1. 1 Albumin-Bound Paclitaxel for the Treatment of Non-small Cell Lung Cancer Monotherapy Studies

2. 2 TitlePhase Monotherapy Studies Phase II study of albumin-bound paclitaxel as first-line treatment in advanced NSCLC 1 II Phase I/II study of albumin-bound paclitaxel as first-line treatment in stage IV NSCLC 2 I/II Summary of Albumin-Bound Paclitaxel Monotherapy Studies in Non-small Cell Lung Cancer NSCLC, non-small cell lung cancer 1.Green et al. Ann Oncol. 2006 2.Rizvi et al. J Clin Oncol. 2008

3. 3 Albumin-Bound Paclitaxel, a Novel Cremophor ® -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 et al. Ann Oncol. 2006;17:1263-1268.

4. 4 Single agent solvent-based paclitaxel plays a central role in the treatment of advanced non-small cell lung cancer, but its use is limited due to poor solubility, toxicity, and long infusion time 1-3 Albumin-bound paclitaxel delivers paclitaxel as a suspension of albumin particles in saline, which obviates the need for Cremophor EL solvent and leads to reduced hypersensitivity and infusion time 4 In a phase III trial, albumin-bound paclitaxel 260 mg/m 2 was superior to paclitaxel 175 mg/m 2 q3w for the treatment of metastatic breast cancer 4 The current study explored the efficacy and safety of single agent albumin-bound paclitaxel in the treatment of advanced NSCLC Green et al. Ann Oncol. 2006;17:1263-1268. 1. Socinski et al. The Oncologist. 1999 2.Gelderblom et al. Eur J Cancer. 2001 3. nab-paclitaxel ® Prescribing Information 2010 4. Gradishar et al. JCO 2005 Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Study Rationale NSCLC, non-small cell lung cancer; q3w, every-3-week

5. 5 Intravenous albumin-bound paclitaxel 260 mg/m 2 over 30 minutes –Day 1, every-3-week (q3w) –Until disease progression or unacceptable toxicity Primary endpoint: –Percentage of patients who achieved complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumors (RECIST) Secondary objectives: –Time to tumor progression (TTP) –Overall survival (OS) –Number of objective responses –Disease control rate (DCR) –Safety/tolerability Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Study Design NSCLC, non-small cell lung cancer

6. 6 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 et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Key Eligibility Criteria NSCLC, non-small cell lung cancer

7. 7 Key exclusion criteria –Clinical evidence of brain metastasis –Serious concurrent illness –Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥ 2 –Peripheral neuropathy grade ≥ 2 –Prior radiotherapy Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Key Eligibility Criteria NSCLC, non-small cell lung cancer

8. 8 Forty-three patients with previously untreated stage IIIB or IV NSCLC enrolled at 6 centers in Russia –Median age: 58 –All patients eligible and evaluable (treated population) –Age < 65: n = 34 (79%) –Visceral disease: n = 36 (84%) –ECOG PS of 0 or 1: n = 43 (100%) –Total number of lesions One: n = 5 (12%) Two to 3: n = 13 (30%) > 3: n = 25 (58%) –Two patients (5%) had preexisting sensory neuropathy (grade 1) Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Select Patient Characteristics NSCLC, non-small cell lung cancer

9. 9 Green et al. Ann Oncol. 2006;17:1263-1268. a Other categories of NSCLC include large-cell carcinoma, undifferentiated NSCLC, and mixed squamous and adenocarcinoma b Includes responders + patients with stable disease ≥ 16 weeks ORR, overall response rate; CI, confidence interval Subgroup/variable (N = 43) Baseline, nResponding patients, n ORR, n (%; 95% CI)437 (16; 5.24-27.31) Response by histology a Confirmed overall response, n (%) Carcinoma/adenocarcinoma Squamous cell carcinoma Other 43 11 29 3 7 (16%) 1 5 1 Disease control, b n (%) Carcinoma/adenocarcinoma Squamous cell carcinoma Other 43 11 29 3 21 (49%) 5 14 2 Death, n (%) Carcinoma/adenocarcinoma Squamous cell carcinoma Other 43 11 29 3 23 (53%) 5 16 2 Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Results: Clinical Response NSCLC, non-small cell lung cancer

10. 10 Median TTP was 6 months (95% CI: 3.9-6.5, treated population) Probability of not having progressed was 50% at 6 months and 13% at 1 year Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Results: TTP NSCLC, non-small cell lung cancer; TTP, time to tumor progression; CI, confidence interval 1.00 0.75 0.50 0.25.0 03691215182124 Months Proportion not Progressed Albumin-bound paclitaxel (N = 43)

11. 11 Median survival was 11 months (95% CI: 9.5-16.2, treated population) The probability of surviving 1 year was 45% Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Results: OS NSCLC, non-small cell lung cancer; OS, overall survival; CI, confidence interval 1.00 0.75 0.50 0.25 0.00 03691215182124 Months Probability of Survival Albumin-bound paclitaxel (N = 43)

12. 12 Ninety-five percent of patients received albumin-bound paclitaxel at protocol-specified dose Ninety-eight percent of cycles were administered at full dose Dose reductions occurred in 2 patients (5%) –Elevated liver function test after cycle 4 (n = 1) –Peripheral neuropathy after cycle 6 (n = 1) Sixty-three percent of patients received at least 6 treatment cycles Two patients (5%) discontinued therapy due to treatment- related adverse events –Grade 3 neuropathy after cycle 7 (n = 1) –Grade 3 fatigue after cycle 2 (n = 1) Patient received 4 additional cycles after onset of fatigue Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Safety NSCLC, non-small cell lung cancer

13. 13 Green et al. Ann Oncol. 2006;17:1263-1268. Note: If a patient reported the same AE more than once, that patient was counted only once for that AE, using the highest grade a Based on central laboratory values AE, adverse event Adverse event reported in ≥ 10% of patients All grades (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) > 1 treatment-related AE40 (93)7 (16)24 (56)9 (21)0 Hematologic a Anemia Neutropenia Leukopenia Thrombocytopenia 32 (74) 21 (49) 10 (23) 6 (14) 24 (56) 9 (21) 7 (16) 6 (14) 8 (19) 3 (7) 0 4 (9) 0 00000000 Nonhematologic Alopecia Sensory neuropathy Arthralgia Fatigue Myalgia Fever 33 (77) 28 (65) 15 (35) 14 (33) 8 (19) 7 (16) 4 (9) 21 (49) 10 (23) 3 (7) 5 (12) 2 (5) 29 (67) 5 (12) 4 (9) 8 (19) 3 (7) 5 (12) N/A 2 (5) 1 (2) 3 (7) 0 N/A 0 Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Safety: Adverse Events NSCLC, non-small cell lung cancer

14. 14 Single agent albumin-bound paclitaxel has considerable activity and a favorable therapeutic index when used as a 30- min IV infusion at 260 mg/m 2 q3w for the treatment of advanced NSCLC The TTP and estimated median OS are closer to those seen with standard combination paclitaxel-carboplatin therapy than with paclitaxel alone 1 Testing combinations of albumin-bound paclitaxel plus a platinum or non-platinum partner as first-line therapy in patients with advanced NSCLC is warranted Given the minimal myelosuppression, use of albumin-bound paclitaxel may also facilitate administration of full-dose chemotherapy concurrently with radiation for the management of patients with stage III NSCLC (such studies are ongoing) Green et al. Ann Oncol. 2006;17:1263-1268. Albumin-Bound Paclitaxel Monotherapy in Advanced NSCLC Conclusions NSCLC, non-small cell lung cancer; IV, intravenous; TTP, time to tumor progression; OS, overall survival

15. 15 Phase I/II Trial of Weekly Intravenous 130-nm 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 et al. J Clin Onc. 2008; 26: 639-634.

16. 16 In a phase III trial, albumin-bound paclitaxel 260 mg/m 2 was superior to paclitaxel 175 mg/m 2 q3w in the treatment of metastatic breast cancer 1 In a phase II study, albumin-bound paclitaxel 260 mg/m 2 administered q3w to chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) patients demonstrated an overall response rate (ORR) of 16%, median time to progression (TTP) of 6 months, and median overall survival (OS) of 11 months 2 Rizvi et al. J Clin Onc. 2008; 26: 639-634. 1. Gradishar et al, JCO 2005 2. Green et al, Ann Oncol 2006 First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Rationale q3w, every-3-week

17. 17 A phase I trial of albumin-bound paclitaxel administered weekly was conducted in patients with solid tumors 1 –Albumin-bound paclitaxel doses ranged from 80 to 200 mg/m 2 and the maximum-tolerated dose (MTD) was defined as 100 and 150 mg/m 2, respectively –Dose-limiting toxicities (DLTs) included grade 3/4 peripheral neuropathy –Partial responses (PR) were observed in 5 patients who had been previously treated with paclitaxel The purpose of this trial was to identify the MTD of albumin- bound paclitaxel administered on a weekly schedule in patients with untreated advanced NSCLC and to determine the safety and ORR Rizvi et al. J Clin Onc. 2008; 26: 639-634. 1. Nyman et al, JCO 2005 First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Rationale (cont.) q3w, every-3-week

18. 18 Single-center, open-label, phase I/II trial Treatment administered –Albumin-bound paclitaxel intravenously (IV) over 30 minutes without premedication –Days 1, 8, and 15, every 28 days Phase I: Dose escalation study to determine MTD –Planned dose escalation over 4 dose levels 100, 125, 150, and 175 mg/m 2 Phase II: 40 patients treated at MTD –Response Evaluation Criteria In Solid Tumors (RECIST): clinical responses reviewed with reference radiologist Primary endpoints –ORR, safety Secondary endpoints –TTP, OS Rizvi et al. J Clin Onc. 2008; 26: 639-634. First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Study Design q3w, every-3-week; MTD, maximum tolerated dose; ORR, overall response rate; TTP, time to tumor progression; OS, overall survival

19. 19 Key inclusion criteria –Stage IV or recurrent NSCLC –Patients may have received chemotherapy in the adjuvant or neoadjuvant setting –Prior treatment with gefitinib or erlotinib for advanced disease was allowed –Laboratory requirements Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times the upper limit of normal range Total bilirubin within the normal range Creatinine ≤ 1.5 mg/dL Absolute neutrophil count ≥ 1.5  10 9 cells/L Platelets ≥ 100  10 9 cells/L Hemoglobin ≥ 9 g/dL Rizvi et al. J Clin Onc. 2008; 26: 639-634. First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Patient Eligibility Criteria NSCLC, non-small cell lung cancer

20. 20 Key exclusion criteria –Prior chemotherapy for advanced NSCLC –Peripheral neuropathy > grade 1 –Radiotherapy received < 3 weeks before study entry Rizvi et al. J Clin Onc. 2008; 26: 639-634. First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Patient Eligibility Criteria (cont.) NSCLC, non-small cell lung cancer

21. 21 Dose limiting toxicities –Dose 100 and 125 mg/m 2 : none –Dose 150 mg/m 2 : 2/6 patients during first cycle Febrile neutropenia (n = 1) Sensory neuropathy (n = 1) Maximum tolerated dose was determined to be 125 mg/m 2 Study expanded to 40 patients in phase II portion Rizvi et al. J Clin Onc. 2008; 26: 639-634. First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Results: Phase I

22. 22 EGFR TKI—epidermal growth factor tyrosine kinase inhibitor Rizvi et al. J Clin Onc. 2008; 26: 639-634. Baseline characteristic (N = 40) n (%) Median age, years (range)70 (43-84) Karnovsky performance status, n (%) 90%-100% 70%-80% 10 (25) 30 (75) Prior chemotherapy, n (%) Neoadjuvant Adjuvant EGFR TKI 3 (8) 6 (15) 5 (13) Histology, n (%) Adenocarcinoma Squamous-cell carcinoma 32 (80) 8 (20) First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Select Baseline Patient Characteristics Seventy-five percent of patients had performance statuses of 70%-80% Eighty percent of patients exhibited non-squamous NSCLC NSCLC, non-small cell lung cancer EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor

23. 23 ORR, overall response rate; CR, complete response; PR, partial response; CI, confidence interval; NR, not reached; OS, overall survival; SD, stable disease; TTP, time to tumor progression Rizvi et al. J Clin Onc. 2008; 26: 639-634. Treatment characteristic (N = 40) n (%) Median number of cycles administered (range)4 (1-14) ORR (PR + CR), n (%) 95% CI 12 (30) 16-44 SD ≥ 16 weeks, n (%)8 (20) Median TTP, months 95% CI 5 3-8 Median OS, months 95% CI 11 (7-NR) 1-year OS, %41% First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Results: Phase II The ORR of the phase II portion of this study was 30% The 1-year survival rate was 41%

24. 24 Rizvi et al. J Clin Onc. 2008; 26: 639-634. Hematologic adverse events occurring in ≥ 20% of patients (n = 40)Grade 1, %Grade 2, %Grade 3, %Grade 4, % Anemia632380 Leukopenia2320 0 Neutropenia1328155 First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Safety: Hematologic Adverse Events (AEs) Occurring in ≥ 20% of Patients Grade 4 neutropenia occurred in 2/40 (5%) of patients (the only grade 4 AE) Grade 3 hematologic AEs: anemia (8%), leukopenia (20%), and neutropenia (15%)

25. 25 Rizvi et al. J Clin Onc. 2008; 26: 639-634. Nonhematologic adverse events occurring in ≥ 20% of patients (n = 40) Grade 1, % Grade 2, % Grade 3, % Grade 4, % Sensory neuropathy3523150 Fatigue2830180 Alopecia106000 Constipation382000 Diarrhea2510130 Nausea38800 Rash35500 Edema181300 Myalgia181000 Anorexia181000 First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Safety: Non-Hematologic Adverse Events (AEs) Occurring in ≥ 20% of Patients

26. 26 This study demonstrated encouraging single-agent activity with weekly albumin-bound paclitaxel 125 mg/m 2 on days 1, 8, and 15 every 28 days With the reduced risk of hypersensitivity reactions reported with albumin-bound paclitaxel compared with solvent-based paclitaxel, albumin-bound paclitaxel may play an important role in the treatment of NSCLC Additional studies to evaluate the safety and efficacy of albumin-bound paclitaxel in platinum combination studies are warranted Rizvi et al. J Clin Onc. 2008; 26: 639-634. First-Line Albumin-Bound Paclitaxel Monotherapy in Stage IV NSCLC Conclusions