0 5 10 15 25 20 % PD-1 C1D1 C1D8 C2D1 C2D8 0 5 10 15 30 20 25 % Ki67 C1D1 C1D8 C2D1 C2D8 0 2 4 6 10 8 % PD-1 C1D1 C1D8 C1D1 C1D8 0 10 20 30 60 40 50 % Ki67 A Novel IL-2 Cytokine Immune Agonist (NKTR-214) Increases Proliferating CD8 + T Cells and PD-1 Expression on Immune Cells in the Tumor Microenvironment in Patients with Prior Checkpoint Therapy Chantale Bernatchez 1 , Salah Eddine Bentebibel 1 , Michael E. Hurwitz 2 , Cara L. Haymaker 1 , Harriet M. Kluger 2 , Michael T. Tetzlaff 1 , Natalie Jackson 1 , Ivan Gergel 3 , Mary Ann Tagliaferri 3 , Jonathan Zalevsky 3 , Ute Hoch 3 , Christie Fanton 3 , Ernesto Iacucci 3 , Sandra Aung 3 , Michael Imperiale 3 , Ej Liao 3 , Ira Smalberg 4 , Brendan D. Curti 5 , Nizar M. Tannir 1 , Patrick Hwu 1 , Mario Sznol 2 , Adi Diab 1 1 The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Yale School of Medicine, New Haven, CT; 3 Nektar Therapeutics, San Francisco, CA; 4 Consultant, Los Angeles, CA; 5 Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR BACKGROUND CONCLUSIONS FUTURE DIRECTIONS REFERENCES ACKNOWLEDGEMENTS RESULTS Efficacy of Sequential Dosing With Nivolumab Durability in the Refractory Setting Robust Immune Activation in Patients Who Have Failed Prior Immunotherapy • NKTR-214 has a favorable safety profile. – No immune-related AEs – No capillary leak syndrome – Short-lived related TEAEs – Drug-related hypotension was predictable, short-lived and managed with fluids • NKTR-214 increases immune cells in the blood and tumor microenvironment even in subjects who have failed multiple prior immunotherapeutic agents. • 3 of 4 RCC IO naïve patients with SD on NKTR-214 who received sequential therapy with nivolumab demonstrated rapid responses at first scan on nivolumab. • Based on the ability of NKTR-214 to prime, proliferate, and activate CD8 + T cells with increased PD-1 expression in the tumor, the combination of NKTR-214 and nivolumab is currently being evaluated in 5 tumor types and 8 indications (PIVOT-02: NCT02983045): – Renal cell carcinoma ♦ 1-2L immunotherapy naïve ♦ 2-3L relapse/refractory on anti-PD-1/PD-L1 therapy – Melanoma ♦ 1L ♦ 2-3L relapse/refractory on anti-PD-1/PD-L1 therapy To evaluate doublet and triple-combination regimens with NKTR-214 to enhance efficacy and minimize toxicity including but not limited to: • Checkpoint inhibitors • TLR agonists • Inhibitors of immune suppression • Vaccines • Bi-specific antibodies The authors would like to acknowledge the contribution of patients and their families in participation of this clinical trial. SITC 2016 Poster ASCO GU 2017 Poster 1) Charych DH, Hoch U, Langowski JL, et al. Clin Cancer Res. 2016;22(3):680-90. 2) SITC 2016 poster (see QR code below) 3) ASCO GU 2017 poster (see QR code below) 4) Daud AI, Wolchok JD, Robert C, et al. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.2016.67.2477. 5) Daud AI, Loo K, Pauli ML, et al. J Clin Invest. 2016;126(9):3447-52. • 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 1 (see Figure below). • In all patients evaluated, NKTR-214 increases newly proliferating (Ki67 + ) T and NK cells in the blood. 2 • NKTR-214 increases tumor-infiltrating immune cells in RCC. 3 • Anti-PD-1 therapies, such as nivolumab, depend on pre-existing T-cell infiltration within the tumors for optimal efficacy. 4,5 • Nivolumab and high-dose IL-2 (HD IL-2) are currently the only two FDA-approved immunotherapies for patients with RCC; however, due to toxicities associated with HD IL-2, use of this treatment option has been limited. NKTR-214 with its favorable safety profile and mechanism of action, combined with other treatment modalities, may be an important advancement for patients suffering from RCC and other cancer types. 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 Monotherapy Study Patient Enrollment Case #3 BOR SD on NKTR-214 PR on Nivolumab Case #1 Confirmed Partial Response BOR SD on NKTR-214 PR on Nivolumab Case #2 BOR SD on NKTR-214 PR on Nivolumab Case #4 Achieved 30% Tumor Reduction on NKTR-214, SD on Nivolumab 28 Patients Enrolled 7 Patients Melanoma 15 Patients RCC 6 RCC IO Naïve, Prior TKI 9 RCC Prior IO 6 Patients Other 2 Breast 2 Sarcoma 1 Colorectal 1 Bladder After EOT with NKTR-214, 4 patients with SD received sequential therapy with nivolumab Case #5: 59-year-old male with melanoma Stage IV Case #6: 56-year-old male with RCC Stage IV Abstract No: 2545 (Board #37). Presented on June 5, 2017, at ASCO, Chicago, IL. αOX40 PD ipi HD IL-2 Nivolumab PD NKTR-214 (23 cycles) Vemurafenib CD4 + T cells CD8 + T cells CD4 + T cells CD8 + T cells Increased Proliferation and PD-1 Expression on T Cells in Blood Increased Proliferation and PD-1 Expression on T Cells in Blood RCC, renal cell carcinoma; EOT, end of therapy; IO, immuno-oncology; TKI, tyrosine-kinase inhibitor; BOR, best overall response; PR, partial response; SD, stable disease TRIAL DESIGN AND TREATMENT Blood and Tumor Biopsy Collection and Analysis EOT, end of treatment. 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) C1D1 C2D1 C2D8 C1D8 C3D1 Baseline Tumor Biopsies: Cycle (C)/Day (D): Week 3 Week 8 EOT EOT = Blood sample Q2W or Q3W NKTR-214 NKTR-214 NKTR-214 – NSCLC ♦ 1-2L immunotherapy naïve ♦ 2-3L relapse/refractory on anti-PD-1/PD-L1 therapy – Bladder ♦ 1L (cisplatin ineligible) – Triple negative breast cancer ♦ 1-2L immunotherapy naïve Prior Therapies Therapy Administered NKTR-214 Treatment Duration of Treatment Ipilimumab (ipi) Vemurafenib ~ 1 mo ~ 7 mos >15 mos Time Interval to Next Treatment HD IL-2 Anti-OX-40 (αOX40) Prior Therapies Therapies Administered NKTR-214 Treatment Nivolumab Duration of Treatment ~ 3 mos ~ 2 mos ~ 2.5 mos >10 mos Time Interval to Next Treatment ~ 45 mos ~ 33 mos Ongoing ~ 22.5 mos ~ 1.5 mos ~ 1 mo Ongoing NKTR-214 Related Treatment-Emergent Adverse Events: All Grade 3 Events and Grade 1-2 Events Occurring in ≥ 20% of Patients *Patients reporting more than one adverse event within the same preferred term are counted once. **Hypotension and abdominal pain occurred in the same patient treated at 0.006 mg/kg q2w. † Hypotension and syncope in the patient treated at 0.012 mg/kg occurred at the same time. • Grade 3 hypotension was rapidly reversible with IV fluids • Management guidelines were implemented to prevent hypotension, especially Grade 3 • Median duration of pyrexia was 2 days • 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 Note: Per protocol, abnormal lab values deemed not clinically significant are not adverse events. Grade 1-2 Grade 3 Preferred Term* Data cut-off: May 26, 2017 0.003 q3w (n=4) 0.006 q3w (n=11) 0.006 q2w (n=6) 0.009 q3w (n=6) 0.012 q3w (n=1) 0.003 q3w (n=4) 0.006 q3w (n=11) 0.006 q2w (n=6) 0.009 q3w (n=6) 0.012 q3w (n=1) 5/28 (18%) Patients Reported Grade 3 Treatment-Related TEAE Hypotension 1 † 1 1 1** 1** 1 Abdominal pain 1 2 6 2 1 2 7 5 4 1 2 7 5 3 5 4 3 1 5 1 3 1 1 2 4 4 2 4 1 3 1 2 3 2 2 1 2 2 2 1 3 3 1 1 1 1 1 1 3 3 4 1 Infusion-related reaction Syncope 1 † Fatigue Pruritus Decreased appetite Chills Cough Pyrexia Arthralgia Influenza like illness Nausea Rash maculo-papular Dizziness Nasal congestion SITC 2016 Poster ASCO GU 2017 Poster 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. CD4 + T Cells 1 Case # 2 4 3 C1D1 C1D8 C2D1 C2D8 0 20 40 60 80 % Ki67 C1D1 C1D8 C2D1 C2D8 0 20 40 % Ki67 60 C1D1 C1D8 C2D1 C2D8 0 10 20 30 % PD-1 C1D1 C1D8 C2D1 C2D8 0 10 20 30 % PD-1 CD8 + T Cells NKTR-214 Promotes Proliferation and PD-1 Upregulation in Lymphocytes in the Blood C1D1 C1D8 C2D1 C2D8 0 10 20 30 40 % NK Cells C1D1 = baseline 0.003 mg/kg q3w 0.006 mg/kg q3w 0.012 mg/kg q3w 0.009 mg/kg q3w 0.006 mg/kg q2w Discontinued treatment due to RECIST PD Discontinued treatment due to AE Discontinued treatment due to other reasons Ongoing PD - Best Overall Response is Progressive Disease SD - Best Overall Response is Stable Disease SD SD SD SD SD (uPR) SD SD PD SD PD PD PD PD PD PD SD SD SD SD SD PD SD PD SD PD Case #5 Case #4 Case #1 Case #2 Case #6 Case #3 W3/C1 W9/C3 W15/C5 W21/C7 W27/C9 W33/C11 W39/C13 W45/C15 W51/C17 W57/C19 W63/C21 W69/C23 Breast Ca RCC RCC Chondrosarcoma Leiomyosarcoma RCC Melanoma RCC RCC Melanoma RCC RCC RCC Triple Neg BC Melanoma Melanoma RCC Colorectal RCC RCC RCC RCC RCC RCC Melanoma Bladder Ca Melanoma Melanoma Time on Study (Weeks/Cycles) Data cut-off: May 26, 2017 0 W8/C4 W16/C8 W24/C12 W32/C16 W40/C20 W48/C24 W56/C28 W64/C32 W72/C36 W80/C40 Prior ipilimumab, BRAF inhibitor Prior HD IL-2, OX40, Nivolumab NKTR-214 (15 cycles) Case #3: 61-year-old male, RCC Stage IV ~1mo *Minute tumor cells Pre NKTR-214 Lung Nodule EOT NKTR-214 POST Nivolumab Confirmed PR PR on 1st scan Nivolumab NKTR-214 (4 cycles) PD-L1 status = 10%* Baseline CD3 CD8 H&E Week 3 Treatment Prior Therapies Sunitinib ~ 2.5 mos (PD) 0 Axitinib ~ 1.5 mo (PD) ~ 2 mos Bevacizumab + CRLX101 ~ 3.5 mos (unknown) ~ 4.5 mos ~ 1.5 mos (SD) > 7 mos ~ 1 mo Ongoing Nivolumab Therapies Administered NKTR-214 Duration of Treatment Time Interval to Next Treatment Immunological Changes on NKTR-214 Therapy (Max tumor response -1% per RECIST 1.1) Number of Tumor Infiltrating Cells 0 FoxP3 + cells CD8 + T cells Baseline Week 3 200 2000 2200 2100 2300 Cells/mm 2 Case #4: 60-year-old female, RCC Stage IV Pre NKTR-214 Left Adrenal Right Adrenal BOR on NKTR-214 POST Nivolumab Unconfirmed PR Nivolumab NKTR-214 (8 cycles) PD-L1 status = 40% ~2 mos 30% reduction at 2nd scan Prior Therapies Therapies Administered NKTR-214 Treatment Pazopanib ~10.5 mos (unknown) 1 mo Axitinib 5 mos (PD) ~2.5 mos ~5.5 mos (SD) ~2 mos Ongoing Nivolumab > 4 mos Duration of Treatment Time Interval to Next Treatment (Max tumor response -30% per RECIST 1.1) Flow Analysis of Cells from Fresh Tumor Biopsy Baseline Week 8 EOT 0 5 10 15 20 % of live cells CD45 + CD3 + CD8 + CD8 + PD-1 + SD on 1st scan Case #2: 66-year-old female, RCC Stage IV EOT NKTR-214 Pre NKTR-214 Pre Nivolumab (Pseudoprogression Observed) POST Nivolumab Duration of Treatment Time Interval to Next Treatment Prior Therapy Therapies Administered Treatment Sunitinib ~ 8 mos (AE disc.) ~ 1.5 mos ~ 1.5 mos (SD) ~ 1 mo Ongoing Nivolumab plus investigational agent > 9 mos NKTR-214 Confirmed PR PR on 1st scan NKTR-214 (3 cycles) PD-L1 status = NA Nivolumab plus investigational agent ~1 mo (Max tumor response -20% per RECIST 1.1) Scan unavailable due to enrollment in another clinical trial Case #1: 59-year-old male, RCC Stage IV EOT NKTR-214 POST Nivolumab Treatment Duration of Treatment Time Interval to Next Treatment Prior Therapy Sunitinib ~ 67 mos (PD) ~ 2 mos Therapies Administered NKTR-214 ~ 5 mos (SD) ~ 1 mo Ongoing Nivolumab > 9 mos ~1 mo Confirmed PR PR on 1st scan Nivolumab CD8 + Ki67 + 0 -10 3 10 3 10 4 10 5 Ki67 + 7.76% 0 50K 100K 25K 75K SSC-A 0 -10 3 10 3 10 4 10 5 Ki67 + 32.8% 0 50K 100K 25K 75K SSC-A Ki67 Pre NKTR-214 Left Lung Nodule NKTR-214 (8 cycles) PD-L1 status † = neg H&E CD3 CD8 Baseline Week 3 Immunological Changes on NKTR-214 Therapy (Max tumor response -10% per RECIST 1.1) RNA Expression (NanoString) Week 3/Baseline 0 IFNG PRF1 GZMB IRF3 IL6 IL6R 1 2 3 4 5 6 Fold Change Functional Markers Inflammation Markers No induction (fold change =1) 1027 mean cells/mm 2 675 mean cells/mm 2 2017 mean cells/mm 2 1620 mean cells/mm 2 IFNG, interferon gamma; PRF1, perforin-1; GZMB, granzyme B; IRF3, interferon regulatory factor 3; IL6, interleukin 6; IL6R, interleukin-6 receptor † PD-L1 status was obtained using the Cell Signaling antibody (Cell Signaling #13684, PD-L1 (E1L3N)) at a 1:100 dilution on the Leica BOND RX m
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A Novel IL-2 Cytokine Immune Agonist (NKTR-214) Increases Proliferating CD8+ T Cells and PD-1 Expression on Immune Cells in the Tumor Microenvironment in Patients with Prior Checkpoint TherapyChantale Bernatchez1, Salah Eddine Bentebibel1, Michael E. Hurwitz2, Cara L. Haymaker1, Harriet M. Kluger2, Michael T. Tetzlaff1, Natalie Jackson1, Ivan Gergel3, Mary Ann Tagliaferri3, Jonathan Zalevsky3, Ute Hoch3, Christie Fanton3, Ernesto Iacucci3, Sandra Aung3, Michael Imperiale3, Ej Liao3, Ira Smalberg4, Brendan D. Curti5, Nizar M. Tannir1, Patrick Hwu1, Mario Sznol2, Adi Diab1
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2Yale School of Medicine, New Haven, CT; 3Nektar Therapeutics, San Francisco, CA; 4Consultant, Los Angeles, CA; 5Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR
BACKGROUND
CONCLUSIONS FUTURE DIRECTIONS
REFERENCES
ACKNOWLEDGEMENTS
RESULTS
Ef�cacy of Sequential Dosing With Nivolumab Durability in the Refractory Setting
Robust Immune Activation in Patients Who Have Failed Prior Immunotherapy
• NKTR-214 has a favorable safety pro�le. – No immune-related AEs – No capillary leak syndrome – Short-lived related TEAEs – Drug-related hypotension was predictable, short-lived and managed with �uids
• NKTR-214 increases immune cells in the blood and tumor microenvironment even in subjects who have failed multiple prior immunotherapeutic agents.
• 3 of 4 RCC IO naïve patients with SD on NKTR-214 who received sequential therapy with nivolumab demonstrated rapid responses at �rst scan on nivolumab.
• Based on the ability of NKTR-214 to prime, proliferate, and activate CD8+ T cells with increased PD-1 expression in the tumor, the combination of NKTR-214 and nivolumab is currently being evaluated in 5 tumor types and 8 indications (PIVOT-02: NCT02983045):
– Renal cell carcinoma ♦ 1-2L immunotherapy naïve ♦ 2-3L relapse/refractory on
anti-PD-1/PD-L1 therapy
– Melanoma ♦ 1L ♦ 2-3L relapse/refractory on
anti-PD-1/PD-L1 therapy
To evaluate doublet and triple-combination regimens with NKTR-214 to enhance ef�cacy and minimize toxicity including but not limited to:
• Checkpoint inhibitors• TLR agonists• Inhibitors of immune suppression• Vaccines• Bi-speci�c antibodies
The authors would like to acknowledge the contribution of patients and their families in participation of this clinical trial.
SITC 2016Poster
ASCO GU 2017 Poster
1) Charych DH, Hoch U, Langowski JL, et al. Clin Cancer Res. 2016;22(3):680-90.
2) SITC 2016 poster (see QR code below)
3) ASCO GU 2017 poster (see QR code below)
4) Daud AI, Wolchok JD, Robert C, et al. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.2016.67.2477.
5) Daud AI, Loo K, Pauli ML, et al. J Clin Invest. 2016;126(9):3447-52.
• 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 Tregs1 (see Figure below).
• In all patients evaluated, NKTR-214 increases newly proliferating (Ki67+) T and NK cells in the blood.2
• NKTR-214 increases tumor-infiltrating immune cells in RCC.3
• Anti-PD-1 therapies, such as nivolumab, depend on pre-existing T-cell infiltration within the tumors for optimal efficacy.4,5
• Nivolumab and high-dose IL-2 (HD IL-2) are currently the only two FDA-approved immunotherapies for patients with RCC; however, due to toxicities associated with HD IL-2, use of this treatment option has been limited. NKTR-214 with its favorable safety profile and mechanism of action, combined with other treatment modalities, may be an important advancement for patients suffering from RCC and other cancer types.
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+
NKTR-214 Monotherapy Study Patient Enrollment
Case #3
BOR SD onNKTR-214
PR on Nivolumab
Case #1
Con�rmed Partial Response
BOR SD onNKTR-214
PR on Nivolumab
Case #2
BOR SD onNKTR-214
PR on Nivolumab
Case #4
Achieved 30% TumorReduction on NKTR-214,
SD on Nivolumab
28 Patients Enrolled
7 PatientsMelanoma
15 PatientsRCC
6 RCC IO Naïve, Prior TKI 9 RCC Prior IO
6 PatientsOther
2 Breast2 Sarcoma1 Colorectal1 Bladder
After EOT with NKTR-214, 4 patients with SDreceived sequential therapy with nivolumab
Case #5: 59-year-old male with melanoma Stage IV Case #6: 56-year-old male with RCC Stage IV
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.
Abstract No: 2545 (Board #37). Presented on June 5, 2017, at ASCO, Chicago, IL.
αOX40PD
ipi HD IL-2Nivolumab
PDNKTR-214(23 cycles)
Vemurafenib
CD4+ T cells CD8+ T cells
CD4+ T cells CD8+ T cells
Increased Proliferation and PD-1 Expression on T Cells in Blood Increased Proliferation and PD-1 Expression on T Cells in Blood
RCC, renal cell carcinoma; EOT, end of therapy; IO, immuno-oncology; TKI, tyrosine-kinase inhibitor; BOR, best overall response; PR, partial response; SD, stable disease
TRIAL DESIGN AND TREATMENT
Blood and Tumor Biopsy Collection and Analysis
EOT, end of treatment.
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)
C1D1 C2D1 C2D8C1D8 C3D1
BaselineTumor Biopsies:
Cycle (C)/Day (D):
Week 3 Week 8
EOT
EOT
= Blood sample
Q2W or Q3WNKTR-214 NKTR-214 NKTR-214
– NSCLC ♦ 1-2L immunotherapy naïve ♦ 2-3L relapse/refractory on anti-PD-1/PD-L1 therapy
– Bladder ♦ 1L (cisplatin ineligible)
– Triple negative breast cancer ♦ 1-2L immunotherapy naïve
PriorTherapies
Therapy Administered NKTR-214
TreatmentDuration ofTreatment
Ipilimumab (ipi)Vemurafenib
~ 1 mo~ 7 mos
>15 mos
Time Interval toNext Treatment
HD IL-2Anti-OX-40 (αOX40)
PriorTherapies
Therapies Administered NKTR-214
Treatment
Nivolumab
Duration ofTreatment
~ 3 mos~ 2 mos
~ 2.5 mos
>10 mos
Time Interval toNext Treatment
~ 45 mos~ 33 mos
Ongoing
~ 22.5 mos~ 1.5 mos
~ 1 mo
Ongoing
NKTR-214 Related Treatment-Emergent Adverse Events: All Grade 3 Events andGrade 1-2 Events Occurring in ≥ 20% of Patients
*Patients reporting more than one adverse event within the same preferred term are counted once. **Hypotension and abdominal pain occurred in the same patient treated at 0.006 mg/kg q2w. †Hypotension and syncope in the patient treated at 0.012 mg/kg occurred at the same time.
• Grade 3 hypotension was rapidly reversible with IV fluids
• Management guidelines were implemented to prevent hypotension, especially Grade 3
• Median duration of pyrexia was 2 days
• 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
Note: Per protocol, abnormal lab values deemed not clinically signi�cant are not adverse events.
Grade 1-2 Grade 3
Preferred Term*
Data cut-off: May 26, 20170.003 q3w (n=4)
0.006 q3w
(n=11)
0.006 q2w (n=6)
0.009 q3w (n=6)
0.012 q3w (n=1)
0.003 q3w (n=4)
0.006 q3w
(n=11)
0.006 q2w (n=6)
0.009 q3w (n=6)
0.012 q3w (n=1)
5/28 (18%) Patients Reported Grade 3 Treatment-Related TEAE
Hypotension 1†1
1
1**
1**
1
Abdominal pain 1
2 6 2 1
2 7 5 4 1
2 7 5 35 4 3
1
5 1 3 1
1 2 4 4
2 4 1 3
1 2
3
2 2
1 2 2 2
1 3 3
1 1 1
11 1 3
3 4 1
Infusion-related reaction
Syncope 1†
Fatigue
Pruritus
Decreased appetite
Chills
Cough
Pyrexia
Arthralgia
In� uenza like illness
Nausea
Rash maculo-papular
Dizziness
Nasal congestion
SITC 2016Poster
ASCO GU 2017 Poster
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.
CD4+ T Cells
1Case #
2
43
C1D1 C1D8 C2D1 C2D80
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10
20
30
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D-1
C1D1 C1D8 C2D1 C2D80
10
20
30
% P
D-1
CD8+ T Cells
NKTR-214 Promotes Proliferation and PD-1 Upregulation in Lymphocytes in the Blood
C1D1 C1D8 C2D1 C2D80
10
20
30
40
% N
K C
ells
C1D1 = baseline
0.003 mg/kg q3w0.006 mg/kg q3w0.012 mg/kg q3w0.009 mg/kg q3w0.006 mg/kg q2w
Discontinued treatment due to RECIST PDDiscontinued treatment due to AEDiscontinued treatment due to other reasonsOngoing
PD - Best Overall Response is Progressive DiseaseSD - Best Overall Response is Stable Disease
SD
SDSD
SDSD (uPR)
SDSD
PDSD
PDPD
PDPD
PD
PDSD
SDSD
SDSD
PDSD
PDSDPD
Case #5
Case #4Case #1
Case #2
Case #6
Case #3
W3/C1 W9/C3 W15/C5 W21/C7 W27/C9 W33/C11 W39/C13 W45/C15 W51/C17 W57/C19 W63/C21 W69/C23
Breast CaRCCRCC
ChondrosarcomaLeiomyosarcoma
RCC
MelanomaRCCRCC
MelanomaRCCRCCRCC
Triple Neg BCMelanoma
Melanoma
RCCColorectal
RCCRCCRCCRCCRCCRCC
MelanomaBladder CaMelanomaMelanoma
Time on Study (Weeks/Cycles)
Data cut-off: May 26, 2017
0 W8/C4 W16/C8 W24/C12 W32/C16 W40/C20 W48/C24 W56/C28 W64/C32 W72/C36 W80/C40
Prior ipilimumab, BRAF inhibitor
Prior HD IL-2, OX40, Nivolumab
NKTR-214(15 cycles)
Case #3: 61-year-old male, RCC Stage IV
~1mo
*Minute tumor cells
Pre NKTR-214Lung Nodule
EOT NKTR-214 POST Nivolumab
Con�rmed PRPR on 1st scan
Nivolumab
NKTR-214(4 cycles)
PD-L1 status= 10%*
Baseline
CD3 CD8H&E
Week 3
Treatment
PriorTherapies
Sunitinib ~ 2.5 mos (PD) 0
Axitinib ~ 1.5 mo (PD) ~ 2 mos
Bevacizumab + CRLX101 ~ 3.5 mos (unknown) ~ 4.5 mos
~ 1.5 mos (SD)
> 7 mos
~ 1 mo
OngoingNivolumabTherapiesAdministered
NKTR-214
Duration ofTreatment
Time Interval toNext Treatment
Immunological Changes on NKTR-214 Therapy
(Max tumor response -1% per RECIST 1.1)
Number of Tumor In�ltrating Cells
0
FoxP3+ cellsCD8+ T cells
Baseline Week 3
200
2000
2200
2100
2300
Cel
ls/m
m2
Case #4: 60-year-old female, RCC Stage IV
Pre NKTR-214
Left Adrenal
Right Adrenal
BOR on NKTR-214 POST Nivolumab
Uncon�rmed PR
NivolumabNKTR-214(8 cycles)
PD-L1 status = 40% ~2 mos
30% reductionat 2nd scan
PriorTherapies
TherapiesAdministered
NKTR-214
Treatment
Pazopanib ~10.5 mos (unknown) 1 mo
Axitinib 5 mos (PD) ~2.5 mos
~5.5 mos (SD) ~2 mos
OngoingNivolumab > 4 mos
Duration ofTreatment
Time Interval toNext Treatment
(Max tumor response -30%per RECIST 1.1)
Flow Analysis of Cells fromFresh Tumor Biopsy
Baseline Week 8 EOT0
5
10
15
20
% o
f liv
e ce
lls
CD45+
CD3+
CD8+
CD8+ PD-1+
SD on 1st scan
Case #2: 66-year-old female, RCC Stage IV
EOT NKTR-214Pre NKTR-214 Pre Nivolumab(Pseudoprogression
Observed)
POST Nivolumab
Duration ofTreatment
Time Interval toNext Treatment
Prior Therapy
TherapiesAdministered
Treatment
Sunitinib ~ 8 mos (AE disc.) ~ 1.5 mos
~ 1.5 mos (SD) ~ 1 mo
OngoingNivolumab plus investigational agent > 9 mos
NKTR-214
Con�rmed PRPR on 1st scan
NKTR-214(3 cycles)
PD-L1status = NA
Nivolumab plus investigational agent~1 mo
(Max tumor response -20% per RECIST 1.1)
Scan unavailabledue to enrollment
in anotherclinical trial
Case #1: 59-year-old male, RCC Stage IV
EOT NKTR-214 POST Nivolumab
TreatmentDuration ofTreatment
Time Interval toNext Treatment
Prior Therapy Sunitinib ~ 67 mos (PD) ~ 2 mos
TherapiesAdministered
NKTR-214 ~ 5 mos (SD) ~ 1 mo
OngoingNivolumab > 9 mos
~1 mo
Con�rmed PRPR on 1st scan
Nivolumab
CD8+ Ki67+
0-103 103 104 105
Ki67+
7.76%
0
50K
100K
25K
75K
SS
C-A
0-103 103 104 105
Ki67+
32.8%
0
50K
100K
25K
75K
SS
C-A
Ki67
Pre NKTR-214Left Lung Nodule
NKTR-214 (8 cycles)PD-L1 status† = neg
H&E CD3 CD8
Baseline
Week 3
Immunological Changes on NKTR-214 Therapy
(Max tumor response -10% per RECIST 1.1)
RNA Expression (NanoString)Week 3/Baseline
0IFNG PRF1 GZMB IRF3 IL6 IL6R
1
2
3
4
5
6
Fold
Cha
nge
Functional MarkersIn�ammation MarkersNo induction (fold change =1)
1027 meancells/mm2
675 meancells/mm2
2017 meancells/mm2
1620 meancells/mm2
IFNG, interferon gamma; PRF1, perforin-1; GZMB, granzyme B; IRF3, interferon regulatory factor 3; IL6, interleukin 6; IL6R, interleukin-6 receptor
†PD-L1 status was obtained using the Cell Signaling antibody (Cell Signaling #13684, PD-L1 (E1L3N)) at a 1:100 dilution on the Leica BOND RXm
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