PIVOT-02: A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-214 and Nivolumab in Patients With Select, Locally Advanced or Metastatic Solid Tumor Malignancies.Vassiliki A. Papadimitrakopoulou1, Nizar M. Tannir1, Chantale Bernatchez1, Cara L. Haymaker1, Salah Eddine Bentebibel1, Brendan D. Curti2, Michael K.K. Wong1, Ivan Gergel3, Mary A. Tagliaferri3, Jonathan Zalevsky3, Ute Hoch3, Sandra Aung3, Michael Imperiale3, Daniel C. Cho4, Scott S. Tykodi5, Igor Puzanov6, Harriet M. Kluger7, Michael E. Hurwitz7, Patrick Hwu1, Mario Sznol7, Adi Diab1

1The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America, 2Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR, United States of America, 3Nektar Therapeutics, San Francisco, CA, United States of America, 4NYU Medical Oncology Associates, New York, NY, United States of America, 5University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America, 6Roswell Park Cancer Institute, Buffalo, NY, United States of America, 7Yale School of Medicine, New Haven, CT, United States of America

BACKGROUND PIVOT-02 STUDY

Presented at the IASLC 18th World Conference on Lung Cancer, Yokohama, Japan. Study sponsored by Nektar Therapeutics.

• 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 followed by an increase in lymphocytes from Day 3 to Day 9

• Transient increase in soluble IL-2 receptor alpha (sCD25) from Day 1 to Day 8, shed from activated T cells

• sCD25 levels return to baseline by Day 15

• Similar PD effects observed across dose levels

Pharmacodynamics(0.006 mg/kg, n=15)

Pharmacokinetics(0.006 mg/kg, n=15)

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

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

Figure 1. NKTR-214 Mechanism of Action• Immune system activation with checkpoint inhibitors has proven to be an effective strategy for inhibiting tumor growth and prolonging survival.1,2

• Anti-PD-1 therapies, such as nivolumab, depend on pre-existing T-cell infiltration within the tumors for optimal efficacy.3,4

• Abundance and functional quality of tumor-infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors.1-4

NKTR-214• NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of

polyethylene glycol (PEG) designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2R) to preferentially activate and expand effector CD8+ T and NK cells over Tregs5 (Figure 1).

NKTR-214 MONOTHERAPY STUDY• A phase 1, multicenter, open-label, dose-escalation study (EXCEL) was conducted to assess the

safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of NKTR-214 in 28 patients with locally advanced or metastatic solid tumors.6-8

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

• NKTR-214 has a favorable safety and tolerability profile.8

– No evidence of immune-mediated AEs or organ related inflammation (eg, colitis, pneumonitis, dermatitis, hepatitis, endocrinopathies).

– Grade 3 hypotension occurred in 14% of patients and was rapidly reversible with IV fluids.

– No patients experienced capillary leak syndrome.

• Maximum-administered dose (MAD) was 0.012 mg/kg q3w.

• Sustained exposure and robust PD changes after a single dose of NKTR-214 (Figure 2).7,9

• NKTR-214 substantially increased CD8+ T cells that were newly proliferative (Ki67+) (Figure 3).9

• Given the favorable safety profile and potentially synergistic mechanism with anti-PD1, a trial combining NKTR-214 plus nivolumab (PIVOT-02) was initiated.

STUDY OBJECTIVES: NKTR-214 IN COMBINATION WITH NIVOLUMAB

Secondary Outcome Measures:

Primary Outcome Measures:

Key INCLUSION Criteria Key EXCLUSION Criteria

• Safety and tolerability• Define the maximum tolerated dose (MTD) and/or

recommended phase 2 dose (RP2D)• Efficacy as assessed by the Objective Response

Rate (ORR) based on RECIST 1.1 at the RP2D

Exploratory Objectives:

• Efficacy as assessed by immune-related RECIST (irRECIST) at the RP2D

• Assess the immunological effects, and accommodate disease-specific pharmacodynamics markers

• Pharmacokinetics (PK) of NKTR-214, nivolumab, and metabolites

• Assess development of anti-drug antibodies• Assess the association between efficacy measures

and PD-L1 expression in tumors

ELIGIBILITY FOR ALL DOSE EXPANSION COHORTS

NSCLC INCLUSION CRITERIA: DOSE ESCALATION AND EXPANSION

DESIGN

STATUS

• Histologically confirmed diagnosis of a locally advanced or metastatic renal cell carcinoma, melanoma, non-small cell lung cancer (NSCLC), bladder, or triple negative breast cancer

• Known BRAF status for patients with melanoma• Immuno-oncology (I-O) relapsed/refractory patients

must have documented disease progression during or following treatment with 1 prior line of therapy with anti-PD-1/PD-L1

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

• Measurable disease per RECIST 1.1• Demonstrated adequate organ function within 14 days

of treatment initiation• Oxygen saturation ≥ 92% on room air• Patients with stable brain metastases may be enrolled if

certain criteria are met• Sample of archival tumor tissue and fresh baseline

tumor biopsies are required

• Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug

• Prior interleukin 2 (IL-2) therapy• Females who are pregnant or breastfeeding• Participants who have an active autoimmune

disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents

• History of organ transplant that requires use of immune suppressive agents

• Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis

• Prior surgery or radiotherapy within 14 days of therapy

• Overall Survival (OS)• Progression-Free Survival (PFS)

• In PIVOT-02 (Figure 4), 38 patients were enrolled in the dose-escalation phase. Approximately 250 patients will be enrolled in the expansion phase in five tumor types and eight indications at the recommended phase 2 dose of NKTR-214 in combination with nivolumab.

• All patients will be monitored for treatment response as well as for any side effects.

• Extensive blood and tumor tissue samples are being collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression.

• Dose Escalation is now closed with 38 patients enrolled. – All 11 patients with metastatic melanoma were treatment naïve. – Of the 22 patients with RCC, 14 were treatment naïve, and 8 were 2nd-line. – Of the 5 patients with NSCLC, 1 was treatment naïve, and 4 were 2nd-line.

• The recommended phase 2 dose is 0.006 mg/kg NKTR-214 + 360 mg nivolumab IV every 3 weeks.

• US sites are currently enrolling, Europe will begin Q4 2017. – US, Canada, Spain, Italy, France, Poland, Ukraine, Belgium and the UK

• For participating trial sites, please visit https://clinicaltrials.gov, and search NCT02983045.

• PIVOT-02 clinical data will be presented in an oral presentation at the Society for Immunotherapy of Cancer (SITC)’s 32nd Annual Meeting held November 10-12, 2017 in National Harbor, MD.

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+

REFERENCES

1) Reck M, Rodríguez-Abreu D, Robinson AG, et al. N Engl J Med. 2016;375(19);1823–33.

2) Brahmer J, Reckamp KL, Baas P, et al. N Engl J Med. 2015;272(2):123–35.

3) Daud AI, Wolchok JD, Robert C, et al. J Clin Oncol. 2016;67:2477.

4) Daud AI, Loo K, Pauli ML, et al. J Clin Invest. 2016;126(9):3447–52.

5) Charych DH, Hoch U, Langowski JL, et al. Clin Cancer Res. 2016;22(3):680–90.

6) Bernatchez C, Haymaker C, Tannir NM, et al. Presented at SITC 2016, National Harbor, MD. Poster #387.

7) Hurwitz ME, Diab A, Bernatchez C, et al. Presented at ASCO GU 2017, Orlando, FL. Poster #D17.

8) Bernatchez C, Bentebibel SE, Hurwitz ME, et al. Presented at ASCO 2017, Chicago, IL. (see QR code)

9) Nektar Therapeutics Analyst & Investor Event at ASCO 2017 Annual Meeting. [online] Available at: http://ir.nektar.com/events.cfm

Copies of this poster obtained through QR (Quick Response) code are for personal use only and may not be reproduced without written permission of the authors.

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Initial Dose Combination Arm: Group 1: 0.006 mg/kg q3w NKTR-214 + 240 mg q2w nivolumab

q2w and q3w Parallel Dose Combination Arms: Group 2: 0.003 mg/kg q2w NKTR-214 + 240 mg q2w nivolumab Group 3: 0.006 mg/kg q2w NKTR-214 + 240 mg q2w nivolumab Group 4: 0.006 mg/kg q3w NKTR-214 + 360 mg q3w nivolumab Group 5: 0.009 mg/kg q3w NKTR-214 + 360 mg q3w nivolumab

Figure 4. Study Design

PHASE 1 DOSE ESCALATIONN = 38 Patients

Enrollment Complete

PHASE 2 EXPANSION COHORTSN = ~250 PatientsEnrollment Open

Melanoma1st-line, N=28

Melanoma2nd- and 3rd-line I-O relapsed/refractory, N=26

Renal Cell Carcinoma1st- and 2nd-line I-O naïve, N=26

Renal Cell Carcinoma2nd- and 3rd-line I-O relapsed/refractory, N=26

Urothelial Carcinoma (Bladder)1st-line, cisplatin ineligible, N=38

Triple Negative Breast Cancer1st- and 2nd-line I-O naïve, N=36

Melanoma1st-line

11 patients treated

Renal Cell Carcinoma1st-line, 2nd-line I-O naïve

22 patients treated

Non-Small CellLung Cancer (NSCLC)1st-line, 2nd-line I-O naïve

5 patients treated (4 with priorchemo doublet; 1 treatment naive)

PIVOT-02

RP2D

RP2D

RP2D

*Data are expressed as %Ki67+ CD8+ T cells on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 8 (C1D8) plotted as Mean ± Standard Error

Figure 3: NKTR-214 Promotes T Cell Proliferation and Selectively Increases T Cells in the Tumor

Selective Increase ofCD8+ T Cells in the Tumor

NKTR-214 Promotes T CellProliferation in Tumor

T Cell Proliferationin Blood

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PIVOT-02 EXPANSION

• Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC lacking epidermal growth factor receptor (EGFR)-sensitizing mutation and/or anaplastic lymphoma kinase (ALK) translocation.

• Patients may have experienced disease recurrence or progression during or after a prior platinum-based chemotherapy-containing regimen for advanced or metastatic disease, or patient refuses standard of care.

• Patients who received platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible.

Subpopulation A NSCLC (I-O naïve)• 1st- and 2nd-line patients must not have received any prior immuno-onco!ogy regimens, including but not

limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 2, 3-dioxygenase pathway inhibitors, cancer vaccines, adoptive-cell therapies, or other cytokine therapies.

Subpopulation B NSCLC (I-O relapsed/refractory)• 2nd- and 3rd-line patients must have received only 1 prior line of therapy with a checkpoint inhibitor (anti-PD-1

or anti-PD-L1) alone or in combination with chemotherapy, which must be their most recent anti-cancer treatment. Patients must have documented disease progression during treatment or within 24 months of completing treatment with a checkpoint inhibitor.

NSCLC1st- and 2nd-line I-O naïve, N=36

NSCLC2nd- and 3rd-line I-O relapsed/refractory, N=37