A Novel Immune Agonist, NKTR-214, Increases the Number and ...€¦ · Abstract No: 454. Poster...
1
Grade 1-2 Grade 3 Preferred Term* 0.003 q21d (N=0) 0.006 q21d (N=7) 0.006 q14d (N=3) 0.009 q21d (N=4) 0.012 q21d (N=1) 0.003 q21d (N=0) 0.006 q21d (N=7) 0.006 q14d (N=3) 0.009 q21d (N=4) 0.012 q21d (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 Influenza-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 Infiltrating Lymphocytes in Patients with Advanced Renal Cell Carcinoma 2 Michael E. Hurwitz, 1 Adi Diab, 1 Chantale Bernatchez, 1 Cara L. Haymaker, 1 Salah Bentebibel, 1 Natalie Jackson, 1 Michael T. Tetzlaff, 3 Ivan Gergel, 3 Mary Tagliaferri, 3 Ute Hoch, 3 Jonathan Zalevsky, 3 Christie Fanton, 3 Ernesto Iacucci, 3 Sandra Aung, 3 Michael Imperiale, 3 EJ Liao , 1 Patrick Hwu, 2 Harriet M. Kluger, 2 Mario Sznol, 1 Nizar 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 with Renal 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 Tregs 3 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 – 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 + NKTR-214 Preferentially Activates IL-2Rβγ Tumor Analysis Fresh TIL analysis by flow 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 C2D8 C1D8 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 fluid for days 1-5 of every cycle – Anti-hypertensive medications were held 24-48 hours prior to dosing – IV fluid 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 significant are not adverse events. uPR (-30%) SD (-10%) SD (-6%) PD SD PD PD PD SD (-11%) SD SD SD PD 0.012 mg/kg q3w 0.009 mg/kg q3w 0.006 mg/kg q2w W3/C1 W6/C2 W9/C3 W12/C4 W15/C5 W18/C6 W21/C7 W24/C8 W27/C9 W30/C10 0.006 mg/kg q3w Time on Study 0 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 PD Discontinued Treatment Due to Other Reasons Checkpoint Therapy Naïve Ongoing PD - Best Overall Response is Progressive Disease SD - Best Overall Response is Stable Disease ( ) - Maximum Tumor Reduction from Baseline uPR - Best Overall Response is Unconfirmed Partial Response Data cut off as of 16Feb2017 • Sustained exposure with half-life of ~20 hours • Gradual increase in active cytokine species, reaching C max 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 C max and AUC, observed concentration-time data were fit to nonlinear-mixed effects models. Complete model-simulated concentration-time data were used to calculate C max and AUC τ (τ = 504 hr of 336 hr post 1st or 2nd dose). C max and AUC τ 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 flow cytometry, and 1 for gene expression analysis • Cell analysis by flow 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 significant tumor regression. Scan post NKTR-214; pre-nivolumab First 8-week scan post-nivolumab Orange: 0.006 mg/kg q3w Blue: 0.009 mg/kg q3w Purple: 0.006 mg/kg q2w Flow cytometry of PBMCs Ki67 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 Conc. (ng/mL) NKTR-214-AC NKTR-214-RC 14 21 0 7 Time (Days) Time (Days) Lymphocytes 15 22 1 8 0 10 20 30 40 Conc. (%) sCD25 Time (Days) 15 22 1 8 0 2 4 6 Conc. (ng/mL) Cycle 1, RCC Cycle 2, RCC Cycle 1, non RCC Cycle 2, non RCC NKTR-214-RC AUC CD8 + Ki67 + H&E CD3 CD8 NKTR-214-AC AUC NKTR-214-RC C max AUC (ng.hr/mL) 1.5 1.0 0.5 0.0 0 2000 4000 6000 Dose (mg) 0 20 40 60 80 C max (ng/mL) NKTR-214-AC C max 1.5 1.0 0.5 0.0 Dose (mg) 0 5000 10000 15000 20000 AUC (ng.hr/mL) 1.5 1.0 0.5 0.0 Dose (mg) 0 100 200 300 400 500 C max (ng/mL) 1.5 1.0 0.5 0.0 Dose (mg) Cycle 1, Linear Regression Cycle 2, Linear Regression % Ki67 + 15 1 8 22 29 0 20 40 60 80 CD4 + T cells Time (days) 0 20 40 60 80 CD8 + T cells % Ki67 + 15 1 8 22 29 Time (days) Orange: 0.006 mg/kg q3w Purple: 0.006 mg/kg q2w CD3 + and CD8 + T cells obtained by IHC Ki67 + and CD8 + cells obtained by flow cytometry of fresh tumor tissue 0 3 0 1000 2000 3000 CD3 + T cells Time (weeks) Cells/mm 2 Cells/mm 2 0 3 0 500 1000 1500 2000 2500 CD8 + T cells Time (weeks) 0 3 0 20 40 60 80 100 Ki67 + CD8 + T cells Time (weeks) %CD8 + T cells Patient 2 Patient 4 Patient 14 Patient 15 Patient 6 Patient 7 References 1) 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 6 Patient 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 % Ki67 + 15 1 8 22 29 Time (days) RCC = patients with renal cell carcinoma; Non-RCC = patients with tumor other than renal cell carcinoma. 0 -10 3 10 3 10 4 10 5 Ki67 + 7.76 0 50K 100K 25K 75K 0 -10 3 10 3 10 4 10 5 Ki67 + 32.8 0 50K 100K 25K 75K SSC-A SSC-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%)
Transcript of A Novel Immune Agonist, NKTR-214, Increases the Number and ...€¦ · Abstract No: 454. Poster...
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%)
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