Grade 1-2 Grade 3

Preferred Term*0.003q21d(N=0)

0.006q21d(N=7)

0.006q14d(N=3)

0.009q21d(N=4)

0.012q21d(N=1)

0.003q21d(N=0)

0.006q21d(N=7)

0.006q14d(N=3)

0.009q21d(N=4)

0.012q21d(N=1)

Hypotension 4 1 1**

Syncope 1**

Fatigue 5 3 4 1

Decreased Appetite 5 3 3

Pruritus 6 2 2 1

Cough 5 1 2 1

Pyrexia 3 2 3

Chills 1 3 3

Arthralgia 3 2

Nausea 2 2 2

In�uenza-Like Illness 1 1 2

Rash Macular 2 2

Rash Maculo-Papular 2 2

3/15 (20%) Patients Reported Grade 3 Related TEAE

1

Abdominal Pain 1

A Novel Immune Agonist, NKTR-214, Increases the Number and Activity of CD8+ Tumor In�ltrating Lymphocytes in Patients with Advanced Renal Cell Carcinoma2Michael E. Hurwitz, 1Adi Diab, 1Chantale Bernatchez, 1Cara L. Haymaker, 1Salah Bentebibel, 1Natalie Jackson, 1Michael T. Tetzlaff, 3Ivan Gergel, 3Mary Tagliaferri, 3Ute Hoch, 3Jonathan Zalevsky, 3Christie Fanton, 3Ernesto Iacucci, 3Sandra Aung, 3Michael Imperiale, 3EJ Liao , 1Patrick Hwu, 2Harriet M. Kluger, 2Mario Sznol, 1Nizar M. Tannir

1. The University of Texas MD Anderson Cancer Center, Houston, TX; 2. Yale Medical Oncology, New Haven, CT; 3. Nektar Therapeutics, San Francisco, CA

Background

Abstract No: 454. Poster Session C (Board #D17). Presented on February 18, 2017, at ASCO GU, Orlando, FL

Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster.

Table 1. Characteristics of Patients withRenal Cell Carcinoma (RCC)

Trial Design and Treatment

Study Design and Treatment• Phase 1 dose escalation study

evaluating the safety, tolerability, and immune phenotyping of NKTR-214 in patients with advanced solid tumors

• NKTR-214 administered as a 15-minute IV infusion every 2 or 3 weeks

• The study is a standard 3+3 dose escalation design

• Tumor and blood samples collected

• Radiographic scans completed at baseline and every 8 weeks

• Patients continued on NKTR-214 monotherapy until they meet criteria for study discontinuation (withdrawal of consent, adverse event [AE], progressive disease [PD], or death)

• ClinicalTrials.gov NCT: NCT02869295

Patient Population• Adults age 18 and older with

histologically confirmed locally advanced or metastatic solid tumors

Table 2. NKTR-214 Related Treatment-Emergent Adverse Events in Patients with RCC • Accumulating evidence suggests that low baseline tumor infiltrating lymphocytes (TILs) predicts for poor response to checkpoint inhibitor immunotherapies.1,2 Thus agents designed to specifically activate and expand TILs may improve the overall success and utility of checkpoint inhibitor therapies in patients with low TILs

• Interleukin-2 (IL-2) is a cytokine that activates and expands tumor killing lymphocytes, but also potently activates suppressive T regulatory cells (Tregs) by binding to the heterotrimeric IL-2Rαβγ

• NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs3

Results

Figure 1. Time on Study and Best Overall Response in Patients with Advanced RCC

Figure 3. Linear Increase in NKTR-214 Exposure

CLONAL EXPANSION

Stimulates Immune Response to Kill Tumor Cells

LEGEND:NKTR-214 – Inactive2-PEG – Active Cytokine1-PEG – Active Cytokine

NKTR-214 (6-PEG)

IrreversibleRelease

2-PEGActive Cytokine

1-PEG Active Cytokine

IrreversibleRelease

IL-2Rαβγ

α

β γβ γ

IL-2Rβγ

Immunosuppressive Cells Limit Anti-Tumor ResponseNKNK

CD8+

CD8+

CD8+

CD4+

Helper

CD4+

Helper

CD4+

Treg

NK NK

NK, CD4+, and CD8+ T cells

CD4+

HelperCD8+

CD4+

Helper

CD4+

HelperCD8+

NK CD4+

Helper

NK

CD8+

CD4+

HelperCD4+

HelperCD8+

CD8+

NK NKNK

CD8+

CD4+

Helper

CD4+

Helper

NK CD8+

NKTR-214 Preferentially Activates IL-2Rβγ

Tumor Analysis Fresh TIL analysis by �ow cytometry IHC T cell receptor gene sequencing Gene expression analysis

Blood Analysis Flow cytometry Cytokines PK PD (sCD25, lymphocytes)

Blood and Tumor Biopsy Collection and Analysis

C1D1 C2D1

C2D8C1D8

3 Weeks

C3D1

Predose Tumor Biopsy Week 3 Tumor Biopsy

= Blood Sample

Future Directions

• NKTR-214 has a favorable safety and tolerability profile – No evidence of autoimmune AEs or organ related inflammation (eg, colitis,

pneumonitis, dermatitis, hepatitis, endocrinopathies) – Grade 3 hypotension was rapidly reversible with fluids – No patients experienced capillary leak syndrome

• Outpatient regimen with convenient 15 minute IV dosing regimen every 2 or 3 weeks

• NKTR-214 as a single agent demonstrated a substantial increase in CD8+ T cells in the tumor microenvironment even in subjects pretreated with multiple prior immunotherapeutic agents

• Clinical activity consistent with NKTR-214’s biological mechanism of biased IL-2 pathway activation

– 6 patients with RCC who had progressed on prior TKI, were checkpoint therapy naïve when enrolled; 3 of these patients had tumor reductions between 6-30%

– 6 of 15 patients (40%) experienced tumor reductions with single-agent NKTR-214

• Q2w dosing schedule appears to be safe and have biological activity similar to q3w dosing schedule

Conclusions

No. of Patients (N=15)* %

Sex

10 67

Female

Male

5 33

Age (years)

Median 60

Range 43-77

Tumor Histology

Renal Cell Carcinoma 15 100

ECOG Performance Status

0 11 73

1 4 27

Prior Therapies

Median 1

Range 1-3

Chemotherapy/Radiation Therapy 1/4 7/27

Immune Checkpoint Inhibitor 9 60

Targeted Therapy 10 67

Study Objectives• Safety and tolerability• Define the maximum tolerated dose (MTD) of NKTR-214• Objective response rate per RECIST 1.1

• Biomarkers of immune activation in the tumor and blood

Management Guidelines • Grade 3 hypotension was rapidly reversible with IV fluids

• Management guidelines were implemented to prevent hypotension, especially Grade 3

• Management guidelines included: – Oral intake of 2L of �uid for days 1-5 of every cycle

– Anti-hypertensive medications were held 24-48 hours prior to dosing

– IV �uid hydration during clinic visits if needed

• No patients experienced capillary leak syndrome

• There were no drug-related Grade 4 AEs or deaths on study

• Only one patient discontinued NKTR-214 due to an adverse event (an infusion-related reaction). Of note, this patient had a history of an infusion-related reaction when previously treated with an immunotherapy antibody

*Patients reporting more than one adverse event within the same preferred term are counted once. **Hypotension and syncope in the patient treated at 0.012 mg/kg occurred at the same time.

*26 total patients were enrolled in the Phase 1 study.

Note: Per protocol, abnormal lab values deemed not clinically signi�cant are not adverse events.

uPR (-30%)

SD (-10%)

SD (-6%)

PD

SD

PD

PD

PD

SD (-11%)

SD

SD

SD

PD

0.012 mg/kgq3w

0.009 mg/kgq3w

0.006 mg/kgq2w

W3/C1 W6/C2 W9/C3 W12/C4 W15/C5 W18/C6 W21/C7 W24/C8 W27/C9 W30/C10

0.006 mg/kgq3w

Time on Study0 W4/C2 W8/C4 W12/C6 W16/C8 W20/C10 W24/C12 W28/C14 W32/C16

Patient 1

Patient 2

Patient 3

Patient 6

Patient 7

Patient 4

Patient 5

Patient 8

Patient 9

Patient 10

Patient 11

Patient 12

Patient 13

Patient 14

Patient 15

Discontinued Treatment Due to RECIST PDDiscontinued Treatment Due to Other ReasonsCheckpoint Therapy Naïve

Ongoing

PD - Best Overall Response is Progressive DiseaseSD - Best Overall Response is Stable Disease

( ) - Maximum Tumor Reduction from BaselineuPR - Best Overall Response is Uncon�rmed Partial Response

Data cut off as of 16Feb2017

• Sustained exposure with half-life of ~20 hours

• Gradual increase in active cytokine species, reaching Cmax 1-2 days post dose

• Exposure increases in proportion to dose

• Transient decrease (Day 3) followed by increase (Day 9) in lymphocytes, consistent with observations after HD-IL-2

• Transient increase in soluble IL-2 receptor alpha (sCD25), shed from activated T cells

• PD effects return to baseline by 14 days post-dose on Day 15• Similar PD effects observed across dose levels NKTR-214-RC and NKTR-214-AC concentrations were determined using validated ELISA methods.

For determination of Cmax and AUC, observed concentration-time data were �t to nonlinear-mixed effects models. Complete model-simulated concentration-time data were used to calculate Cmax and AUCτ(τ = 504 hr of 336 hr post 1st or 2nd dose). Cmax and AUCτ were plotted against the administered dose.

• Every patient evaluated had proliferating CD4, CD8, & NK cells

• Effects observed across dose levels and schedules

• Effects reproduced with repeat administration

• Also observed increases in total cell numbers

• Tumor biopsy was taken from the right adrenal gland for both baseline and Week 3• Core biopsies were divided into 3 portions, 1 for IHC, 1 for T cell analysis by �ow cytometry,

and 1 for gene expression analysis• Cell analysis by �ow cytometry was performed on fresh samples

• Increases in immune cell populations observed in all patients

• CD8+ T cells have increased expression of Ki67

• The immune-cell elevations (observed at Week 3) outlasted measurable plasma exposure to NKTR-214

59-year-old male with RCC who progressed on prior TKI therapy received 8 cycles of NKTR-214. Patient discontinued NKTR-214 with stable disease and initiated treatment with nivolumab. After 4 cycles of nivolumab, the patient had signi�cant tumor regression.

Scan post NKTR-214; pre-nivolumab

First 8-week scan post-nivolumab

Orange: 0.006 mg/kg q3wBlue: 0.009 mg/kg q3wPurple: 0.006 mg/kg q2wFlow cytometry of PBMCsKi67 is marker of cell proliferation

Pharmacodynamics(0.006 mg/kg, n=9)

Pharmacokinetics(0.006 mg/kg, n=9)

Figure 2. Sustained Exposure and Robust PD Changes After a Single Dose of NKTR-214

Figure 4. Peripheral Blood: NKTR-214 Promotes Proliferation of CD4, CD8, and NK Cells

Figure 5. A) Tumor IHC and Flow Cytometry Analysis of Fresh TILs B) Subsequent Treatment with Nivolumab

Figure 6. NKTR-214 Increases Proliferating CD8+ T cells in the Tumor

RC: Related Cytokine, total protein detection assay measures 6-PEG NKTR-214 and all derived species; AC: Active Cytokine, detection assay for 2-PEG and lower active species

0.01

0.1

1

10

100

1000

Co

nc. (

ng/m

L) NKTR-214-AC

NKTR-214-RC

14 210 7Time (Days) Time (Days)

Lymphocytes

15 221 8

0

10

20

30

40

Co

nc.

(%

)

sCD25

Time (Days)15 221 8

0

2

4

6

Co

nc. (

ng/m

L)

Cycle 1, RCC Cycle 2, RCC

Cycle 1, non RCCCycle 2, non RCC

NKTR-214-RC AUC

CD8+ Ki67+ H&E CD3 CD8

NKTR-214-AC AUC

NKTR-214-RC Cmax

AU

C (n

g.h

r/m

L)

1.51.00.50.00

2000

4000

6000

Dose (mg)

0

20

40

60

80

Cm

ax (n

g/m

L)

NKTR-214-AC Cmax

1.51.00.50.0Dose (mg)

0

5000

10000

15000

20000

AU

C (n

g.h

r/m

L)

1.51.00.50.0Dose (mg)

0

100

200

300

400

500

Cm

ax (n

g/m

L)

1.51.00.50.0Dose (mg)

Cycle 1, Linear RegressionCycle 2, Linear Regression

% K

i67+

151 8 22 29

0

20

40

60

80 CD4+ T cells

Time (days)

0

20

40

60

80 CD8+ T cells

% K

i67+

151 8 22 29Time (days)

Orange: 0.006 mg/kg q3wPurple: 0.006 mg/kg q2wCD3+ and CD8+ T cells obtained by IHCKi67+ and CD8+ cells obtained by �ow cytometry of fresh tumor tissue

0 3

0

1000

2000

3000CD3+ T cells

Time (weeks)

Cel

ls/m

m2

Cel

ls/m

m2

0 3

0

500

1000

1500

2000

2500CD8+ T cells

Time (weeks)0 3

0

20

40

60

80

100Ki67+ CD8+ T cells

Time (weeks)

%C

D8+

T c

ells

Patient 2Patient 4

Patient 14Patient 15

Patient 6Patient 7

References1) Daud AI, Wolchok JD, Robert C, et al. J Clin Oncol. [Epub ahead of print]

DOI:10.1200/JCO.2016.67.2477.2) Daud AI, Loo K, Pauli ML, et al. J Clin Invest. 2016;126(9):3447-52.3) Charych DH, Hoch U, Langowski JL, et al. Clin Cancer Res. 2016;22(3):680-90.

Baseline

Week 3

SD (-18%)

W33/C11

Patient 2

Patient 4

Patient 6Patient 7

Patient 10

Patient 3

Patient 12

Patient 9

Patient 11

Patient 1

Patient 13

Patient 5

0

20

40

60

80

100 NK cells

% K

i67+

151 8 22 29Time (days)

RCC = patients with renal cell carcinoma;Non-RCC = patients with tumor other than renal cell carcinoma.

0-103 103 104 105

Ki67+

7.76

0

50K

100K

25K

75K

0-103 103 104 105

Ki67+

32.8

0

50K

100K

25K

75K

SS

C-A

SS

C-A

Ki67

RC: Related Cytokine, total protein detection assay measures 6-PEG NKTR-214 and all derived species; AC: Active Cytokine, detection assay for 2-PEG and lower active species

The combination of NKTR-214 and nivolumab is being evaluated in 5 tumor types and 8 indications (PIVOT-02: NCT02983045):

• Renal cell carcinoma − 1L immunotherapy naïve − 2L relapse/refractory on

anti-PD-1/PD-L1 therapy

• Melanoma − 1L − 2L relapse/refractory on

anti-PD-1/PD-L1 therapy

• NSCLC − 1L immunotherapy naïve − 2L relapse/refractory on

anti-PD-1/PD-L1 therapy

• Bladder − 1L

• Triple negative breast cancer − 1-2L immunotherapy naïve

SD (-2%)