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

2 TitlePhase Combination Therapy with Carboplatin Phase II study of albumin-bound paclitaxel + carboplatin for first-line advanced NSCLC (weekly dosing) 1 II 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 2 II Phase II trial of albumin-bound paclitaxel plus carboplatin for advanced NSCLC in patients at risk of bleeding from VEGF directed therapies 3 II Ongoing phase III study Phase III study of albumin-bound paclitaxel + carboplatin vs paclitaxel + carboplatin for first-line advanced NSCLC 4 III Combination Therapy with Carboplatin and Bevacizumab Phase II study albumin-bound paclitaxel + carboplatin + bevacizumab for treatment of advanced NSCLC 5 II Combination with carboplatin and radiotherapy A phase I study of albumin-bound paclitaxel with carboplatin and thoracic radiation in patients with locally advanced NSCLC 6 I Summary of Albumin-Bound Paclitaxel Combination Therapy Studies in Non-small Cell Lung Cancer NSCLC, non-small cell lung cancer 1.Allerton et al. ASCO Socinski et al. J Thoracic Oncol Bertino et al. ASCO Socinski et al. ASCO Reynolds et al. J Thoracic Oncol Keedy et al. ASCO. 2010

3 Albumin-Bound Paclitaxel in Non-small Cell Lung Cancer Combination Therapy with Carboplatin

4 A Phase II Evaluation of the Combination of Albumin-Bound Paclitaxel and Carboplatin in the First-line Treatment of Advanced Non-Small Cell Lung Cancer J.P. Allerton, C.T. Hagenstad, R.T. 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. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

5 The Belani et al. study of solvent-based paclitaxel followed by carboplatin in the treatment of patients with advanced non- small cell lung cancer (NSCLC) 1 : –Twenty-eight day cycle –Solvent-based paclitaxel 100 mg/m 2 administered on Days 1, 8, and 15 –Carboplatin AUC = 6 administered on Day 1 only –Favorable therapeutic index in 390 evaluable patients in comparison to other dosing schedules Albumin-bound paclitaxel has shown a clinical advantage over solvent-based paclitaxel in patients with metastatic breast cancer 2-4 Primary objective: to determine the antitumor activity of the combination of albumin-bound paclitaxel and carboplatin in patients with advanced, previously-untreated NSCLC Secondary objective: to describe the side effects and safety profile 1. Belani et al, J Clin Oncol, Gradishar et al, J Clin Oncol, Ibrahim et al, J Clin Oncol, Ibrahim et al, Clin Cancer Res, 2002 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Study Rationale and Objectives NSCLC, non-small cell lung cancer; AUC, area under the curve Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

6 Open-label, phase II study Twenty-eight day treatment cycle –Albumin-bound paclitaxel 100 mg/m 2 intravenously over 30 minutes Days 1, 8, and 15 –Carboplatin AUC = 6 over 30 minutes Day 1 only Primary endpoints –Overall response rate (ORR) Secondary endpoints –Response duration –Time to progression (TTP) –Adverse events (AEs) First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Study Endpoints NSCLC, non-small cell lung cancer; AUC, area under the curve Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

7 Key inclusion criteria –Inoperable stage IIIB or IV NSCLC –Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥ 2 at screening and on the first day of treatment –Life expectancy > 12 weeks –Blood counts Neutrophils > 1500/mm 3 Platelets > 100,000/mm 3 –Clinical chemistry/liver function tests (normal limit defined by institution) Key exclusion criteria –Grade 2 or greater peripheral neuropathy First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Patient Eligibility Criteria NSCLC, non-small cell lung cancer Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

8 Baseline characteristic (N = 56)n (%) Median age, years (range)66 (37-83) Male sex39 (70) Disease stage, n Stage IIIB Stage IV Median ECOG performance score1 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Select Patient Demographics Forty-two of 56 (75%) patients in this study had stage IV disease The median age was 66 years Seventy percent of patients were male NSCLC, non-small cell lung cancer ECOG, Eastern Cooperative Oncology Group Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

9 Six of 56 patients removed from study after < 2 cycles due to: –Death due to progression (n = 3) –Adverse events Thrombocytopenia (n = 1) Neutropenia (n = 1) –Therapy refused (n = 1) Fifty patients evaluable –Twelve with stage IIIB –Thirty-eight with stage IV Six patients experienced progressive disease A total of 258 cycles were administered; 228 (88%) were at the full planned dose of albumin-bound paclitaxel First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

10 ORR: 25/50 patients (50%) –One patient had a complete response (CR) –Twenty-four patients exhibited partial responses (PR) Stable disease ≥ 12 weeks: 18/50 patients Median TTP: 28 weeks First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results TTP, time to tumor progression Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

11 Median TTP: 28 weeks Maximum follow-up: 39 weeks First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: TTP TTP, time to tumor progression Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006 Albumin-bound paclitaxel (N = 43)

12 Grade 3/4 adverse event (n = 50)n (%) Neutropenia24 (44) Thrombocytopenia14 (25) Anemia5 (9) Neuropathy1 (2) Arthralgia0 Myalgia0 Nausea1 (2) Vomiting1 (2) Diarrhea0 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Safety: Adverse Events Twenty-four patients (44%) experienced grade 3/4 neutropenia Grade 3/4 neuropathy occurred in 14 patients (25%) Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

13 Based on preliminary safety data, the protocol was amended to increase the weekly albumin-bound paclitaxel dose (9/2005) –Twenty-eight day cycle Albumin-bound paclitaxel 125 mg/m 2 IV over 30 minutes –Days 1, 8, and 15 Carboplatin AUC = 6 over 30 minutes –Day 1 only Forty patients enrolled –Median age: 65 years (range 47-82) –Thirteen women; 26 men Thirty-two patients evaluable –Stage IIIB: n = 3 –Stage IV: n = 29 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Protocol Amendment: 125 mg/m 2 AUC, area under the curve Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006

14 Data cutoff was October 10, 2006 Overall response: 12/40 patients (30%, 95% CI 17-46%) –Complete response: n = 2 –Partial response: n = 10 Stable disease ≥ 12 weeks: 15/40 patients Median projected TTP = 30 weeks Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Amended Protocol CI, confidence interval; TTP, time to tumor progression

15 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006 Adverse event (N = 40)Grade 3, n (%)Grade 4, n (%) Neutropenia7 (18)12 (30) Neuropathy3 (8)1 (3) First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Safety: Amended Protocol Grade 4 neutropenia occurred in 12/40 (30%) patients

16 Combining albumin-bound paclitaxel and carboplatin is tolerable and active in the treatment of advanced, newly diagnosed NSCLC Results of this study compare favorably to previously reported results with solvent-based paclitaxel and carboplatin in a study of similar design 1 1) Belani et al, J Clin Oncol, 2003 Allerton JP et al. Presented at ASCO Annual Meeting 2006; Abs 7127 Greco FA et al. Presented at Chemotherapy Foundation Symposium 2006 First-Line Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Conclusions NSCLC, non-small cell lung cancer

17 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 et al. J Thorac Oncol Jun;5(6):

18 Solvent-based paclitaxel 175–225 mg/m 2 every-3-week (q3w) combined with carboplatin AUC = 6 demonstrated a 17% to 32% overall response rate (ORR) in patients with advanced non-small cell lung cancer (NSCLC) 1-4 In a phase I/II study with a similar patient population, weekly albumin-bound paclitaxel alone as monotherapy demonstrated a 30% ORR and an overall survival (OS) of 11 months 5 This study presents the final efficacy and safety results of weekly or q3w albumin-bound paclitaxel combined with carboplatin AUC = 6 q3w as first-line therapy for patients with advanced NSCLC 1. Kelly et al. JCO Lilenbaum et al. JCO Scagliotti et al. JCO Schiller et al. NEJM Rizvi et al. JCO Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Study Rationale AUC, area under the curve

19 To identify the optimal dose of albumin-bound paclitaxel plus carboplatin AUC = 6 q3w as first-line therapy in patients with advanced NSCLC Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Study Objective AUC, area under the curve; q3w, every-3- weeks; NSCLC, non-small cell lung cancer

20 Treatment –Open-label, multicenter, phase II study –Sequential enrollment in escalating dose cohorts of 25 patients –Patients received q3w or weekly albumin-bound paclitaxel followed by q3w carboplatin AUC = 6 as first-line treatment Q3W Weekly (Days 1, 8 every 21 days) Weekly (Days 1, 8, 15 every 21 days) Cohort mg/m 2 Cohort mg/m 2 Cohort mg/m 2 Cohort mg/m 2 Cohort mg/m 2 Cohort mg/m 2 Cohort mg/m 2 Albumin-bound paclitaxel doses and schedules Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Study Design AUC, area under the curve; q3w, every-3- weeks

21 Primary endpoint: Complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) Secondary endpoints: –Disease control rate (DCR) –Progression-free survival (PFS) –Overall survival (OS) –Safety Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Objectives

22 Key inclusion criteria –≥ 18 years old –Previously untreated –Histologically or cytologically confirmed advanced NSCLC with pleural effusion or evidence of inoperable local recurrence or metastasis (stages IIIB and IV) –Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Key exclusion criteria –Peripheral neuropathy, grade > 1 –Other concurrent malignancy –History of allergy or hypersensitivity to either of the study drugs –Brain metastases NSCLC, non-small cell lung cancer Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Patient Eligibility Criteria

23 *Poorly differentiated or non-differentiated NSCLC; ECOG, Eastern Cooperative Oncology Group; q3w, every-3-week Socinski et al. J Thorac Oncol Jun;5(6): Baseline characteristic (N = 175) Q3WWeekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) Mean age (years) Men, n (%)23 (92)18 (72)17 (68)20 (80)22 (88)21 (84)20 (80) Histology, n (%) Adenocarcinoma Squamous cell Large cell Other* 8 (32) 11 (44) 1 (4) 5 (20) 7 (28) 18 (72) 0 9 (36) 14 (56) 0 2 (8) 7 (28) 16 (64) 2 (8) 0 (0) 10 (40) 15 (60) 0 (0) 9 (36) 16 (64) 0 13 (52) 10 (40) 0 2 (8) ECOG, n (%) (4) 24 (96) 0 25 (100) 3 (12) 22 (88) 7 (28) 18 (72) 5 (20) 20 (80) 4 (16) 21 (84) 3 (12) 22 (88) Disease stage, n (%) IIIB IVB 10 (40) 15 (60) 8 (32) 17 (68) 4 (16) 21 (84) 3 (12) 22 (88) 4 (16) 21 (84) 4 (16) 21 (84) 7 (28) 18 (72) First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Baseline Patient Characteristics

24 *DCR = CR + PR + SD ≥ 16 wks ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; PFS, progression- free survival; OS, overall survival; CI, confidence interval; q3w, every-3-week Socinski et al. J Thorac Oncol Jun;5(6): Clinical response (N = 175) Q3WWeekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) ORR, n (%) 95% CI 10 (40) (24) (24) (32) (56) (48) (36) CR, n (%)0 (0)1 (4)0 (0) 1 (4) PR, n (%)10 (40)5 (20)6 (24)8 (32)14 (56)11 (44)8 (32) SD ≥ 16 wks, n (%)5 (20)8 (32)3 (12)0 (0)2 (8) 3 (12) DCR* 95% CI 15 (60) (56) (36) (32) (64) (56) (48) PFS, months 95% CI OS, months 95% CI > >18.4 First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Efficacy

25 Median PFS ranged from 4.8 to 6.9 months in the q3w cohorts and 5.6 to 6.4 months in the weekly cohorts Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: PFS PFS, progression-free survival; q3w, every- 3-weeks Months Proportion Not Progressed Months Proportion Not Progressed 225 mg/m 2 (c1, n = 25) 260 mg/m 2 (c2, n = 25) 300 mg/m 2 (c3, n = 25) 340 mg/m 2 (c4, n = 25) 140 mg/m 2 (c5, n = 25) 100 mg/m 2 (c6, n = 25) 125 mg/m 2 (c7, n = 25)

26 Median OS ranged from 8.3 to 14.6 months in the q3w cohorts and from 11.3 to 15.0 months in the weekly cohorts Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: OS OS, overall survival; q3w, every-3-weeks 140 mg/m 2 (c5, n = 25) 100 mg/m 2 (c6, n = 25) 125 mg/m 2 (c7, n = 25) Months Months Probability of Survival 225 mg/m 2 (c1, n = 25) 260 mg/m 2 (c2, n = 25) 300 mg/m 2 (c3, n = 25) 340 mg/m 2 (c4, n = 25)

Albumin-Bound Paclitaxel Doses and Schedules Socinski et al. J Thorac Oncol Jun;5(6): *DCR = CR + PR + SD ≥16 wks; ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; CI, confidence interval; q3w, every-3-weeks Clinical response (N = 175) Q3WWeekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) ORR, n (%) 95% CI 5 (45) (28) (36) (38) (53) (31) (30) CR, n (%)01 (6)00000 PR, n (%)5 (45)4 (22)5 (36)6 (38)8 (53)5 (31)3 (30) SD ≥ 16 wks, n (%) 2 (18)6 (33)1 (7)0 1 (6)1 (10) DCR* 95% CI 7 (64) (61) (43) (37) (60) (38) (40) PFS, months 95% CI OS, months 95% CI > First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Efficacy (Squamous Cell Carcinoma)

28 Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Efficacy Stratified by Histologic Status q3w, every-3-weeks; NS, not statistically significant Non-squamous Squamous ORR, overall response rate; PFS, progression-free survival N/S P = 0.003P = P = 0.014N/S

29 Socinski et al. J Thorac Oncol Jun;5(6): Grade 3/4 adverse event occurring in ≥ 5% of patients (N = 175) Q3W Weekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) Neutropenia Grade 3 Grade 4 8 (32) 9 (36) 6 (24) 9 (36) 3 (12) 7 (28) 5 (20) 8 (32) 11 (44) 9 (36) 7 (28) 8 (32) Leukocytopenia Grade 3 Grade 4 8 (32) 1 (4) 6 (24) 0 (0) 7 (28) 0 (0) 9 (36) 1 (4) 12 (48) 0 (0) 6 (24) 0 (0) 5 (20) 1 (4) Neuropathy Grade 3 Grade 4 3 (12) 0 (0) 4 (16) 0 (0) 6 (24) 0 (0) 12 (48) 0 (0) 2 (8) 0 (0) 2 (8) 0 (0) 4 (16) 0 (0) Fatigue Grade 3 Grade 4 3(12) 0 (0) 1 (4) 0 (0) 4 (16) 0 (0) 3 (12) 0 (0) 1 (4) 0 (0) 4 (16) 0 (0) Thrombocytopenia Grade 3 Grade 4 7 (28) 3 (12) 5 (20) 1 (4) 5 (20) 2 (8) 5 (20) 1 (4) 5 (20) 3 (12) 4 (16) 1 (4) 5 (20) 4 (16) Anemia Grade 3 Grade 4 4 (16) 1 (4) 6 (24) 0 (0) 3 (12) 1 (4) 2 (8) 1 (4) 4 (16) 1 (4) 4 (16) 0 (0) 10 (40) 1 (4) Myalgia Grade 3 Grade 40 1 (4) 0 6 (24) 0000 Arthralgia Grade 3 Grade 40 1 (4) 0 1 (4) 0 2 (8) 0000 First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Select Adverse Events q3w, every-3-weeks

30 Peripheral neuropathy was the most common nonhematologic treatment- related AE: 118 (67%) patients –All grades: 80 (80%) in the q3w cohorts and 38 (51%) in the weekly cohorts –Grade 3: 25 (25%) in the q3w cohorts and 8 (11%) in the weekly cohorts Time to improvement defined as time from first occurrence of grade 3 to improvement to at least grade 2. Patients were followed for 30 days from time of most recent occurrence. CI, confidence interval; q3w, every-3-weeks Socinski et al. J Thorac Oncol Jun;5(6): Improvement in treatment-related peripheral neuropathy (n = 118) Q3WWeekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) Improved to grade ≤ 2, n (%) 2 (67)4 (100)2 (33)7 (58)1 (50)2 (100)1 (25) Median time to improvement, days* > > % CI > > > >24.0 First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Peripheral Neuropathy Improvement AE, adverse event

31 Socinski et al. J Thorac Oncol Jun;5(6): *DCR = CR + PR + SD ≥ 16 weeks ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate; PFS, progression- free survival; OS, overall survival; CI, confidence interval Clinical response (N = 175) Q3WWeekly (D1, 8)Weekly (D1, 8, 15) C1 225 mg/m 2 (n = 25) C2 260 mg/m 2 (n = 25) C3 300 mg/m 2 (n = 25) C4 340 mg/m 2 (n = 25) C5 140 mg/m 2 (n = 25) C6 100 mg/m 2 (n= 25) C7 125 mg/m 2 (n = 25) ORR, n (%) 95% CI 4 (44) (14) (11) (22) (60) (78) (46) CR, n (%) (11)1 (8) PR, n (%)4 (44)1 (14)1 (11)2 (22)6 (60)6 (67)5 (38) SD ≥ 16 wks, n (%) 1 (11)2 (29)2 (22)01 (10)1 (11)1 (8) DCR* 95% CI 5 (56) (43) (33) (22) (70) (89) (54) PFS, months 95% CI OS, months 95% CI > > > > > >18.4 First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Results: Efficacy (Non-Squamous Cell Carcinoma) NSCLC, non-small cell lung cancer

32 The albumin-bound paclitaxel and carboplatin combination demonstrated efficacy across treatment regimens and was well tolerated Based on descriptive statistics, weekly treatments with albumin- bound paclitaxel demonstrated improved clinical outcomes compared with q3w regimens Patients receiving weekly treatment with albumin-bound paclitaxel vs q3w experienced fewer incidences of peripheral neuropathy, alopecia, myalgia, and arthralgia Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Conclusions q3w, every-3-weeks

33 Incidence of peripheral neuropathy was lowest in the 100 mg/m 2 and 140 mg/m 2 weekly arms –In the 100 mg/m 2 arm, all severe neuropathy cases improved to grade 2 or better within 15.5 days The 100 mg/m 2 weekly arm demonstrated the optimal combination of safety and efficacy As a result, a phase III, randomized, multicenter study comparing 100 mg/m 2 albumin-bound paclitaxel weekly and carboplatin AUC = 6 q3w to solvent-based paclitaxel and carboplatin has been initiated Socinski et al. J Thorac Oncol Jun;5(6): First-Line Sequential Albumin-Bound Paclitaxel and Carboplatin in Advanced NSCLC Conclusions (cont.)

34 Phase II Trial of Albumin-Bound Paclitaxel Plus Carboplatin for Advanced NSCLC in Patients at Risk of Bleeding From VEGF-Directed Therapies E.M. Bertino, M.A. Villalona-Calero, S.P. Nana-Sinkam, A.M. Ghany, K. Donthireddy, N.A. Karim, S. Cantrell, M. Rahmani, G.S. Phillips, G.A. Otterson Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291

35 Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers diagnosed In advanced NSCLC, a platinum-based doublet remains the standard of care for front-line therapy Bevacizumab, an anti-angiogenic agent, is approved for use in first-line therapy of advanced NSCLC in combination with chemotherapy The addition of bevacizumab results in improved response rates and survival, but pulmonary hemorrhage is a significant toxicity In phase II/III clinical trials, an increased risk of life-threatening or fatal bleeding was identified in patients with squamous histology 1,2 Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Background 1. Johnson et al. JCO Sandler et al. NEJM VEGF, vascular endothelial growth factor

36 Theoretical safety concerns also exist for patients with brain metastases and those on anticoagulation therapy, although recent trials have not identified increased risk 1,2 At this time, patients with squamous histology and/or hemoptysis are excluded from bevacizumab therapy due to increased bleeding risk Albumin-bound paclitaxel is a novel formulation, composed of a nanometer-sized albumin bound to a paclitaxel particle The albumin particle improves intracellular transport of the paclitaxel molecule into tumor cells, as demonstrated by in vivo murine tumor models 5,6 Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Background (cont.) 1. Reck et al. JCO Socinski et al. JCO Rizvi et al. JCO Reynolds et al J Thorac Oncol 2009 NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

37 The albumin-bound formulation also demonstrates higher dose tolerability and decreased hypersensitivity reactions In NSCLC patients, albumin-bound paclitaxel was safe and effective in phase I/II studies, producing 16-30% response rates (RR) 7-9 A recent phase II trial evaluated carboplatin, albumin-bound paclitaxel, and bevacizumab in non-squamous NSCLC with promising results: toxicity was tolerable and partial response rate was 31% with a median survival of 16.8 months 10 Similarly, it was recently announced that a phase III trial comparing albumin-bound paclitaxel plus carboplatin to paclitaxel plus carboplatin in advanced NSCLC met its primary endpoint of improved ORR Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Background (cont. 2) NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; ORR, overall response rate

38 The combination of albumin-bound paclitaxel and carboplatin in patients with advanced NSCLC who are not eligible for bevacizumab therapy may have superior efficacy and tolerability compared with the standard approach of a platinum agent plus a third generation non-platinum agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Hypothesis NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

39 Phase II, single arm, non-randomized, 2-stage Simon model –First stage: 27 patients –Second stage: 36 patients Treatment plan –Albumin-bound paclitaxel 300 mg/m 2 and carboplatin AUC = 6 on Day 1 of a 21-day cycle for up to 6 cycles Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Study Design NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

40 Inclusion criteria –Adults with advanced NSCLC (stage IIIB with pleural effusion, stage IV, or recurrent) who are ineligible for bevacizumab therapy due to: Squamous histology Thrombotic or embolic events within 6 months History of hemoptysis (controlled, non-life threatening) Cavitary lung lesions Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Select Patient Inclusion Criteria NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

41 Exclusion criteria –Prior treatment for advanced NSCLC –Pre-existing neuropathy ≥ grade 2 –Uncontrolled brain metastases –Major surgery within 4 weeks of study drug –Non-healing wounds –Uncontrolled cardiac dis ease –HIV or hepatitis B or C Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Select Patient Exclusion Criteria NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

42 Primary endpoint: –Overall response rate (complete and partial responses) –A response rate of at least 35% will be considered acceptable for further study of this combination Secondary endpoints: –Evaluation of safety/toxicity –Overall and progression-free survival –Tumor SPARC expression (exploratory) –Serum micro RNA expression profiles (exploratory) Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Trial Endpoints NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; SPARC; secreted protein acidic and rich in cysteine

43 Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Baseline characteristic (N = 35)n (%) Mean age, years (range)63.9 (36-82) Caucasian, %82.8 Tobacco use, mean pack years (min, max) 46.4 (4, 150) Histology, n Squamous Adenocarcinoma Adenosquamous Poorly differentiated Large cell Eligibility criteria, n Hemoptysis Squamous histology Thrombotic event Anticoagulation Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Study Population NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor Twenty-three patients (66%) had squamous histology, while 12 patients (34%) had non-squamous histology

44 Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Adverse event (n = 35)Grade 3 (%)Grade 4 (%) Hematologic Anemia Neutropenia Thrombocytopenia Neurologic Sensory neuropathy Motor neuropathy Confusion Seizure Muscle weakness Infectious Neutropenic fever/infection Infection without neutropenia Metabolic Alkalosis Hyperglycemia Hypokalemia Hyponatremia Hypophosphatemia Hypermagnesemia Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Safety: Adverse Events (AEs) NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

45 Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Adverse event (n = 35)Grade 3 (%)Grade 4 (%) Pulmonary Hypoxia Respiratory failure Airway obstruction Dyspnea Pulmonary hemorrhage Bronchospasm/wheezing Cardiac Hypertension Hypotension Gastrointestinal Dehydration Diarrhea Nausea Renal Renal failure33 Other Anorexia Fatigue Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies Safety: Adverse Events (AEs) NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

46 1. Gradishar WJ, et al. J Clin Oncol 2005;23: Nyman DW, et al. J Clin Oncol 2005;23: Green MR, et al. Ann Oncol 2006;17: Stinchcombe TE, et al. Cancer Chemother Pharmacol 2007;60: Rizvi NA, et al. J Clin Oncol 2008;26: Reynolds CD, et al. J Thorac Oncol 2009;4: Bertino et al. Presented at ASCO Annual Meeting, 2010; Abstract #TPS291 Albumin-Bound Paclitaxel + Carboplatin in NSCLC Patients at Risk of Bleeding from VEGF-Directed Therapies References NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor

47 Results of a Randomized, Phase III Trial of Albumin-bound Paclitaxel Plus Carboplatin Compared With Cremophor-based Paclitaxel Plus 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, J. Iglesias Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.

48 Platinum-based doublets have reached a therapeutic plateau in advanced NSCLC Paclitaxel plus carboplatin produces 15-25% overall response and survival outcomes comparable to all other doublets 1-3 The solvent polyoxyethylated castor oil (cremophor) decreases efficacy and contributes to the toxicities observed with paclitaxel including hypersensitivity reactions and neuropathy Albumin-bound paclitaxel has been shown to be more efficacious than solvent-based paclitaxel in MBC 4 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Background NSCLC, non-small cell lung cancer; MBC, metastatic breast cancer 1. Kelly Sandler Schiller Gradishar et al. JCO. 2005

49 Albumin-bound paclitaxel leverages the gp60 / caveolin-1 / SPARC transcytosis pathway to establish a portal to the tumor microenvironment resulting in high intratumoral drug concentration 1 Overexpression of caveolin-1 and SPARC occurs in NSCLC and is associated with poor prognosis 2-4 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Rationale 1. Desai et al Yoo et al Chin et al Koukorakis et al NSCLC, non-small cell lung cancer; SPARC, secreted protein acidic and rich in cysteine

50 A 7-arm trial investigated the safety and efficacy of albumin- bound paclitaxel plus carboplatin at both weekly and q3w dosing schedules: –Weekly albumin-bound paclitaxel (100 mg/m 2 D1, 8, 15) plus carboplatin AUC = 6 q3w demonstrated optimal therapeutic index Overall response rate = 48% Median PFS = 6.2 months Median OS = 11.3 months Grade 3/4 toxicities: neutropenia 64%, neuropathy 8%, thrombocytopenia 20%, anemia 16% Based on the phase II results, a phase III trial was designed to investigate the efficacy / safety of albumin-bound paclitaxel plus carboplatin vs paclitaxel plus carboplatin as first-line therapy in advanced NSCLC Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Background NSCLC, non-small cell lung cancer; q3w, every-3-weeks; AUC, area under the curve; PFS, progression-free survival; OS, overall survival 1. Socinski et al. JTO. 2010

51 Stratification factors: Stage (IIIb vs IV) Age ( 70) Sex Histology (squamous vs nonsquamous) Geographic region Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Study Design NSCLC, non-small cell lung cancer; PS, Eastern Cooperative Oncology Group performance status; AUC, area under the curve Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 Albumin-bound paclitaxel 100 mg/m 2 d1, 8 15 Carboplatin AUC 6 d1 No Premedication n = 525 Albumin-bound paclitaxel 100 mg/m 2 d1, 8 15 Carboplatin AUC 6 d1 No Premedication n = 525 Paclitaxel 200 mg/m 2 d1 Carboplatin AUC 6 d1 With Premedication of Dexamethasone + Antihistamines n = 525 Paclitaxel 200 mg/m 2 d1 Carboplatin AUC 6 d1 With Premedication of Dexamethasone + Antihistamines n = 525 1:1 Randomization

52 Primary endpoints: –Objective response rate by independent radiologic review based on RECIST Complete + partial responses (CR, PR) Secondary endpoints: –Progression-free and overall survival –Disease control rate: CR + PR + stable disease (SD) ≥ 16 weeks –Safety (based on the National Cancer Institute’s common terminology criteria for adverse events [CTCAE] version 3) Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Study Endpoints NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors

53 Major inclusion criteria –Adult patients with histologically / cytologically confirmed stage IIIB/IV NSCLC –ECOG performance status of 0 or 1 –Measurable disease by RECIST –Adequate hematologic, hepatic, and renal function Major exclusion criteria –Prior treatment for metastatic disease (adjuvant therapy was allowed if it was > 1 year prior to study entry) –Active brain metastases (treated, controlled metastases allowed) –Baseline peripheral neuropathy > grade 2 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Selected Patient Eligibility Criteria NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors; ECOG, Eastern Cooperative Oncology Group

54 Objective response rate of paclitaxel plus carboplatin therapy in ECOG 1594 = 17% Based on the activity of albumin-bound paclitaxel in MBC, a relative improvement of ~40% for albumin-bound paclitaxel plus carboplatin over paclitaxel plus carboplatin was assumed –The predicted overall response rate would, therefore, be 24% Based on this assumption, 525 patients in each arm provides 80% power with a two-sided type I error of to reject the null hypothesis Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Statistical Considerations NSCLC, non-small cell lung cancer; MBC, metastatic breast cancer; ECOG, Eastern Cooperative Oncology Group

55 Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Patient Accrual US 12% (25 sites) Russia 45% (29 sites) Australia1% (5 sites) Japan14% (21 sites) Canada 4% (6 sites) Ukraine 24% (16 sites) Planned enrollment: from Dec to Aug 1, 2009 Actual enrollment: from Dec to July 14, 2009 Planned follow-up: 18 months # of patients enrolled: 1052 # of patients evaluable for efficacy: 1052 # of patients evaluable for toxicity: 1038 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511.

56 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Baseline characteristic AB-P/C (n = 521)P/C (n = 531)All patients (N = 1052) Median age, years (range) < 70 years, n (%) ≥ 70 years, n (%) 60 (28, 81) 448 (86) 73 (14) 60 (24, 84) 449 (85) 82 (15) 60 (24, 84) 897 (85) 155 (15) Female sex, n (%)129 (25)134 (25)263 (25) ECOG, n (%) (26) 385 (74) 113 (21) 416 (78) 246 (23) 801 (76) Histology of primary diagnosis, n (%)* Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Other 254 (49) 228 (44) 9 (2) 29 (6) 264 (50) 221 (42) 13 (2) 33 (6) 518 (49) 449 (43) 22 (2) 62 (6) Stage at current diagnosis, n (%)* Stage III Stage IV 99 (19) 421 (81) 107 (20) 424 (80) 206 (20) 845 (80) Prior chemotherapy, n (%)12 (2)8 (2)20 (2) Smoking status, n (%) Never smoked Smoked and quit Smoked and still smokes (27) 165 (32) 210 (41) (28) 146 (28) 231 (44) (27) 311 (30) 441 (43) Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Baseline Patient Characteristics * Data were missing for 1 patient at the time of this analysis AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin; ECOG, Eastern Cooperative Oncology Group NSCLC, non-small cell lung cancer

57 Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Results: Patient Responses, All Histologies NSCLC, non-small cell lung cancer; AB- P/C; albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin Response Ratio = 1.31 (1.082 – 1.593) P = Response Ratio = 1.26 (1.060 – 1.496) P = (n = 521) (n = 531)) Percent Responses

58 SquamousNonsquamous * Not a pre-specified endpoint Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Results: Patient Responses by Histologic Stratification Percent Responses P < 0.001P = 0.060P = 0.808P = n = 228n = 221n = 292n = 310 NSCLC, non-small cell lung cancer; AB- P/C; albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin

59 There was no limitation on the number of cycles Patients in the albumin-bound P/C arm received a higher median dose intensity Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Treatment characteristic AB-P/C (n = 514) P/C (n = 524) Taxane dose intensity (mg/m 2 /wk) Median (min, max)83 (26.7, 102.9)66 (32.9, 88.9) Cycles administered Median (min, max)6 (1, 17)6 (1, 22) Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Results: Dose Characteristics NSCLC, non-small cell lung cancer AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin

60 *Favors albumin-bound P/C; ** Favors P/C AB-P/C, albumin-bound paclitaxel plus carboplatin; P/C, paclitaxel plus carboplatin Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Adverse event, % AB-P/C (n = 521) P/C (n = 531) P value Grade 3Grade 4Grade 3Grade 4 Hematologic Neutropenia Thrombocytopenia Anemia Febrile neutropenia < < < * <.001** NS Nonhematologic Fatigue Sensory neuropathy Anorexia Nausea Myalgia < < 1 2 < 1 0 < 1 0 NS <.001* NS.011* Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Safety NSCLC, non-small cell lung cancer

61 In this phase III randomized trial, albumin-bound paclitaxel plus carboplatin demonstrated a statistically significant higher response rate than paclitaxel plus carboplatin (33% vs 25%, P <.001) The response rate in the squamous cell subset was 41% in the albumin-bound paclitaxel plus carboplatin arm vs 24% in the paclitaxel plus carboplatin arm (P <.001) Albumin-bound paclitaxel plus carboplatin was well tolerated and associated with less sensory neuropathy, myalgia, and neutropenia than paclitaxel plus carboplatin Albumin-bound paclitaxel plus carboplatin was associated with more anemia and thrombocytopenia than paclitaxel plus carboplatin Progression-free survival analysis is planned for later this year Socinski et al. Presented at ASCO 2010; Abstract #LBA7511. Albumin-Bound Paclitaxel + Carboplatin vs. Cremophor- Paclitaxel + Carboplatin in Advanced NSCLC Conclusions NSCLC, non-small cell lung cancer

62 Albumin-Bound Paclitaxel in Non-small Cell Lung Cancer Combination Therapy with Carboplatin and Bevacizumab

63 An Open-Label, Phase II Trial of Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in First-Line Patients With Advanced Non- Squamous Non-small Cell Lung Cancer C. Reynolds, D. Barrera, D. Q. Vu, R. Jotte, A. I. Spira, C. H. Weissman, K. A. Boehm, D. Ilegbodu, S. Pritchard, L. Asmar Reynolds et al. J Thoracic Onc. 2009;4(12):

64 The development of albumin-bound paclitaxel has circumvented many of the infusion difficulties that are associated with standard solvent-based paclitaxel In this phase II trial, patients with advanced (stage IIIB or IV) non-small cell lung cancer (NSCLC) received the combination of albumin-bound paclitaxel, carboplatin and bevacizumab Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Study Rationale

65 Primary endpoint –Antitumor activity, based upon RECIST criteria Secondary endpoints –Time to disease progression (TTP) –Duration of response –Stable disease (SD) ≥16 weeks) –1- and 2-year survival –Changes in quality of life (QOL) –Safety Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Objectives RECIST, response evaluation criteria in solid tumors

66 Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Study Design CycleStudy daysCarboplatin Albumin-bound paclitaxelBevacizumab 1 1AUC = 6300 mg/m 2 15 mg/kg 2-21Rest 2 1AUC = 6300 mg/m 2 15 mg/kg 2-21Rest Open-label, single arm, phase II study carboplatin  albumin-bound paclitaxel  bevacizumab NSCLC, non-small cell lung cancer AUC, area under the curve

67 Key inclusion criteria –Histologically or cytologically confirmed advanced stage IIIB/IV non-squamous NSCLC with evidence of inoperable local recurrence or metastasis –Measurable disease as per RECIST criteria –No prior chemotherapy for the treatment of metastatic disease –Prior radiation therapy permitted; Measurable disease must not have been irradiated Prior irradiation of measurable disease permitted only if it had progressed since radiation therapy –Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 –Adequate renal, hepatic, and hematological function Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Patient Eligibility NSCLC, non-small cell lung cancer; RECIST, response evaluation criteria in solid tumors

68 Key exclusion criteria –Another concurrent active malignancy –Pre-existing peripheral neuropathy of NCI grade >1 –Creatinine clearance 1.0 at registration –Uncontrolled blood pressure > 150/100 mmHg –Unstable angina –Clinically significant cardiac disease, symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication, or myocardial infarction within the last 6 months Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Patient Eligibility (cont.) NSCLC, non-small cell lung cancer; NCI, National Cancer Institute

69 Key exclusion criteria (cont.) –Impaired pulmonary function –Clinically significant peripheral vascular disease –History of thrombosis or stroke within the past 6 months –History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 4 weeks –Uncontrolled coagulopathy –History of seizure activity –Current or recent use (within 2 weeks) of aspirin, anticoagulants or thrombolytic agents –Evidence of active brain metastasis Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Patient Eligibility (cont.) NSCLC, non-small cell lung cancer; NCI, National Cancer Institute

70 Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Select Patient Demographics Baseline characteristic (N = 50)n (%) Median age, years 67 (32-83) Female sex 28 (56) Histology Adenocarcinoma Bronchioalveolar Large cell NOS 43 (86) 1 (2) 4 (8) 2 (4) Prior surgery 19 (30) Prior radiation therapy 4 (8) Number of metastatic sites (38) 15 (30) 9 (18) 1 (2) Baseline ECOG performance status (52) 24 (48) NSCLC, non-small cell lung cancer NOS, not otherwise specified; ECOG, Eastern Cooperative Oncology Group

71 a Of 50 enrolled patients, 48 were treated, and 43 were evaluable. Two patients who enrolled were not treated; one patient withdrew consent before treatment and the other ineligible due to brain metastasis b Deaths were due to PD (26 patients, 87%), COPD, pulmonary embolus, pulmonary hemorrhage, and suicide (1 patient each) PR, partial response; SD, stable disease; PD, progressive disease; OS, overall survival Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Best Response After Treatment Treatment characteristic (n a = 43)n (%) PR 15 (35) SD ≥ 6 months < 6 months 26 (60) 11 (26) 15 (35) PD 2 (4.7) Not evaluated 5 (12) Clinical benefit rate (CR + PR + SD ≥ 6 months) 26 (60) Non-evaluable due to discontinuation 4 (9) Non-evaluable due to lack of baseline tumor value 1 (2.3) Reason for discontinuation Normal study completion Adverse event Investigator request PD Consent withdrawal or treatment refusal 17 (40) 16 (37) 1 (2.3) 11 (26) 5 (12) OS 20 (47) NSCLC, non-small cell lung cancer

72 Median PFS: 9.8 (Range, < Months) Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Median Progression-Free Survival NSCLC, non-small cell lung cancer; PFS, progression-free survival Median PFS: 9.8 (Range, < Months)

73 Median Survival Time: 16.8 (Range, < Months) Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Median Time to Tumor Progression NSCLC, non-small cell lung cancer

74 Median Survival Time: 16.8 (Range, < Months) Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Median Overall Survival NSCLC, non-small cell lung cancer

75 Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Safety Grade 3/4 adverse event occurring in ≥ 1 patient (n a = 48)All grades (%)Grade 3 (%)Grade 4 (%) Neutropenia 26 (54.2)8 (16.7)18 (37.5) Thrombocytopenia 5 (10.4)4 (8.3)1 (2.1) Leukopenia 2 (4.2) 0 Fatigue 8 (16.7)6 (12.5)2 (4.2) Febrile neutropenia 5 (10.4)3 (6.3)2 (4.2) Neuropathy 5 (10.4) 0 Constipation 3 (6.3) 0 Anorexia 2 (4.2) 0 Diarrhea 2 (4.2) 0 Peripheral neuropathy2 (4.2) 0 a Number of treated patients Grade 3/4 neutropenia occurred in 26/48 (54%) patients Grade 3 neuropathy in 5/28 (10%) patients (no grade 4) NSCLC, non-small cell lung cancer

76 Although response rate in this study was similar to that previously reported for combination therapy for advanced NSCLC, the PFS and OS results were higher than previously reported in patients with advanced NSCLC After completion of this study, 54% of patients went on to receive second-line therapy: 14% received pemetrexed, 8% received docetaxel, 6% received paclitaxel, and 6% received the combination of carboplatin and paclitaxel Subsequent trials have shown that pemetrexed may be particularly active in non-squamous NSCLC, which may have contributed to the positive OS results observed in this trial; however, the prolonged PFS observed suggests that some of the benefit was likely derived from the combination therapy used in this trial Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Conclusions NSCLC, non-small cell lung cancer; PFS, progression-free survival; OS, overall survival

77 In this study, toxicity was generally acceptable; the low incidence of grade 3 peripheral neuropathy and the absence of any obvious exacerbation of chemotherapy-induced myelosuppression by the addition of bevacizumab to this regimen are particularly noteworthy Phase III evaluation of this combination would determine whether it is truly more efficacious than previous regimens The optimal dosing schedule of albumin-bound paclitaxel (weekly versus q3w) and the role of maintenance bevacizumab are important issues that should be addressed Reynolds et al. J Thoracic Onc. 2009;4(12): First-Line Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non-Squamous NSCLC Conclusions (cont.) NSCLC, non-small cell lung cancer; q3w, every- 3-week

78 The Effect of Adding Bevacizumab to Albumin-Bound Paclitaxel/Carboplatin Therapy for Patients With 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 et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612

79 Addition of bevacizumab to chemotherapy for advanced NSCLC patients improves survival and demonstrates the benefit of antiangiogenic therapy Mechanism of antitumor activity is still poorly understood Studies are needed to understand the mechanism of action and to identify biomarkers for the efficacy of bevacizumab in NSCLC patients Preliminary analyses of correlative studies are presented Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Background NSCLC, non-small cell lung cancer

80 Open-label phase II trial of carboplatin, albumin-bound paclitaxel, and bevacizumab All patients receive bevacizumab 15 mg/kg at day -14 Patients then receive carboplatin (AUC = 6) on day 1, albumin-bound paclitaxel (100 mg/m 2 ) on days 1, 8, and 15, and bevacizumab (15 mg/kg) on day 1 Planned enrollment: 36 Primary endpoint: 6-month PFS rate Secondary endpoints: safety, RR, OS Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Study Design NSCLC, non-small cell lung cancer; AUC, area under the curve; PFS, progression-free survival; RR, response rate; OS, overall survival

81 To examine the effect of bevacizumab monotherapy on tumor perfusion, as assessed by CT scan before and after single dose of bevacizumab To examine the effect of bevacizumab monotherapy on serum levels of angiogenic cytokines and circulating endothelial cells before and after single dose of bevacizumab To examine the relationship between tumor response and changes in tumor perfusion, as assessed by perfusion CT scan, before and after combination therapy with carboplatin, albumin-bound paclitaxel, and bevacizumab To examine the relationship between tumor response and changes in serum levels of angiogenic cytokines and circulating endothelial cells, before and after combination therapy with carboplatin, albumin-bound paclitaxel, and bevacizumab Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Correlative Study Endpoints CT, commuted tomography

82 Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Study Design BEV, bevacizumab 15 mg/kg; CAB, carboplatin AUC = 6, albumin-bound paclitaxel 100 mg /m 2, bevacizumab 15 mg/kg; CT, commuted tomography; FDG-PET, fludeoxyglucose positron emission tomography; CEC, circulating endothelial cells Day Day After After At Time of Cycle 2 Cycle 4 Progression BEVCAB BEV At each time point: perfusion CT, FDG-PET (except Day -2), CECs, angiogenic cytokines

83 Bevacizumab alone significantly decreased circulating CD34+ progenitor cells Bevacizumab alone significantly decreased soluble c-KIT Among those evaluable for response, blood flow at Day -2 correlated directly with best percentage change in RECIST Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Results: Correlative Findings RECIST, response evaluation criteria in solid tumors 1.0 CPC at Day -2 Relative to Day Day -14Day -2 P = c-KIT at Day -2 Relative to Day Day -14Day -2 Blood Flow after Bev [mL/min/100g] RECIST Change (%) Kendall's t p = 0.58, P = P = 0.033

84 Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Results: Correlative Findings RECIST, response evaluation criteria in solid tumors; FDG-PET, fludeoxyglucose positron emission tomography; SUV, standardized uptake value Contrast CT (RECIST) Baseline CT Perfusion Blood Flow FDG PET Post-Bevacizumab SUV 7.62 SUV 4.01 SUV 2.1 Post-Treatment Blood flow mL/100g/minBlood flow mL/100g/minBlood flow 7.59 mL/100g/min

85 Evaluation of imaging characteristics and tumor response is ongoing Preliminary analysis of 12 evaluable patients shows no definite correlation between RECIST change and change in blood flow Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Results: Correlative Findings RECIST, response evaluation criteria in solid tumors

86 Pharmacodynamic blood and imaging biomarker studies in bevacizumab-treated NSCLC patients are feasible, and preliminary data suggest they may predict for tumor response Enrollment and continued biomarker analyses are ongoing Heist et al. Presented at ASCO Annual Meeting, 2010; Abstract #7612 Albumin-Bound Paclitaxel, Carboplatin, and Bevacizumab in Advanced NSCLC Conclusions NSCLC, non-small cell lung cancer

87 Albumin-Bound Paclitaxel in Non-small Lung Cancer Combination Therapy with Carboplatin and Radiation

88 A Phase I Study of Albumin-Bound Paclitaxel With Carboplatin and Thoracic Radiation (TRT) in Patients With Locally Advanced NSCLC V. L. Keedy, B. Lu, Y. Shyr, L. Horn, D. P. Carbone, A. Sandler, D. H. Johnson Keedy et al. Abstract only, ASCO 2010; Abstract # e17504

89 One third of patients with non-small cell lung cancer (NSCLC) present with localized, unresectable disease Concurrent chemoradiotherapy (e.g. weekly paclitaxel + radiotherapy) is well established, with median survival ≈ 14 months Albumin-bound paclitaxel is a cremophor-free formulation of paclitaxel designed to improve solubility and intratumor delivery of active drug This phase I trial evaluates weekly albumin-bound paclitaxel + carboplatin + concurrent thoracic radiation (TRT) in patients with unresectable stage III NSCLC Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Background

90 Patients were enrolled in escalating dose cohorts in a design of albumin-bound paclitaxel weekly, beginning at 40 mg/m 2 and increasing by 20 mg/m 2, in combination with carboplatin (AUC = 2) weekly for 7 weeks and concurrent thoracic radiation therapy (TRT) at 66 Gy/33 fractions Patients received 2 cycles of consolidation therapy with full dose albumin-bound paclitaxel (100 mg/m 2 weekly for 3 weeks) plus carboplatin AUC = 6 on Day 1 of each cycle) every 21 days The dose-limiting toxicity (DLT) period is defined as the concurrent chemoradiation period Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Study Design

91 Eight patients have been treated at 2 dose levels of albumin- bound paclitaxel: –40 mg/m 2 –60 mg/m 2 One patient gave their consent and then withdrew it Seven patients have completed all cycles of therapy Three patients were treated at 40 mg/m 2 with no DLT reported The 40 mg/m 2 cohort is expanded and 1 patient remains on concurrent treatment Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Patient Dispositions DLT, dose-limiting toxicity

92 Four patients treated at 60 mg/m 2 had 2 grade 3 DLTs: –Radiation dermatitis –Esophagitis Grade 2-3 toxicities during concurrent treatment include: neutropenia, neutropenic fever, anemia, thrombocytopenia, fatigue, esophagitis, nausea, dermatitis, hypoxia, and dehydration No grade 4 toxicities have emerged during concurrent treatment Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Results: Safety DLT, dose-limiting toxicity

93 Seven patients are evaluable for response, and all 7 achieved partial responses –Three patients have progressed at 5, 7, and 8 months after enrollment –Four patients remain stable at 5, 7, 13, and 18 months Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Results: Efficacy

94 Weekly albumin-bound paclitaxel at 60 mg/m 2 exceeds the maximum tolerated dose, but appears to be safe and well tolerated at 40 mg/m 2 when used in combination with weekly carboplatin and TRT Enrollment in this cohort is ongoing Keedy et al. Abstract only, ASCO 2010; Abstract # e17504 Albumin-Bound Paclitaxel, Carboplatin, and Radiation in Locally-Advanced NSCLC Conclusions TRT, thoracic radiation therapy