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. Papadimitrakopoulou 1 , Nizar M. Tannir 1 , Chantale Bernatchez 1 , Cara L. Haymaker 1 , Salah Eddine Bentebibel 1 , Brendan D. Curti 2 , Michael K.K. Wong 1 , Ivan Gergel 3 , Mary A. Tagliaferri 3 , Jonathan Zalevsky 3 , Ute Hoch 3 , Sandra Aung 3 , Michael Imperiale 3 , Daniel C. Cho 4 , Scott S. Tykodi 5 , Igor Puzanov 6 , Harriet M. Kluger 7 , Michael E. Hurwitz 7 , Patrick Hwu 1 , Mario Sznol 7 , Adi Diab 1 1 The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America, 2 Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR, United States of America, 3 Nektar Therapeutics, San Francisco, CA, United States of America, 4 NYU Medical Oncology Associates, New York, NY, United States of America, 5 University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America, 6 Roswell Park Cancer Institute, Buffalo, NY, United States of America, 7 Yale 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 Tregs 5 (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 – Inactive 2-PEG – Active Cytokine 1-PEG – Active Cytokine NKTR-214 (6-PEG) Irreversible Release 2-PEG Active Cytokine 1-PEG Active Cytokine Irreversible Release IL-2Rαβγ α β γ β γ IL-2Rβγ Immunosuppressive cells limit anti-tumor response NK NK CD8 + CD8 + CD8 + CD4 + Helper CD4 + Helper CD4 + Treg NK NK NK, CD4 + , and CD8 + T cells CD4 + Helper CD8 + CD4 + Helper CD4 + Helper CD8 + NK CD4 + Helper NK CD8 + CD4 + Helper CD4 + Helper CD8 + CD8 + NK NK NK CD8 + CD4 + Helper CD4 + Helper NK CD8 + 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. ng/mL (Mean+SE) NKTR-214-AC NKTR-214-RC 15 22 1 8 Time (days) Lymphocytes 0 1 2 3 10 9 /L (Mean+SE) Time (Days) 15 22 1 8 Time (Days) sCD25 15 22 1 8 0 2 4 6 ng/mL (Mean+SE) ASCO 2017 Poster 0.1 1 10 100 1000 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 ESCALATION N = 38 Patients Enrollment Complete PHASE 2 EXPANSION COHORTS N = ~250 Patients Enrollment Open Melanoma 1st-line, N=28 Melanoma 2nd- and 3rd-line I-O relapsed/refractory, N=26 Renal Cell Carcinoma 1st- and 2nd-line I-O naïve, N=26 Renal Cell Carcinoma 2nd- and 3rd-line I-O relapsed/refractory, N=26 Urothelial Carcinoma (Bladder) 1st-line, cisplatin ineligible, N=38 Triple Negative Breast Cancer 1st- and 2nd-line I-O naïve, N=36 Melanoma 1st-line 11 patients treated Renal Cell Carcinoma 1st-line, 2nd-line I-O naïve 22 patients treated Non-Small Cell Lung Cancer (NSCLC) 1st-line, 2nd-line I-O naïve 5 patients treated (4 with prior chemo 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 of CD8 + T Cells in the Tumor NKTR-214 Promotes T Cell Proliferation in Tumor T Cell Proliferation in Blood Monotherapy 0 10 20 30 40 50 C1D1 C1D8 Ki67 + CD8 + T Cells* 0 20 40 60 10 30 50 Monotherapy Fold-Change (Week 3 / Predose Values) Monotherapy 0.0 0.5 1.0 1.5 2.0 2.5 Fold-Change in Ki67 + CD8 + T Cells (Week 3 / Predose Values) CD8 + Tregs 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. NSCLC 1st- and 2nd-line I-O naïve, N=36 NSCLC 2nd- and 3rd-line I-O relapsed/refractory, N=37