12 th European International Kidney Cancer Symposium April 2017

Transcription

1 PEGylated Human IL-1 (AM1) in Cmbinatin with Nivlumab in Renal Cell Cancer Aung Naing, Jeffrey R. Infante, Debrah J. Wng, W. Michael Krn, Raid Aljumaily, Kyriaks P. Papadpuls, Karen A. Auti, Shubham Pant, Tdd M. Bauer, Alexandra Drakaki, Naval G. Daver, Annie Hung, Peter Van Vlasselaer, Gail L. Brwn, Martin Oft and Nizar Tannir Cancer Sympsium April 217

2 AM1 activates Tumr infiltrating CD8 + T cells The Prblem AM1 (PEG-IL-1) Lw T cell infiltratin Tumr infiltrating CD8+ T cells recgnize the tumr cell, but they are nt active T cell apptsis Inflammatry, tumr prmting T cells IL-1 is an anti-inflammatry cytkine and activates tumr specific CD8+ T cells at higher cncentratins AM1 induces prliferatin, IFNg, IL-4, Granzymes and FasL in CD8+ T cells in patients Granzyme and FasL induce tumr cell death IFNg and IL-4 induce immunizatin t the tumr antigens P-STAT3 P-STAT1 Cancer Sympsium April 217

3 IL -1 8 (p g /m L ) IF N g (p g /m L ) F a s L (p g /m L ) T G F (n g /m L ) IL -1 8 (p g /m L ) IF N g (p g /m L ) F a s L (p g /m L ) T G F (n g /m L ) AM1 Induces Th1/CD8 + T cell Immune Signature in Patients AM1 induces Th1 cytkines in the serum cancer patients Similar in respnse t AM1 alne r the cmbinatin f AM1 + pembrlizumab AM1 (n=16) IL IF N g F a s L T G F p <. 1 p =. 2 p =. 4 3 p = IL IF N g 5 F a s L 1 5 T G F AM1 + Pembrlizumab (n=16) p <. 1 p =. 1 7 p =. 4 9 p = Cancer Sympsium April 217

4 Day 215 N u m b e r f C l n e s expanded clnes (n) (> 1 -f ld in c re a s e ) Day 14 expanded clnes (n) n u m b e r f e x p a n d in g c l n e s C l n e n u m b e r A ll Clnal T cell Expansin Crrelates with Objective Tumr Respnse AM1 induces nvel T cell clnes t expand in the bld Expanded clnes becme 1-1% f the ttal T cell repertire Number f >1 fld expanded T cell clnes crrelates with tumr respnse RCC (PR) AM1 Mntherapy Expanded clnes Cntracted clnes Day 1 Tumr Respnse P D S D C l n e n u m b e r A ll m n 1 + p = p e. mb 4r3 P R p =. 2 2 RCC (PR; -1%) Expanded clnes 1 AM1 + Pembrlizumab 1 Abslute Number f Expanded Unique T cell Clnes; stratified by tumr respnse ( n / patient) Day 1 Cntracted clnes 1 P D S D P R p =. 12 th R e s p n s e Eurpean Internatinal Kidney Cancer Sympsium April 217 4

5 RCC Patient Characteristics Demgraphic, Baseline Characteristics, and Prir Therapy f All Treated Patients Mntherapy 2mg (2 µg/kg) n=19 AM1-1mg / 2mg (1 µg/kg / 2 µg/kg) + Pembrlizumab n=9 AM1 2mg (2 µg/kg) + Nivlumab n=29 Median Age, years (range) 61 (22, 68) 54 (32, 75) 66 (36, 77) Sex, n (%) Male 12 (63%) 6 (67%) 21 (72%) Female 7 (37%) 3 (33%) 8 (28%) ECOG Perfrmance Status, n (%) 11 (58%) 3 (33%) 9 (32%) 1 8 (42%) 6 (67%) 2 (68%) Number f Prir Therapies, 3 (-7) 2 (-5) 1 (1-3) median (range) IMDC (intermediate t pr risk) 19 (1%) 9 (1%) 24 (92%) IMDC risk: 2 favrable, 2 intermediate, 4 pr, 3 nt available Cancer Sympsium April 217

6 Treatment related Adverse Events AM1 + Anti-PD-1 in RCC AM1 and anti-pd-1 is well tlerated (RCC: n=38) (RCC, melanma, NSCLC ttal n=11) TrAEs include thrmbcytpenia, anemia, fatigue, fever, rash, pruritus, pneumnitis G3/4 TrAEs were reversible and transient Anemia, thrmbcytpenia, fatigue, ALT/AST increase, hypertriglyceridemia 1 RCC patient n 2mg/kg AM1 + nivlumab had a reversible G3 hemphagcytsis, mst likely triggered by Th1 cytkine inductin N exacerbatin f aut-immune related TrAEs cmpared t expected anti-pd-1 TrAEs The selected MTD / Ph2 dse fr AM1 + anti- PD-1 is 1mg/kg AM1 Treatment related adverse events AM1 + pembrlizumab / nivlumab in RCC Grade 1/2 Grade 3/4 AM1 Dse 1µg/kg 2µg/kg 1µg/kg 2µg/kg Pembr Niv Pembr Niv Pembr Niv Pembr Niv Number f Patients N=5 N=1 N=4 N=28 N=5 N=1 N=4 N=28 Bld and lymphatic system Anaemia 2 (4.%) 1 (1%) 6 (21.4%) 9 (32.1%) Thrmbcytpenia 2 (4.%) 3 (1.7%) 1 (25.%) 5 (17.9%) Splenmegaly 1 (3.6%) 1 (3.6%) Endcrine Hypthyridism 1 ( 25%) Nausea 1 ( 25%) 1 (3.6%) Vmiting 2 ( 7.1%) General disrders and administratin site cnditins Chills 4 (14.3%) Fatigue 3 (6%) 2 (5%) 8 (28.6%) 1 (3.6%) Dyspnea 3 (1.7%) Pyrexia 1 (25%) 8 (28.6%) Applicatin site erythema 2 (5%) Investigatins Alanine amintransferase increased 2 (7.1%) 1 (25%) Aspartate amintransferase increased 1 (3.6%) 1 (25%) Metablism and nutritin disrders Decreased appetite 1 (2%) 2 ( 7.1%) Hyperglycaemia 3 (1.7%) Hypertriglyceridaemia 1 (2%) 1 (1%) 6 (21.4%) 1 (2%) 4 (14.3%) Musculskeletal and cnnective tissue disrders Myalgia 5 (17.8%) Headache 5 (17.8%) Dyspne 3 (1.7%) Pruritus 2 (5%) 5 (17.9%) 1 (2%) Rash 1 (1%) 1 (25%) 4 (14.3%) 1 (2%) Rash, macul-papular 1 (2%) 2 (5%) 3 (1.7%) 1 (2%) Table includes all patients with a G1-4 TrAEs accrding t NCI-CTCAE, (1 event was nt cded) Patients in the AM1+Pembr chrt received 1 r 2 mg/kg AM1 daily and 2mg/kg Pembrlizumab every three weeks Cancer Sympsium April 217 6

7 C h a n g e in T u m r B u rd e n (% ) C h a n g e i n T u m r B u r d e n ( % ) AM1 Mntherapy and AM1 + Pembrlizumab in Metastatic Renal Cell Cancer (Intermediate t pr risk - IMDC) RCC with AM1 Mntherapy RCC with AM1 + Pembrlizumab AM1 AM1 P e m b r H S p i d e r S C A N Pembr m g / k g A M 1 2 m g / k g A M 1 Objective respnses ORR (cnfirmed) Prir Therapies, median (range) 4 PR (n=15) 26.7% (n=15) 4 PR ) 5% (n=8) 3 (-7) 2 (-5) Late respnse 2-2 R C C R C C -X 5-3 R C C -X R C C -X 8-4 R C C -X R C C -X R C C -X w e e k s R C C -X R C C -X Naing et al. JCO R C C -X R C C -X 7-6 R C C -X 6-7 R C C -X R C C 7-8 R C C -X - 1 Cntinuing n study w e e k s R C C - H R C C - H 2 NR: nt anti-pd-1 and AM1 naïve RCC # median fllw-up 22.4 mnths (range ) median fllw-up 2.5 mnths (range ) Cancer Sympsium April R C C - H R C C H R C C - H R C C H X 1 7

8 C h a n g e i n T u m r B u r d e n ( % ) AM1 + Nivlumab in Metastatic Renal Cell Cancer (92% Intermediate t pr risk - IMDC) 1 P e m b r H S p i d e r S C A N RCC with AM1 + nivlumab AM1 AM1 + Pembr Objective respnses 4 PR (n=15) 4 PR (n=8) AM1 + Niv 9 PR (n=26) 5 2 m g / k g A M 1 1 m g / k g A M 1 ORR 26.7% # (n=15) 5% (n=8) 35% (n=26) SD (3-49% tumr reductin) 1 (12.5%) 6 (27%) DCR n (%) 9 (6%) 8 (1%) 21 (81%) mpfs 16.7 NR - 5 Number f Prir Therapies, median (range) 3 (-7) 2 (-5) 1 (1-3) Late respnse w e e k s # median fllw-up 22.4 mnths (range ) median fllw-up 2.5 mnths (range median fllw-up 4.9 mnths (range ) NR nt reached R C C R C C Cancer Sympsium April 217 8

9 AM1 - Cnclusins AM1 leads t Th1/Th2 cytkine inductin, T cell activatin and sustained expansin f selected T cell clnes T cell expansin crrelates with bjective respnses Unique mechanism f actin cmplementary t checkpint inhibitrs Remarkable single agent activity in RCC Cmbinatin f AM1 + anti-pd-1 in RCC shws increased respnse rate cmpared t anti-pd-1 r AM1 alne Initiatin f a Randmized Phase 3 Study is planned fr H2 217 Cancer Sympsium April 217 9