Grade 1-2 Grade 3

Preferred Term* 0.003 q3w (n=4)

0.006 q3w (n=9)

0.006 q2w (n=5)

0.009 q3w (n=6)

0.012 q3w (n=1)

0.003 q3w (n=4)

0.006 q3w (n=9)

0.006 q2w (n=5)

0.009 q3w (n=6)

0.012 q3w (n=1)

4/25 (16%) Patients Reported Grade 3 Drug-Related TEAE

Hypotension 2 5 2 1 1 1 1†

Infusion-related reaction** 1

Syncope 1†

Fatigue 2 6 3 4 1

Pruritus 2 6 2 3 1

Cough 5 1 3 1

Decreased appetite 5 2 3

Pyrexia 2 3 2 3

Chills 1 1 3 4

Dizziness 1 3 1 1

Nasal congestion 1 1 1 3

Nausea 1 2 1 2

Arthralgia 3 2

In� uenza like illness 1 2 1 1

Myalgia 2 1 2

Edema peripheral 3 1 1

Rash maculo-papular 2 3

Headache 2 1 1

Rash erythematous 1 2 1

A CD122-biased agonist increases CD8+ T cells and natural killer cells in the tumor microenvironment; making cold tumors hot with NKTR-214Chantale Bernatchez1, Cara Haymaker1, Nizar M. Tannir1, Harriet Kluger2, Michael Tetzlaff1, Salah Eddine Bentebibel1, Natalie Jackson1, Ivan Gergel3, Mary Tagliaferri3, Jonathan Zalevsky3, Ute Hoch3, Michael Imperiale3, Sandra Aung3, Patrick Hwu1, Mario Sznol2, Michael Hurwitz2, Adi Diab1

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

Trial Design and Treatment

Poster #387 | Presented at SITC2016, National Harbor, Maryland

• NKTR-214 has a favorable safety and tolerability pro�le – No evidence of autoimmune AEs or organ-related in�ammation (eg, colitis, pneumonitis, dermatitis, hepatitis, endocrinopathies) – Grade 3 hypotension was observed in 3/25 patients and was rapidly reversible with �uids; all 3 patients continued on NKTR-214 – No patients experienced capillary leak syndrome – Outpatient regimen with convenient 15 minute IV dosing regimen every 2 or 3 weeks

• Clinical activity consistent with NKTR-214’s biological mechanism of biased IL-2 pathway activation – 5 patients with metastatic RCC who had progressed on 1 prior TKI were enrolled to the 0.006 mg/kg q3 dose cohort

• 1/5 had an uncon�rmed partial response per RECIST 1.1 • 2/5 had tumor reductions per RECIST 1.1

• NKTR-214 induces a robust immune-stimulatory response in the tumor and blood – Substantial elevation of newly proliferating Ki67+ CD8+ T cells and NK cells in the blood also observed in the tumor – Greater abundance of CD8+ T cells to T regulatory immune suppressive cells accumulate in the tumor – Increased cell-surface expression of PD-1 on CD4+ and CD8+ T cells in blood and tumor

• Tolerability, activity and pharmacokinetic pro�le supported evaluation of q2w dosing, which commenced in September 2016

• The ability of NKTR-214 to increase TILs and increase PD-1 expression on immune cells provides a sound biological basis for combination with anti-PD1 checkpoint inhibitors

AcknowledgementsThe authors would like to acknowledge the contribution of patients and their families in participation of this clinical trial.

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.

• 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

Pharmacodynamics(0.006 mg/kg, n=9)

Pharmacokinetics(0.006 mg/kg, n=9)

Figure 3. Sustained Exposure and Robust PD Changes After a Single Dose of NKTR-214

Table 1. Patient CharacteristicsNo. of PatientsCharacteristics %

16 64369

6034-77

15 606 241 41 4 1 4 1 4

15 6010 40

21-12

915

Sex MaleFemale

Age (years) MedianRange

Tumor Histology Renal cell carcinomaMalignant melanomaBladder cancerChondrosarcomaColorectal adenocarcinomaLeiomyosarcoma

ECOG Performance Status 01

Prior Therapies MedianRangeChemotherapyImmune checkpoint inhibitorTargeted therapy 16

366064

ECOG, Eastern Cooperative Oncology Group

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 2-3 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 met criteria for study discontinuation (withdrawal of consent, adverse event [AE], progressive disease [PD], or death)

Patient Population• Adults age 18 and older with histologically confirmed locally advanced or metastatic solid tumors

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

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 weeksC3D1

Predose tumor biopsy Week 3 tumor biopsy0.01

0.1

1

10

100

1000

Co

nc. (

ng/m

L) NKTR-214-AC

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

NKTR-214-RC

Table 2. NKTR-214 Related Treatment-Emergent Adverse Events

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

Figure 5. Peripheral Blood: NKTR-214 Induces CD4+ T Cell Activation

Figure 6. Tumor: NKTR-214 Increases Immune Cells Including CD8+ and NK Cells

Figure 7. Peripheral Blood and Tumor: NKTR-214 Increases the Abundance of Proliferating CD8+ and PD-1+ T Cells

• Every patient evaluated showed elevation in at least one activation marker• Effects reproduced with repeat administration• Increase in ICOS, TIM-3, and CTLA-4 not observed in CD8+ Cells

• Every patient evaluated had proliferating CD4+, CD8+, and NK cells

• Effects reproduced with repeat administration

• Correlates with increase in lymphocytes shown in Figure 3

• Increases in immune cell populations observed in 5/5 patients• The immune cell elevations (observed at Week 3) outlasted measurable plasma exposure to NKTR-214

• Accumulating evidence suggests that low baseline tumor infiltrating lymphocytes (TILs) are predictive 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

14 210 7Time (Days)

Results

• 16 wk scan, -30.4% RECIST 1.1

Figure 2. 60-Year-Old Female with RCC, Progressed on Prior TKI

Day 1

Right Adrenal Left Adrenal

Week 16 Day 1 Week 16

Figure 1. Time on Study and Best Overall Response

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

• Management guidelines 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

• Since implementation of hydration guidelines on May 1, 2016, Grade 3 drug-related hypotension decreased to 1/20 (5%) patients

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

• No patients have discontinued NKTR-214 due to an adverse event other than one patient who experienced an infusion-related reaction. Of note, this patient had a history of an infusion-related reaction when previously treated with an immunotherapy antibody.

0

10

20

30

40

Proliferating CD4+ T Cells

%K

i67

inC

D4

1 8 15 22 29 360

20

40

60

Proliferating CD8+ T Cells

%K

i67

inC

D8

1 8 15 22 29 360

20

40

60

80

100

Proliferating NK Cells

%K

i67

inN

K

1 8 15 22 29 36

0

5

10

15

20

25

PD-1

%PD

-1in

CD

4

1 8 15 22 29 360

10

20

30

ICOS

%IC

OS

inC

D4

1 8 15 22 29 360.0

0.5

1.0

2

3

4

5

TIM-3

%TI

M-3

inC

D4

1 8 15 22 29 360

1

2

45

CTLA-4

%C

TLA

-4in

CD

4

1 8 15 22 29 36

0

2

4

6

8

10

Total Immune Cells

%Li

veC

D45

+

0

5

10

15

20

NK Cells

%N

Kce

llsof

CD

45+

0

500

1000

1500

2000

CD8+ T Cells

CD

8+T

cells

(cel

ls/m

m2 )

Purple: 0.003 mg/kg (n=4)

Orange: 0.006 mg/kg (n=5)

Dosing Day

Flow cytometry of PBMCs

Ki67 is a marker of cell proliferation

Purple: 0.003 mg/kg (n=4) Orange: 0.006 mg/kg (n=5) Dosing DayFlow cytometry of PBMCsPD-1, ICOS, TIM-3, and CTLA-4 are markers of CD4+ T cell activation

Purple: 0.003 mg/kg (n=2) Orange: 0.006 mg/kg (n=3) Hatched bars are predose and solid bars are Week 3 biopsy samplesTotal immune cells (CD45+) and NK cells (CD3-,CD19-,CD56+) obtained from fresh tissue flow cytometry; CD8+ T cells from IHC

Line ChartPurple: 0.003 mg/kg (n=4)Orange: 0.006 mg/kg (n=5) Dosing DayBar ChartsPurple: 0.003 mg/kg (n=2)Orange: 0.006 mg/kg (n=3)ND = None detected

1 8 15 22

0

10

20

30

40

Time (Days)

Con

c.(%

)

1 8 15 22

0

2

4

6

Time (Days)

Con

c.(n

g/m

L)

0.00.30.6

20

40

60

80

100

PD-1+ CD8 T CellsTumor

%PD

-1+

inC

D8

0

2

4

6

8

10

CD4+ Treg CellsBlood

%Tr

egs

inC

D4

1 8 15 22 29 360

5

10

15

20

CD4+ Treg CellsTumor

%Tr

egs

ofC

D4

ND ND ND

sCD25Lymphocytes

Pred

ose

Wee

k 3

ND

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

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

*Patients reporting more than one adverse event within the same preferred term are counted once. **Patient had a previous infusion-related reaction to immunotherapy prior to NKTR-214.†Hypotension and syncope in the patient treated at 0.012 mg/kg occurred at the same time.

0.003 mg/kgq3w

0.006 mg/kgq3w

0.009 mg/kgq3w

0.012 mg/kgq3w

SDSD

SD

PD

PR (-30%)

SD

SDPDRCC

MelanomaRCC

MelanomaRCCRCCRCC

MelanomaRCCRCCRCC

ColorectalRCCRCCRCCRCC

MelanomaBladder

MelanomaMelanoma

Time on Study (Weeks/Cycles)

0 W4/C2 W8/C4 W12/C6 W16/C8 W20/C12 W24/C12 W28/C14 W32/C16 W36/C18 W40/C20

W3/C1 W6/C2 W9/C3 W12/C4 W15/C5 W18/C6 W21/C7 W24/C8 W27/C9 W30/C10 W33/C11 W36/C12 W39/C13

0.006 mg/kgq2w

RCCRCC

LeiomyosarcomaChondrosarcoma

RCC

PDPD

PDSD

SD

SD

SD (-6%)SD (-10%)

SD

SD

Discontinued treatment due to PD

Discontinued treatment due to other reasons

Ongoing

RCC patients who progressed on prior TKI

PD - Best Overall Response is Progressive Disease

SD - Best Overall Response is Stable Disease

PR - Uncon�rmed

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 response

NKNK

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+

NKNK

NK

CD8+

CD4+

Helper

CD4+

Helper

NKCD8+

= Blood sample

Figure 8. NKTR-214 Transiently Increases Treg Cell Frequency in Blood but Not in TumorLine ChartPurple: 0.003 mg/kg (n=4)Orange: 0.006 mg/kg (n=5) Dosing DayBar ChartPurple: 0.003 mg/kg (n=2)Orange: 0.006 mg/kg (n=3)ND = None detected

0

10

20

30

40

50

Ki67+ CD8 T CellsTumor

%K

i67+

inC

D8

ND ND ND

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Pred

ose

Wee

k 3

Future Directions• Combination of NKTR-214 and nivolumab is being evaluated in 5 tumor types and 7 indications: – Melanoma (1L, 2L relapsed on immunotherapy agent) – Renal cell carcinoma (1L immunotherapy naïve, 2L relapsed on immunotherapy agent) – NSCLC (2L immunotherapy naïve) – Bladder (1L) – Triple negative breast cancer (2L immunotherapy naïve)

Conclusions

0

10

20

30

40

PD-1+ CD8 T CellsBlood

% P

D-1

+ in

CD

8

1 8 15 22 29 36