Women with Platinum-Resistant/ Gautam Rao, Daniel Spitz, Nicholas Reed, Graham Dark, Agustin Garcia, Daniel Maslyar, Gordon Rustin

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1 Phase 2 Study of NKTR-12 in Women with Platinum-Resistant/ Refractory Ovarian Cancer Ignace Vergote John Micha Charles Pippitt Ignace Vergote, John Micha, Charles Pippitt, Gautam Rao, Daniel Spitz, Nicholas Reed, Graham Dark, Agustin Garcia, Daniel Maslyar, Gordon Rustin

2 Disclosure None of the authors have any commercial relationships to disclose in relationship to this study except D. Maslyar who was employed by Nektar Therapeutics This study was supported by funding from Nektar Therapeutics

3 Ovarian Cancer Treatment Algorithm Ovarian Cancer 1st-line therapy Carboplatin/paclitaxel iv Platinum-sensitive (relapse > 12 mo) Platinum partially - sensitive (relapse 6-12 mo) Platinum-resistant / refractory (relapse < 6 mo / progression during) Evaluate surgery (prim or IDS) Re-challenge: Platinum- based combination chemotherapy PLD/carbo, gemcitabine/carbo, paclitaxel/carbo, PLD (MITO-8/ENGOT-ov1) trabectedin/pld PLD, topotecan, Wkly carbo/paclitaxel Experimental drugs Vergote I, 29, adapted from the NICE Guidelines

4 Analysis of GINECO Studies Therapy-Free Interval and Efficacy Survival Response (days) Rate (%) Refractory/ Resistant Overall Survival Response Rate PFS -3/Pr >18 Therapy-Free Interval, months Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 22;21: Abstract 829.

5 NKTR-12: Topoisomerase I inhibitor (irinotecan)-polymer conjugate Irinotecan has high C-max 1 Plasma SN-38 Conc (n ng/ml) 1 No exposure of drug to tumor cells SN-38 from irinotecan Time (weeks)

6 NKTR-12: Topoisomerase I inhibitor (irinotecan)-polymer conjugate NKTR-12 extends half-life of active metabolite to ~5 days (normally ~2 days) Continuous long-term exposure with markedly reduced peak concentration Plasma SN-38 Conc (n ng/ml) NKTR-12 blunted C-max Continuous exposure of drug to tumor cells Time (weeks) Phase 1 data demonstrated significant anti-tumor activity in patients with refractory solid tumors (RECIST confirmed response rate 11%) SN-38 from NKTR-12 SN-38 from irinotecan

7 Study 8-PIR-4 Design: Two-Stage Platinum resistant/ refractory ovarian cancer (N=7) NKTR mg/m 2 q14d NKTR mg/m 2 q21d Stage 1 Stage 2 N=2 / N=15 / regimen regimen Primary Endpoint: Objective Response Rate (RECIST evaluation every 6 weeks) Statistical Hypotheses: 2-stage design (with power of.85 for a RR of 2% and with alpha of.3 for RR of 5% Stage 1: Stage 2: If 1 patient responds, that treatment regimen proceeds to the next stage An additional 15 are patients enrolled If 5 patients respond out of 35 patients (Stage 1 and Stage 2 combined), the drug has met the efficacy threshold.

8 Inclusion Criteria and Objectives Key Inclusion / Exclusion Criteria Ovarian, fallopian, or primary peritoneal carcinoma Platinum resistant or refractory disease to any line of platinum-based chemotherapy (platinum-free interval less than 6 months) Evaluable disease by RECIST or CA-125 No prior treatment with topotecan or irinotecan Key Objectives Objective Response Rate (RECIST and GCIG response criteria [i.e., combines RECIST and CA-125]) Safety

9 Demographics (1) Age Median (range) 65 ECOG PS 1 NKTR-12 NKTR mg/m 2 q14d 145 mg/m 2 q21d (N = 36) (N = 35) 6 (42,83) 33% 5% 5% 63 (26,8) 46% 54% 46% Total (N = 71) 61 (26,83) 39% 52% 48% Measurable disease 97% 91% 94% CA125 evaluable 86% 83% 85% Histological Subtype Serous 89% 83% 86% Clear Cell Mucinous Endometrioid Other 6% 6% 6% 6% 6% 3% 3% 3% 6% All data presented herein from the May 15, 21 data capture

10 Demographics (2) NKTR mg/m 2 q14d (N = 36) NKTR mg/m 2 q21d (N = 35) Total (N = 71) Platinum-Free Interval* <1 month (refractory) 1-3 months (resistant) 3-6 months (resistant) 39% 17% 39% 57% 23% 17% 48% 2% 28% > 6 months (platinum sensitive)** 6%* 3%* 4%* Previous Platinum Regimens % 44% 17% 6% 31% 4% 14% 14% 32% 42% 16% 1% Prior Lines of Therapy (median) Prior PLD Prior bevacizumab Prior gemcitabine Prior taxane 44% 11% 39% 97% 49% 14% 46% 94% 47% 13% 42% 96% * From date of last dose of platinum to progression **These patients not included in following efficacy tables

11 Objective Response Rates (Platinum Resistant / Refractory Patients) RECIST N (evaluable) GCIG N (evaluable) CA-125 N (evaluable) NKTR-12 NKTR mg/m 2 q14d 145 mg/m 2 q21d Confirmed + Unconfirmed 8 (24%) 9 (29%) Confirmed 7 (21%) 7 (23%) Confirmed + Unconfirmed 14 (41%) 14 (41%) Confirmed 1 (29%) 13 (38%) Confirmed 11 (38%) 11 (38%) Clinical Benefit (CR+PR+[SD 3 months]) N (evaluable) Confirmed RECIST (52%) (45%)

12 ORR by Platinum Free-Interval (From date of last dose of platinum to progression) PFI 1 month (refractory) NKTR-12 NKTR mg/m 2 q14d 145 mg/m 2 q21d PFI 3 months PFI 1-6 months PFI 1 month (refractory) PFI 3 months PFI 1-6 months RECIST N (evaluable) Conf + Unconf Confirmed (21%) 3 (16%) 19 8 (42%) 7 (37%) 18 4 (22%) 3 (17%) 25 5 (2%) 4 (16%) 13 5 (39%) 4 (31%) GCIG N (evaluable) Conf + Unconf Confirmed 14 4 (29%) 1 (7%) 2 8 (4%) 5 (25%) 2 1 (5%) 9 (45%) 2 7 (35%) 7 (35%) 28 1 (36%) 1 (36%) 14 7 (5%) 6(43%)

13 ORR by Prior Lines of Platinum (Platinum Resistant / Refractory Patients) Prior Platinum NKTR-12 NKTR-12 Lines 145 mg/m 2 q14d 145 mg/m 2 q21d RECIST N (evaluable) 11 1 Confirmed + Unconfirmed 2 (18%) 3 (3%) Confirmed 1 (9%) 2 (2%) RECIST N (evaluable) Confirmed + Unconfirmed 4 (25%) 3 (25%) Confirmed 4 (25%) 3 (25%) RECIST N( (evaluable) 6 9 Confirmed + Unconfirmed 2 (33%) 3 (33%) Confirmed 2 (33%) 2 (22%)

14 ORR by Prior PLD (Platinum Resistant / Refractory Patients) NKTR-12 NKTR mg/m 2 q14d 145 mg/m 2 q21d Prior PLD RECIST N (evaluable) Confirmed + Unconfirmed Confirmed 15 4 (27%) 3 (2%) 14 6 (43%) 4 (29%) No Prior PLD RECIST N (evaluable) Confirmed + Unconfirmed Confirmed 18 4 (22%) 4 (22%) 17 3 (18%) 3 (18%)

15 Maximum Decline by RECIST or CA q14d and q21d patients combined q14d and q21d patients combined 2% Increase (RECIST) 3% Decrease (RECIST) 5% Increase (CA125) 5% Decrease (CA125) Platinum Resistant / Refractory Patients

16 Rapid Decline for CA-125 Responders (Platinum Resistant / Refractory Patients) 145 mg/m 2 q14d Schedule 145 mg/m 2 q21d Schedule % Cha ange In CA A W2 W4 W6 W8 W1 W3 W6 W9 W12 W15 Treatment Week Treatment Week

17 PFS on NKTR-12 versus Prior PFI (All Platinum Resistant / Refractory Patients) 1 PFS on NKTR-12 (months) Median PFS = 18 weeks Progression event No progression event at time of data cutoff (censored) -2 Median PFI = 4 weeks Platinum-free Interval on prior platinum (months)

18 NKTR-12 Safety Profile: All Patients Most Common* Drugrelated Grade 3 and 4 AEs *>5% overall NKTR mg/m 2 q14d (N = 36) NKTR mg/m 2 q21d (N = 35) Grade 3 Grade 4 Grade 3 Grade 4 Diarrhea 25% % 14% % Dehydration 22% % 6% % Hypokalemia 17% 3% 9% % Fatigue 6% % 14% % Nausea 14% % 3% % Vomiting 11% % 3% % Abdominal pain 6% % 6% % Hyponatremia 8% % 3% % Neutropenia 6% % 6% 3% Two NKTR-12 related deaths: q14d: acute renal failure q21d: neutropenic sepsis

19 Principal Investigators Belgium Ignace Vergote, MD, PhD University Hospital Leuven Christine Gennigens, MD CHU de Liege Luc Dirix, MD AZ St. Augustinus United Kingdom Gordon Rustin, MD, MBBS Mount Vernon Cancer Centre Nicholas Reed, MD Beatson Oncology Centre Graham Dark, MD Freeman Hospital Christopher Poole, MD University Hospital Coventry United States Agustin Garcia, MD USC Norris Comprehensive Cancer Center Gautam G. Rao, MD Sarah Cannon Research Institute John Micha, MD Gynecologic Oncology Associates Charles Pippitt, MD Piedmont Hematology Oncology Associates Daniel Spitz, MD Palm Beach Cancer Institute Emad Ibrahim, MD Highland, CA Linda Duska, MD University of Virginia Vincent Armenio, MD Pharma Resourse Jeffrey Smith, MD Surgical Gynecological Michelle Ferguson, MD Ninewells Hospital Joseph Meunier, MD Sparrow Regional Cancer Center

20 Conclusions Survival (days) Response Rate (%) % of women in NKTR-12 study with platinum resistant/refractory disease Refractory/ Resistant Overall Survival Response Rate PFS /Pr >18 Therapy-Free Interval, months Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 22;21: Abstract 829.

21 Conclusions NKTR-12 is well tolerated, especially with the q21d regimen Due to a better toxicity profile, q21d is the preferred regimen for Phase 3 NKTR-12 has a notably higher than expected objective response rate in this group of heavily pretreated platinum resistant / refractory ovarian cancer patients Median 4 th line treatment 57% platinum refractory in q21d regimen Confirmed RECIST/GCIG response rates of 23%/38%, respectively, in the q21d regimen Phase 3 Study planning underway