: Scagliotti GV, et al. J Clin Oncol. 2002;20: Lilenbaum RC, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor® EL is a registered trademark of BASF; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; RR, response rates.

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Background (cont.) Weekly CrEL paclitaxel 100 mg/m2 qw 3/4 + carboplatin AUC = 6 on day 1 achieved ORR of 32% in advanced NSCLC1 Substituting AB-paclitaxel for CrEL paclitaxel at an identical dose achieved response rates of 50%2 Based on the efficacy of AB-paclitaxel vs CrEL paclitaxel observed in these studies, a phase II trial was conducted3 Showed that 100 mg/m2 weekly AB-paclitaxel + carboplatin AUC = 6 q3w is the optimal dose/schedule for treatment of advanced NSCLC3 Based on these phase II results, a phase III regulatory pathway trial was designed4 Investigated the efficacy and safety of AB-paclitaxel + carboplatin vs CrEL paclitaxel + carboplatin as first-line therapy in advanced NSCLC4 Final survival outcomes are also presented here AB, albumin-bound: AUC, area under the curve; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; ORR, objective response rate; q3w, every 3 weeks; qw 3/4, weekly for 3 of 4 weeks. Belani CP, et al. J Clin Oncol. 2003;21(15): Allerton JP, et al. ASCO [abstract 7127]. Socinski MA, et al. J Thoracic Oncol. 2010;5(5): Socinski MA, et al. ASCO [abstract LBA7511].

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Objective Objective Investigate efficacy and safety of AB-paclitaxel + carboplatin vs CrEL paclitaxel + carboplatin as first-line therapy for advanced NSCLC Primary endpoint ORR (CR + PR) by independent radiologic review based on RECIST Secondary endpoints PFS and OS DCRa Safety a DCR = CR + PR + SD ≥ 16 weeks. AB, albumin-bound ; CR, complete response; CrEL, Cremophor ® EL; DCR, disease control rate; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Socinski MA et al. ASCO [Abstract 7551].

Socinski MA, et al. ASCO. 2010 [abstract LBA7511].
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Key Eligibility Criteria Key inclusion criteria Adult patients with histologically/cytologically confirmed stage IIIB or IV NSCLC Measurable disease by RECIST No prior treatment for metastatic disease Adjuvant therapy was allowed if it was > 1 year prior to study entry ECOG PS of 0 or 1 Adequate hematologic, hepatic, and renal function Key exclusion criteria Active brain metastases Treated, controlled metastases were allowed Baseline peripheral neuropathy ≥ grade 2 ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors. Socinski MA, et al. ASCO [abstract LBA7511].

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Study Design Chemotherapy-naïve ECOG PS 0-1 Stage IIIB/IV NSCLC (N = 1052) Randomized 1:1 AB-paclitaxel 100 mg/m2 days 1, 8, 15 Carboplatin AUC = 6 day 1 Cycles of 21 days No Premedication (n = 521) CrEL paclitaxel 200 mg/m2 day 1 Carboplatin AUC = 6 day1 Premedication with Dexamethasone + Antihistamines (n = 531) Key points: Stratification factors: Stage, IIIB vs. IV; Age, < 70 vs. ≥ 70 years of age; Gender; Histology (squamous cell vs. non-squamous cell); Geographic region # of patients evaluable for efficacy: 1052 # of patients evaluable for toxicity: 1038 AB, albumin-bound; AUC, area under the curve; CrEL, Cremophor® EL; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. Socinski MA et al. ASCO [Abstract 7551].

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.

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Results: ORR, Stratified by Histologya 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

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].

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

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; Carbo, carboplatin; 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

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

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; Carbo, carboplatin; CI, confidence interval; CrEL, Cremophor EL; HR, hazard ratio; OS, overall survival. Socinski MA et al. ASCO [Abstract 7551]. * Not a pre-specified endpoint

AB-paclitaxel + carboplatin CrEL paclitaxel + carboplatin
Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Results: Safety Treatment-related grade 3/4 AEsa AB-paclitaxel + carboplatin (n = 514) CrEL paclitaxel + carboplatin (n = 524) P-value Hematologic, % Neutropenia Thrombocytopenia Anemia Febrile neutropenia 42 18 24 1 48 7 6 .081 < .001 NS Nonhematologic, % Fatigue Sensory neuropathy Anorexia Nausea Myalgia 5 3 2 < 1 12 .011 Time in days to improvement of sensory neuropathy to grade 1, median 38 104 .238 AB, albumin-bound; AE, adverse event; CrEL, Cremophor EL; NS, not statistically significant;. a By National Cancer Institute Common Terminology Criteria for Adverse Events. Key points: There was a 70% reduction in high-grade neuropathy in the albumin-bound paclitaxel + carboplatin arm No hypersensitivity reactions occurred in the albumin-bound paclitaxel arm without prophylactic premedication, while 3 occurred in the paclitaxel arm (grade 1, 2, and 3, respectively) Neutropenia and sensory neuropathy were both significantly higher in the paclitaxel plus carboplatin arm than the albumin-bound paclitaxel plus carboplatin arm Socinski MA et al. ASCO [Abstract 7551].

Albumin-Bound Paclitaxel + Carboplatin vs Cremophor® EL Paclitaxel + Carboplatin in Advanced NSCLC Conclusions The primary endpoint of a higher ORR albumin-bound paclitaxel plus carboplatin compared with Cremophor® EL palictaxel plus carboplatin was met Overall: 33% vs. 25% (P = .005) Within the squamous cell subset, the ORR of albumin-bound paclitaxel plus carboplatin was higher than Cremophor EL paclitaxel plus carboplatin: 41% vs. 24% (P < .001) There was no significant difference in PFS or OS between the 2 arms HRs trended in favor of the albumin-bound paclitaxel arm, particularly in the elderly and in patients with squamous cell histology The albumin-bound paclitaxel arm exhibited higher rates of grade 3/4 anemia and thrombocytopenia and lower rates of grade 3/4 myalgia and sensory neuropathy HR, hazard ratio; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Socinski MA et al. ASCO [Abstract 7551].

Otterson GA, et al. IASLC 2011 [Abstract P3.183].
Phase II Trial of Albumin-Bound Paclitaxel Plus Carboplatin in Patients With Advanced NSCLC at Risk of Bleeding From VEGF Directed Therapies G. A. Otterson, E. M. Bertino, N. A. Karim, K. Donthireddy, A. M. Ghany, R. Rupert, S. Cantrell, M. Rahmani, M. Lynn, S. P. Nana-Sinkam, G. S. Phillips, M. A. Villalona-Calero NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Background A phase II trial of albumin-bound paclitaxel plus carboplatin and bevacizumab in patients with advanced NSCLC produced an ORR of 31% and a median OS of 16.8 months1 Albumin-bound paclitaxel plus carboplatin produced a higher ORR vs Cremophor® EL paclitaxel plus carboplatin in a phase III trial of patients with advanced NSCLC2 Difference particularly pronounced in patients with squamous histology (ORR = 41% vs 24%; P < .001) Albumin-bound paclitaxel plus carboplatin may be a viable option for patients who can not receive bevacizumab due to characteristics such as squamous histology or risk of bleeding ® Cremophor is a registered trademark of BASF. NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; VEGF, vascular endothelial growth factor. Reynolds C, et al. J Thorac Oncol ;4(12): Socinski MA et al. ASCO [Abstract 7551]. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Objective Objective: to determine the efficacy of albumin-bound paclitaxel plus carboplatin in patients who are ineligible for treatment with bevacizumab Primary endpoint: overall response rate by RECIST Secondary endpoints Safety/toxicity OS PFS Exploratory Tumor SPARC expression Serum micro RNA expression profiles NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SPARC, Secreted Protein Acidic and Rich in Cysteine; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Key Eligibility Criteria Inclusion criteria Advanced NSCLC Stage IIIB with pleural effusion Stage IV Recurrent Not eligible to receive bevacizumab because of Squamous histology Thrombotic or embolic events within 6 months History of controlled, non-life–threatening hemoptysis Cavitary lung lesions NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Key Eligibility Criteria (cont.) Exclusion criteria Prior treatment of advanced NSCLC Pre-existing ≥ grade 2 neuropathy Uncontrolled brain metastases Major surgery within 4 weeks Nonhealing wounds Uncontrolled cardiac disease HIV Hepatitis B or C NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-bound paclitaxela 300 mg/m2 Day 1
Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Study Design Study design: phase II, single-arm, 2-stage Simon model First stage: 27 patients Second stage: 36 patients Twenty-one day cycles Patients allowed to receive up to 6 cycles of therapy Albumin-bound paclitaxela 300 mg/m2 Day 1 Carboplatin AUC = 6 Day 1 a The dose of albumin-bound paclitaxel was reduced from 300 mg/m2 for the first 40 patients to 260 mg/m2 for the subsequent patients due to excessive grade 3 neuropathy. AUC, area under the curve; NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Baseline Patient Characteristics Baseline characteristic N = 52 Age in years, mean 64 Race, n (%) White Black Other 42 (81) 9 (17) 1 (2) Tobacco pack years, mean 49 Histology, n (%) Squamous Adenocarcinoma Adenosquamous Poorly differentiated NSCLC 37 (71) 8 (15) 2 (4) 5 (10) ECOG PS, n (%) 1 2 18 (35) 24 (46) 10 (19) ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small cell lung cancer. VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Results: Clinical Outcomes Clinical response, n (%) N = 52 Partial response 16 (31)a Stable disease 18 (35) Progressive disease 10 (19) Not evaluable 8 (15) a Thirteen (25%) of the 16 partial responses were confirmed responses. NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Results: Adverse Events Grade 3 or 4 adverse events in > 5% of patientsa (N = 52) Grade 3 Grade 4 Hematologic, n (%) Anemia Neutropenia Thrombocytopenia 2 (4) 4 (8) 5 (10) 1 (2) 8 (15) Nonhematologic, n (%) Sensory neuropathy Febrile neutropenia Infection in the absence of neutropenia Hyponatremia Hypoxia Dyspnea Dehydration Fatigue 13 (25) 7 (13) 6 (12) 10 (20) 3 (6) a Adverse events per Common Terminology Criteria for Adverse Events, version 3.0. Note to client: the % for grade 3 fatigue in the poster says 20%, however, it’s not possible to have 20% of 52 (10/52 = 19% and 11/52 = 21%). Perhaps somebody simply doubled the 5 (10%) value previously listed in the table, although this is not correct because of decimals. NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Albumin-Bound Paclitaxel Plus Carboplatin in Patients With NSCLC at Risk of Bleeding From VEGF Directed Therapies Conclusions This treatment regimen offers a reasonable first-line treatment option for patients with advanced squamous NSCLC who are not eligible to receive bevacizumab Fifty-two patients have been enrolled in this ongoing study; 11 more patients are required to complete accrual The clinical response data from the first stage of this trial (30% of the 27 patients exhibited partial responses) allowed for continuation to the second stage Exploratory endpoints examining tumoral SPARC and serum micro RNA profiles are pending NSCLC, non-small cell lung cancer; SPARC, Secreted Protein Acidic and Rich in Cysteine; VEGF, vascular endothelial growth factor. Otterson GA, et al. IASLC 2011 [Abstract P3.183].

Combination Therapy with Carboplatin and Bevacizumab
Albumin-Bound Paclitaxel for the Treatment of Non-Small Cell Lung Cancer Combination Therapy with Carboplatin and Bevacizumab

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.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Background Cremophor® EL paclitaxela + platinum agents are recommended as first-line chemotherapy for advanced NSCLC1 In phase III trials, CrEL paclitaxel + carboplatin showed efficacy: Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4 CrEL use is associated with severe hypersensitivity reactions6 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions5 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7 Use of albumin as a vehicle eliminates solvent-related toxicities8 No premedication to prevent hypersensitivity reactions is required prior to administration7 NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Kelly K, et al. J Clin Oncol. 2001;19: Scagliotti GV, et al. J Clin Oncol. 2002;20: Lilenbaum RC, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor® EL is a registered trademark of BASF; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; RR, response rates. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Background (cont.) Bevacizumab is a VEGF-specific angiogenesis inhibitor1 Indicated with CrEL paclitaxel + carboplatin as first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC1 In a phase III trial, AB-paclitaxel + carboplatin achieved a higher ORR than CrEL paclitaxel + carboplatin in advanced NSCLC2 33% vs 25%, P = .0052 A phase II trial was designed to evaluate AB-paclitaxel + carboplatin + bevacizumab in advanced nonsquamous NSCLC3 AB-paclitaxel, albumin-bound paclitaxel; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; ORR, objective response rate; VEGF, vascular endothelial growth factor. Avastin (bevacizumab) package insert. San Francisco, CA, Genentech, Inc., 2011. Socinski MA, et al. ASCO [abstract LBA7511]. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Objective Objective Evaluate the safety and antitumor activity of AB-paclitaxel + carboplatin + bevacizumab q21d in advanced stage IIIB/IV NSCLC Primary endpoint Response rate based upon RECIST criteria Secondary endpoints TTP Duration of response Safety 1- and 2-year survival Proportion of patients with SD ≥ 16 weeks Changes in QOL using FACT-Taxane questionnaires AB, albumin-bound: FACT, Functional Assessment of Cancer Therapy; NSCLC, non-small cell lung cancer; q21d, every 21 days; QOL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; TTP, time to disease progression. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Key Eligibility Criteria Key inclusion criteria Histologically or cytologically confirmed advanced stage IIIB (wet)/IV nonsquamous NSCLC Evidence of inoperable local recurrence or metastasis Measurable disease by RECIST No prior chemotherapy Prior RT permitted as long as the measurable disease Was outside the field of radiation Had progressed since completion of radiation ECOG PS of 0-1 Key Points: Other entry criteria included age > 18 years, adequate renal, hepatic, and hematological function ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status; RECIST, response evaluation criteria in solid tumors ; RT, radiation therapy. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Key Eligibility Criteria (cont.) Key exclusion criteria Another active malignancy Pre-existing peripheral neuropathy of NCI grade > 1 Exclusion criteria related to the administration of bevacizumab Presence of CNS metastases Gross hemoptysis Unstable angina Use of therapeutic anticoagulation Key Points: Other exclusion criteria included pregnancy or breast feeding, significant renal disease or proteinuria, active cardiac disease, or history of seizure disorder CNS, central nervous system; NSCLC, non-small cell lung cancer; NCI, National Cancer Institute. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

Albumin-bound paclitaxel 300 mg/m2 IV
First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Study Design Open-label, single arm, phase II study Albumin-bound paclitaxel 300 mg/m2 IV + Carboplatin AUC = 6 IV Bevacizumab 15 mg/kg On day 1 of each 21 day cycle Patients did not receive maintenance bevacizumab Patients were to receive a minimum of 4 cycles of treatment Key Points: Patients who progressed or who developed an intolerable toxicity were taken off treatment. At the discretion of the treating physician, patients who achieved a complete response (CR) or partial response (PR) could receive an additional 2 cycles to a maximum of 6 cycles. Responses were evaluated between days 14 and 21 of cycles 2 and 4 (and 6 if applicable). All patients who received at least one dose of nab-paclitaxel, carboplatin, and bevacizumab were evaluable for response and toxicity. AUC, area under the curve; IV, intravenous; NSCLC, non-small cell lung cancer . Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Baseline Patient Characteristics Baseline characteristic (N = 50) Value Age, years Median Range 67 Sex, n (%) Male Female 22 (48) 28 (56) Histology, n (%) Adenocarcinoma Bronchioalveolar Large cell NOS 43 (86) 1 (2) 4 (8) 2 (4) ECOG PS, n (%) 1 26 (52) 24 (48) Prior treatment, n (%) Surgery Radiation 19 (30) Number of metastatic sites per patient, n (%) 2 3 4 19 (38) 15 (30) 9 (18) Key Points: 80% of patients were white, 10% were black, 8% were Asian, 2% were Hispanic Two patients who enrolled were not treated; one patient withdrew consent before treatment and the other was found to have brain metastases and therefore was ineligible ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified; PS, performance status. NSCLC, non-small cell lung cancer. 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.

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.

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.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Time to Progression NSCLC, non-small cell lung cancer; TTP, time to progression. 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.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Results: Quality of Life QOL was assessed using the FACT-Taxane scale1 Over the course of the study, QOL decreased significantly with the exception of emotional well-being Emotional well-being increased throughout cycles 1-5 and was significantly higher than baseline at cycle 3 (P = 0.05) Key Points: Changes at cycles 5 and 6 were interpreted with care as patient numbers completing the survey at these time points, and at the end of treatment and follow-up, were limited FACIT Functional Assessment of Chronic Illness Therapy, FACT-Taxane Questionnaire v4. Available at . Accessed May 20, 2011. FACT, Functional Assessment of Chronic Illness Therapy; NSCLC, non-small cell lung cancer; QOL, quality of life. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

First-Line Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced Nonsquamous NSCLC Conclusions Efficacy conclusions PFS and OS rates were higher than previously reported in patients with advanced NSCLC PR occurred in 31% of patients SD in 54% of patients Safety conclusions Toxicity was generally acceptable Low incidence of grade 3 peripheral neuropathy Absence of any obvious exacerbation of chemotherapy-induced myelosuppression by the addition of bevacizumab Phase III evaluation of this combination would determine whether it is more efficacious than previous regimens NSCLC, non-small cell lung cancer; PFS, progression-free survival; PR, partial response; SD, stable disease; OS, overall survival. Reynolds C, et al. J Thoracic Oncol. 2009;4(12):1-7.

Heist RS, et al. ASCO. 2010 [abstract 7612].
In Vivo Assessment of the Effects of Bevacizumab in Advanced Non-Small Cell Lung Cancer R. Suk Heist, D.G. Duda, D.V. Sahani, N.Pennell, J. Neal, M. Ancukiewicz, J. Engelman, T.J. Lynch, R.K. Jain Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Background
Cremophor® EL paclitaxela + platinum agents are recommended as first-line chemotherapy for advanced NSCLC1 In phase III trials, CrEL paclitaxel + carboplatin showed efficacy: Objective RR of 25%,2 overall RR of 32%,3 RR of 30%4 CrEL use is associated with severe hypersensitivity reactions6 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions5 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel7 Use of albumin as a vehicle eliminates solvent-related toxicities8 No premedication to prevent hypersensitivity reactions is required prior to administration7 NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Kelly K, et al. J Clin Oncol. 2001;19: Scagliotti GV, et al. J Clin Oncol. 2002;20: Lilenbaum RC, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Green MR, et al. Ann Oncol. 2006;17(8): a Cremophor® EL is a registered trademark of BASF; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; RR, response rates.

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Background (cont.)
Bevacizumab is a VEGF-specific angiogenesis inhibitor1 Indicated with CrEL paclitaxel + carboplatin as first-line treatment of patients with locally advanced, recurrent, or metastatic nonsquamous NSCLC1 Phase II trial evaluated the antitumor activity of AB-paclitaxel + carboplatin + bevacizumab2 Demonstrated higher PFS and OS than previously reported in advanced nonsquamous NSCLC2 Phase II trial was designed to identify biomarkers for bevacizumab in NSCLC patients treated with AB-paclitaxel + carboplatin + bevacizumab3 AB, albumin-bound; CrEL, Cremophor EL; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; VEGF, vascular endothelial growth factor. Avastin (bevacizumab) package insert. San Francisco, CA, Genentech, Inc., 2011. Reynolds C, et al. J Thorac Oncol. 2009;4:1-7. Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Objective Objective Identify biomarkers for bevacizumab in patients with NSCLC Primary endpoint 6-month PFS rate Secondary endpoints RR and OS Safety Exploratory correlative endpoints Effect of bevacizumab on Tumor perfusion Serum levels of angiogenic cytokines and CECs Relationship between tumor response and changes in CECs, circulating endothelial cells; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; RR, response rate. Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Study Design
Open-label, phase II study Correlative studies included Perfusion CT FDG-PET CECs Angiogenic cytokines Correlative studies performed On day -14 On day -2 (except FDG-PET) After cycles 2 and 4 At time of progression Day -14: Bevacizumab 15 mg/kg Day 1: Albumin-bound paclitaxel 100 mg/m2 + Carboplatin AUC = 6 Bevacizumab 15 mg/kg Days 8 and 15: Albumin-bound paclitaxel 100 mg/m2 Key Points: Planned enrollment: 36 Note to Client: Key eligibility criteria and baseline characteristics were not included in poster AUC, area under the curve; CECs, circulating endothelial cells; CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; NSCLC, non-small cell lung cancer. Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Results: Preliminary Analysis of Correlative Studies Bev, bevacizumab; NSCLC, non-small cell lung cancer; RECIST, response evaluation criteria in solid tumors. Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Results: Preliminary Analysis of Correlative Studies Key points: Ongoing evaluation of imaging characteristics and tumor response. Preliminary analysis of 12 evaluable patients shows no definite correlation between RECIST change and change in blood flow CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; NSCLC, non-small cell lung cancer; RECIST, response evaluation criteria in solid tumors; SUV, standardized uptake value. Heist RS, et al. ASCO [abstract 7612].

Albumin-Bound Paclitaxel + Carboplatin + Bevacizumab in Advanced NSCLC Conclusions Pharmacodynamic blood and imaging biomarker studies in bevacizumab-treated NSCLC patients are feasible Preliminary data suggest that such studies may predict tumor response Enrollment and biomarker analyses are ongoing Heist RS, et al. ASCO [abstract 7612]. NSCLC, non-small cell lung cancer.

Combination Therapy with Carboplatin and Radiation
Albumin-Bound Paclitaxel for the Treatment of Non-Small Cell Lung Cancer Combination Therapy with Carboplatin and Radiation

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].

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Background In selected patients with unresectable stage III NSCLC, concurrent chemoradiation is superior to sequential therapy1,2 NCCN-preferred1: cisplatin + etoposide3 and cisplatin + vinblastine4 NCCN category 2B1,a: carboplatin + Cremophor® EL paclitaxel5,b CrEL use is associated with severe hypersensitivity reactions7 All patients should be premedicated prior to CrEL paclitaxel administration to prevent severe hypersensitivity reactions6 Albumin-bound paclitaxel is a solvent-free formulation of paclitaxel8 No premedication to prevent hypersensitivity reactions is required prior to administration8 Phase I trial was designed to evaluate carboplatin + albumin-bound paclitaxel + thoracic radiation in unresectable stage III NSCLC9 Bullet 1 is supported by info in NCCN guidelines, pages 38, 59-61 NCCN Clinical Practice Guidelines in OncologyTM, Non-Small Cell Lung Cancer, v Auperin A, et al. J Clin Oncol. 2010;28: Albain KS, et al. J Clin Oncol. 2002;20: Curran WJ, et al. Proc Am Soc Clin Oncol. 2003;22:621[abstract 2499]. Belani CP, et al. J Clin Oncol. 2005;23: Taxol (paclitaxel) package insert. Princeton, NJ, Bristol-Myers Squibb Co, 2010. Gelderblom H, et al. Eur J Cancer. 2001;37: nab-paclitaxel (paclitaxel protein-bound particles) package insert. Bridgewater, NJ, Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation, 2010. Keedy VL, et al. J Clin Oncol. 2010;28(suppl):abstract e17504. a Recommendation is based on lower-level evidence and there is nonuniform NCCN consensus but no major disagreement. b Cremophor® is a registered trademark of BASF. CrEL, Cremophor EL; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Objective Objective Determine the MTD of weekly albumin-bound paclitaxel + carboplatin + concurrent thoracic radiation followed by consolidation therapy with albumin-bound paclitaxel plus carboplatin in patients with unresectable stage III NSCLC Endpoints Safety and tolerability Keedy VL et al. ASCO [Abstract 7046]. NSCLC, non-small cell lung cancer.

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Key Eligibility Criteria Inclusion criteria Nonmetastatic, inoperable Stage IIIA or IIIB NSCLC without pleural effusion Measurable disease Patients ≥ years of age ECOG performance status = 0 or 1 Adequate hepatic, renal, and bone marrow function Force Expiratory volume in 1 second > 800 mL Exclusion criteria Known hypersensitivity to carboplatin or albumin-bound paclitaxel Prior systemic chemotherapy, thoracic radiotherapy, or surgical resection Peripheral neuropathy ≥ grade 2 Concomitant malignancy Pregnant or nursing women ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer. Keedy VL et al. ASCO [Abstract 7046].

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].

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Results: Baseline Patient Characteristics Baseline characteristic N = 11 Age in years, median (range) 67 (45 – 75) Smoker, n (%) 11 (100) Male, n (%) 9 (82) Race, n (%) White Black 10 (91) 1 (9) ECOG PS, n (%) 1 5 (45) 6 (55) Histology Adenocarcinoma Squamous Not otherwise specified 4 (36) 2 (18) Disease stage, n (%) IIIA IIIB 7 (64) ECOG PS, Eastern Cooperative Oncology Group performance status. 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].

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].

Albumin-Bound Paclitaxel + Carboplatin + Thoracic Radiation in Unresectable Stage III NSCLC Results: Safety and Tolerability ≥ grade 2 AEs during concurrent chemoradiotherapy, n Albumin-bound paclitaxel dosea 40 mg/m2 (n = 6) 60 mg/m2 (n = 4) Grade 2 Grade 3 Esophagitis 2 1 1b Fatigue 3 Dehydration Neutropenia Hypoxia Anemia Febrile neutropenia Thrombocytopenia Chest pain Nausea Dermatitis Dyspnea AE, adverse event. a No grade 4 toxicities were observed. b Dose-limiting toxicity. Keedy VL et al. ASCO [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 = 6 + radiation therapy for patients with stage III NSCLC is 40 mg/m2 A phase II study to evaluate this treatment is currently ongoing 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].

Albumin-Bound Paclitaxel for the Treatment of Small Cell Lung Cancer
Combination Therapy with Carboplatin

Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].
A Randomized Phase II Study of Carboplatin and Albumin-Bound Paclitaxel With 2 Different Schedules in Patients With Extensive Stage Small Cell Lung Cancer J. E. Grilley-Olson, V. L. Keedy, A. Sandler, D. Moore, M. A. Socinski, T. E. Stinchcombe Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Background The NCCN considers etoposide plus a platinum agent to be the standard treatment regimen for patients with SCLC1 Clinicians often prescribe carboplatin over cisplatin in an effort to reduce the risk of emesis, neuropathy, and nephropathy1 Etoposide treatment is associated with substantial toxicity, including myelosuppression, nausea, and vomiting2 Albumin-bound paclitaxel given weekly or every 3 weeks in combination with carboplatin may lead to improved tolerability and acceptable efficacy in patients with ES-SCLC First bullet: NCCN SCLC v Page 24; right column; last sentence in top paragraph. Second bullet: NCCN SCLC v Page 23: left column; third sentence in second paragraph. NCCN Clinical Practice Guidelines in OncologyTM, Small Cell Lung Cancer, v Spira A, et al. N Engl J Med. 2004; 350(4): ES-SCLC, extensive stage small cell lung cancer; NCCN, National Comprehensive Cancer Network; SCLC, small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Objective Objective: to evaluate the efficacy of 2 different dosing regimens of albumin-bound paclitaxel plus carboplatin in patients with ES-SCLC Endpoints Primary: ORR per RECIST Secondary DoR PFS OS Toxicity profile per CTCAE version 3.0 CTCAE, Common Terminology Criteria for Adverse Events; DoR, duration of response; ES-SCLC, extensive stage small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Key Eligibility Criteria Inclusion criteria Histologically or cytologically confirmed ES-SCLC ECOG PS 0 - 2 Adequate organ function Patients ≥ 18 years of age If brain metastases are present, they must be stable ECOG PS, Eastern Cooperative Oncology Group performance status; ES-SCLC, extensive stage small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Key Eligibility Criteria (cont.) Exclusion criteria Prior systemic chemotherapy, immunotherapy, or biologic therapy for ES-SCLC Prior malignancies within 5 years Serious concomitant illness Grade ≥ 2 neuropathy Previous anaphylactic reaction to carboplatin, paclitaxel, or docetaxel Severe or uncontrolled cardiac disease Note to client: for exclusion for neuropathy the poster does not indicate whether this is sensory or motor, though it’s most likely sensory. ES-SCLC, extensive stage small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Study Design Study design: randomized (1:1) phase II study of 2 different schedules of albumin-bound paclitaxel plus carboplatin in patients with ES-SCLC Twenty-one day cycles Response assessments were performed after cycles 2 and 4 Albumin-bound paclitaxela mg/m2 IV Day 1 Carboplatin AUC = 6 IV Day 1 Note to client: this trial was closed early due to poor accrual. OR Albumin-bound paclitaxela mg/m2 IV Days 1, 8, and 15 a Doses of albumin-bound paclitaxel were originally planned to be 300 mg/m2 and 100 mg/m2 in the q3w and qw schedules, respectively, but excessive toxicity required reductions to 240 mg/m2 and 80 mg/m2, respectively. AUC, area under the curve; ES-SCLC, extensive stage small cell lung cancer; IV, intravenous; q3w, every 3 weeks; qw, weekly. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Baseline Patient Characteristics Baseline Characteristic Carbo + AB-Paclitaxel q3w (n = 14) Carbo + AB-Paclitaxel qw (n = 13) Age in years, median (range) 60 ( ) 67 ( ) ECOG PS, n (%) 1 2 5 (36) 8 (57) 1 (7) 2 (15) 11 (85) Male, n (%) 10 (71) 8 (62) White, n (%) 13 (93) AB, albumin-bound; carbo, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; q3w, every 3 weeks; qw, weekly. EGFR TKI—epidermal growth factor tyrosine kinase inhibitor ES-SCLC, extensive stage small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Results: Clinical Outcomes Clinical Outcome Carbo + AB-Paclitaxel q3w (n = 14) Carbo + AB-Paclitaxel qw (n = 13) Partial response, n (%) 11 (79) 11 (85) PFS in months, median (95% CI) 5.8 ( ) 5.2 ( ) OS in months, median (95% CI) 8.6 ( ) 11.6 ( ) 1-year survival, % (95% CI) 36 ( ) 42 ( ) AB, albumin-bound; carbo, carboplatin; CI, confidence interval; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks; qw, weekly. ES-SCLC, extensive stage small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Results: Adverse Events Grade 3 or 4 AEs, n (%) Carbo + AB-Paclitaxel q3w (n = 14) Carbo + AB-Paclitaxel qw (n = 13) Hematologic Neutropeniaa Anemia Thrombocytopenia 8 (57) 4 (29) 3 (21) 5 (38) 4 (31) 3 (23) Nonhematologic Sensory neuropathy Pain Fatigue Nausea Vomiting Diarrhea 1 (7) 1 (8) 2 (15) AB, albumin-bound; AE, adverse event; carbo, carboplatin; q3w, every 3 weeks; qw, weekly. a No cases of febrile neutropenia were reported in either arm. ES-SCLC, extensive stage small cell lung cancer. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

Carboplatin and Albumin-Bound Paclitaxel at 2 Different Schedules in Patients With ES-SCLC Conclusions Response rates of 79% and 85% in the q3w and qw schedules of albumin-bound paclitaxel, respectively, demonstrate clinical activity of this combination therapy in patients with ES-SCLC The majority of grade 3 or 4 adverse events were hematologic in both arms Protocol dose reductions in both arms were necessary due to excessive toxicities at the originally specified doses ES-SCLC, extensive stage small cell lung cancer; q3w, every 3 weeks; qw, weekly. Grilley-Olson JE, et al. IASLC 2011 [Abstract P3.272].

BACK UP NSCLC Clinical Data 136

nab-paclitaxel in Advanced NSCLC
Trial Patients Treatment ORR Median Survival Neuropathy Neutropenia Anemia Gr 3 Gr 4 CA031 Socinski1 Advanced, 1st Line N=1052 ABX 100 mg/m2 qw + carboplatin paclitaxel + carboplatin 33% 25% OS: 12.1 mo OS: 11.2 mo 3% 10% 12% 23% 22% 6% 5% 21% CA028 Socinski2 N=250 (dose-finding study) ABX 100 mg/m2 qw+ carboplatin 48% PFS: 6.2 OS: 11.3 8% 36% 28% 16% CA015 Rizvi3 Advanced, 1st Line, N=40 ABX 125 mg/m2 qw 30% TTP: 5 mo OS: 11 mo 15% 0 5% 8% CA018 Green4 Advanced, metastatic 1st-line N=43 ABX 260 mg/m2 q3w TTP: 6mo 9% ABX014 Allerton, Greco5 Advanced; 1st-line NSCLC N=50 50% TTP: 28 wks 44% (Gr 3 or 4) 9% (Gr 3 or 4) ABX036 Reynolds6 Advanced non-squamous; 1st-line N=48 ABX 300 mg/m2 q3w + carboplatin + BEV 31% PFS: 9.8 mo OS: 16.8 mo 17% 37% NR ABX255 Otterson7 BEV-ineligible; advanced, 1st-line NSCLC N=52 (safety) N=27 (efficacy) ABX 260 mg/m2 q3w + carboplatin 15% 4% 2% ABX014: Grade 3/4 toxicites were not reported separately 1. Socinski IASCL Socinski JTO Rizvi JCO Green Ann Onc Allerton ASCO Reynolds JTO Otterson IASLC 2011. 137 137

CA031 vs Historical Phase 3 Data with Taxol/Carboplatin
Trial Patients Treatment ORR Median Survival Neuropathy Neutropenia Anemia Gr 3 Gr 4 CA031 Socinski Advanced, 1st Line N=1052 ABX 100 mg/m2 qw + carboplatin Taxol+ carboplatin 33% 25% OS: 12.1 mo OS: 11.2 mo 3% 10% 12% 23% 22% 6% 5% 21% Belani 2003 N=390 Taxol 100 mg/m2 qw + Carbo 32% TTP: 30 wks OS: 49 wks 7% ECOG 1594 Schiller 2002 N=1207 Taxol 225 mg/m2 q3w + Carbo 17% TTP: 3.1 mo OS: 8.1 mo 20% 43% 8% 2% ECOG 4599 Sandler 2005 N=878 Taxol 200 mg/m2 q3w + Carbo 15% PFS: 4.5 mo OS: 10.3 mo 0S NR0 NR 1% INTACT2 Herbst 2004 N=1037 29% TTP: 5.0 mo OS: 9.9 mo 0.9% 5.9% 0.6% ESCAPE Scagliotti 2010 N=926 24% PFS 5.4 mo OS: 10.6 mo 0% ABX014: Grade 3/4 toxicites were not reported separately 138 138

Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer 51 5 ESA 1217 00004853 2007 05 14 - 04:33:17 PM 5 ESA 1255 2007 09 27 - 02:06:42.

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Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer 51 5 ESA 1217 00004853 2007 05 14 - 04:33:17 PM 5 ESA 1255 2007 09 27 - 02:06:42.

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