Safety, immune activation and anti-tumor efficacy of PEGylated recombinant human IL-10 (AM0010)

Transcription

1 Safety, immune activation and anti-tumor efficacy of PEGylated recombinant human IL-1 (AM1) Jeffrey R. Infante, MD AACR 216 Aung Naing 1, Kyriakos P. Papadopoulos 2, Karen A. Autio 3, Patrick A. Ott 4, Manish Patel 5, Deborah J. Wong 6, Gerald S. Falchook 7, Shubham Pant 8, Melinda Whiteside 9, John B. Mumm 9, Ivan H. Chan 9, Johanna C. Bendell 1, Todd M. Bauer 1, Rivka Colen 1, David Hong 1, Peter Van Vlasselaer 9, Nizar Tannir 1, Martin Oft 9 and Jeffrey R. Infante 1 1 MD Anderson Cancer Center, 2 START Center for Cancer Care, San Antonio, TX; 3 Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Dana-Farber Cancer Institute, Boston, MA; 5 Sarah Cannon Research Institute/Florida Cancer Specialists, 6 University of California Los Angeles (UCLA), Los Angeles, CA, 7 Sarah Cannon Research Institute at HealthONE, Denver, CO, 8 Oklahoma University, 9 ARMO BioSciences, Redwood City CA; 1 Sarah Cannon Research Institute / Tennessee Oncology, PLLC;

2 Disclosures Jeffrey R. Infante has no conflict of interest. John B. Mumm, Ivan Chan, Melinda Whiteside, Peter Van Vlasselear, Martin Oft are employees of ARMO BioSciences. 1

3 Immuno-Oncology Challenges Immune checkpoint inhibitors have changed the prospect of many cancer patients Even immuno-sensitive cancers such as melanoma, NSCLC and RCC have a high refractory rate to checkpoint inhibition Indication % of Patients refractory after 1 year Anti-PD-1 Anti-PD-1/ CTLA4 Melanoma 55% 1 5% 1, 2 NSCLC 8% 3 8% 4 RCC 69% 5 55% 6 1 Larkin NEJM 215; 2 Postow NEJM Rizvi LancOnc 215; 4 Antonia ASCO Motzer NEJM 215; 6 Hammers ASCO 215 Limited response rates are observed in immuno-insensitive cancers such as CRC, PDAC, TNBC, etc. AM1 increases the vulnerability of tumors to immune mediated destruction 2 2

4 Tumor Immune Therapy for Patients Resistant to Immune Checkpoint Blockade Immune resistant phenotypes Tumors with limited T cell recognition Low mutation rate Limited immune detection by T cells Immune modifying tumor microenvironment No tumor infiltration by CD8+ T cells no T cell survival factors Non cytotoxic inflammatory T cells: Tc17, Tc22 Deficient in Granzyme and IFNg expression No MHC expression in the tumor AM1 activates cytotoxicity of tumor infiltrating CD8+ T cells 3

5 IL-1 Inhibits Inflammation but Activates Tumor Infiltrating CD8+ T cells IL-1 controls exuberant inflammatory responses to bacterial products or cellular debris Inhibition of IL-12/23 and macrophages; sustains CD4 T regulatory cells Li and Flavell, Immunity 28 Humans and mice deficient for IL-1R or IL-1 develop colitis and cancer Glocker et al., NEJM 29; Neven et al., Blood 213 IL-1 and PEG-IL-1 stimulate antigen activated CD8+ T cells Mumm et al., Cancer Cell 211; Chan et al JICR 215 PEG-IL-1 induces proliferation, survival and cytotoxicity of intratumoral CD8+ T cells Mumm et al. Cancer Cell 211; Emmerich et al., Cancer Research 212 Treatment of mouse tumor models with PEG-IL-1 leads to the rejection of tumors and metastases Mumm et al., Cancer Cell 211, Chan et al., RCI 215 4

6 IL-1 Enhances Antigen Activated CD8+ T cells PEG-IL-1 (or IL-1) inhibits monocytes, but enhances antigen activated CD8+ T cells Inhibits inflammation Activates CD8+ T cell and antigen specific immunity Chan et al., JICR 215 Monocytes / Neutrophils CD8+ T cells Control PEG-IL-1 PBMC derived human monocytes or CD8+ T cells 5

7 PEG-IL-1 induces Tumor Rejection and Tumor Immune Memory in Mice Treatment with PEGylated IL-1 (surrogate for AM1) induces rejection of large tumors PEG-IL-1 - cured mice develop long term immune memory Tumor Rejection and Immune Memory Rechallenge 8 months later PEG-IL-1 expands tumor specific CD8+ T cells in the blood Tumor rejection is dependent on CD8+ T cells Mumm et al., Cancer Cell 211 Tumor specific CD8+ T cells Stimulation with 6

8 AM1 (PEG-IL-1) Increases and Activates Tumor Infiltrating CD8+ T cells Tumor antigen recognition by CD8+ T cells induces PD-1 and the IL-1 receptor on CD8+ T cells PD-1 inhibits the TCR signal in CD8+ T cells Negative feedback ( Immune Checkpoint ) IL-1 activates CD8+ T cells Positive feedback ( Cytotoxic License ) PEG-IL-1 induces cytotoxicity, proliferation and survival of CD8+ T cells and leads to the expansion of antigen activated, PD-1+ intratumoral CD8+ T cells p-stat3 p-stat1 AP-1 AM1 IL1R Survival + Activation IFNg ACTIVATION TCR Anti- PD-1 Apoptosis 7

9 Rationale for FIH Study PEG-IL-1 has strong single agent anti tumor activity in mouse tumor models Mumm et al., Cancer Cell 211 PEG-IL-1 increases the activation of tumor infiltrating CD8+ T cells Non-PEGylated recombinant IL-1 was safely dosed in several phase 2 and 3 trials in psoriasis, colitis and rheumatoid arthritis Increased granzmes and IFNg observed at higher doses Asadullah et al., Pharmac. Rev 23 AM1 (PEG-rHuIL-1) is safe in rodents and non-human primates Phase 1 with AM1 started in November 213 8

10 Objectives Primary Objective Safety, tolerability, MTD), and pharmacokinetic (PK) of AM1 after daily subcutaneous (SC) administrations in patients with advanced solid tumors as monotherapy or in combination with chemotherapy or immunotherapy Secondary Objective To measure the tumor response in radiographically measurable disease by immune related Response Criteria (irrc) Exploratory Objective To investigate biomarkers for patient stratification and treatment response 9

11 Eligibility Criteria Treatment refractory melanoma, castrate resistant prostate cancer (CRPC), ovarian cancer (OvCa), renal cell carcinoma (RCC), colorectal carcinoma (CRC), pancreatic carcinoma or nonsmall cell lung carcinoma (NSCLC) Adequate organ function Excluded prior Guillain-Barré syndrome and neuro-inflammatory diseases Allowed all other autoimmune diseases incl. RA, Crohn s disease, psoriasis 1

12 AM1 Ph1/Ph1b Study Design 1 mg/kg Dose Escalation (n=3-6) 2.5 mg/kg Dose Escalation (n=3-6) 5 mg/kg Dose Escalation (n=3-6) 1 mg/kg Dose Escalation (n=3-6) 2 mg/kg Dose Escalation (n=3-6) 4 mg/kg Dose Escalation (n=3-6) Escalation cohorts N=

13 AM1 Phase 1 Dose Escalation Cohorts Patient Characteristics Characteristic N (%) Sex* Male 31 Female 2 Age, years* Median 61 Range Tumor histology total 33 Dose Escalation Colorectal cancer 16 (48.5) Renal cell carcinoma 6 (18.2) Pancreatic cancer 4 (12.1) Melanoma 4 (12.1) Non-small-cell lung cancer 1 (3) Ovarian cancer 1 (3) Prostate cancer 1 (3) Dose Expansion (2mg/kg) Renal cell carcinoma 18 (1) ECOG PS* 26 (51) 1 25 (49) Prior therapies Dose Escalation Median 4 Range 11 Chemotherapy /Radiation therapy 3 / 3 Immunotherapy 7 Biologics /Targeted therapy 19 /15 Prior Therapies - RCC Median 3 Range -1 Immunotherapy (anti PD-1) 6 (2) Antiangiogenic 15 * Include escalation and expansion cohort Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status 12

14 AM1 is Safe and Well Tolerated AM1 is safe and well tolerated in 51 patients The selected Ph2 dose is 2mg/kg in monotherapy G1/2 TrAEs included fever (3%), injection side reaction (36%), fatigue (45%), anemia and thrombocytopenia G3 TrAEs at 2mg/kg were anemia (2%) or thrombocytopenia (1%) All G3/4 TrAEs were reversible (discontinuation rate below 1%) One patient had a DLT (anemia) No immune related TrAEs, such as colitis, pneumonitis or endocrine disorders 13

15 Treatment related Adverse Events - AM1 Adverse Events Dose Escalation Cohort (µg/kg) n Event Grade 1-2 Grade 3-4 ALT increased 2 Anemia Anorexia Arthralgia 1 1 Back pain 1 1 Chills Diarrhea Dyslipidemia Fatigue Fever Flu-like symptoms hypoalbuminemia 1 1 Increased lipase 1 Injection site reaction Leukopenia 1 1 Myalgia 1 1 Nausea Night Sweats 1 1 Pruritis Rash Rash Maculo-popular 3 1 Thrombocytopenia Transaminitis 1 Vomiting Weakness Table does not include events that occurred in less than three patients at grade 1-2 severity 14

16 Stable Exposure to AM1 Required serum trough determined in mouse efficacy models is 1 ng/ml AM1 serum trough (C min ) is continuously above 5% effective concentration in patients receiving > 5 mg/kg Recommended Phase 2 dose is 2 mg/kg Required AM1 serum trough 15

17 L A P -T G F b (p g /m L ) AM1 Induces Dose Dependent Immune Signature in Patients AM1 treatment induced a dose dependent immune signature in patients (of 96 tested) Th1 & Th2 cytokines CD8+ T cell activation Immune suppression IFNg, IL-4, IL-18 IL-7, FasL TGF-b IL-18 FasL TGFb m g /k g Q D 2.5 m g /k g Q D m g /k g Q D 1 m g /k g Q D 2 m g /k g Q D 4 m g /k g Q D fold stimulation D a y s o n tre a tm e n t -1 8 % +.6 % -2 4 % -2 9 % -4 2 % -4 % c h a n g e Change from day 1 16

18 % C h a n g e in T u m o r b u r d e n (irr C ) AM1 has Anti-tumor Activity as Monotherapy Objective Responses in RCC and Uveal melanoma at 2-4 mg/kg 1 Dose Escalation Melanoma and RCC A M 1 CRC and pancreatic cancer patients with prolonged stable disease (up to 1.5y) 5 * m g 2 /krg C C 5 2m -g /k 8 g R C C R C C 1 4 -m g /k 4 g R* C C 2 2 -m g 2/k gr C C CR in Cutaneous T cell lymphoma * 1 1m -g /k 1 g M E L 5 1m -g /k 5 g M E L M e la n o m a 2 4 -m g /k 5 g M* E L m g 2/k 4 gm E L * m ix e d re s p o n s e (s o m e le s io n s re d u c e d ) w e e k s Continuing 17

19 AM1 Eliminates Tumor Cells and Increases CD8+ T cell Infiltration in Uveal Melanoma Metastasis AM1 monotherapy in uveal melanoma patient with PR results in expansion of activated PD-1 + CD8 + T cells and subsequent removal of stomach metastasis Stomach metastasis Pre Treatment Tumor Cells Day 225 of Treatment Tumor Infiltrating Cytotoxic PD-1 + CD8 + T Cells (TILs) IHC: Granzyme / CD8 IHC: Granzyme / CD8 18

20 % C h a n g e in T u m o r b u r d e n ( ir R C ) AM1 Monotherapy - Activity in RCC RCC treated at 2 mg/kg AM1 Monotherapy - Renal Cell Cancer ORR: 27% objective responses (n=15(19)) 1 Delayed responses after 2+ weeks ( ) w e e k s Continuing on study 2-2 R C C R C C -X 19

21 AM1 Monotherapy - RCC Pre-Treatment 29 Weeks Treatment 2 mg/kg irpr (-71%) lung lung subscapular subscapular paratracheal paratracheal Tumor burden was reduced by -12%, -6%, and -71% at 7, 13 and 22 weeks, respectively 2

22 % C h a n g e in T u m o r b u rd e n RCC AM1 Monotherapy RCC patient on study for 5+ weeks AM1 monotherapy (2mg/kg) Initially continued growth of lung lesions for 16 weeks Delayed tumor reduction (-92%; SD) after 28 weeks Lung metastasis w e e k s Pre-treatment 16 weeks (+18%) 21 weeks (-38%) 28 weeks (-92%) 21

23 KI-67 KI-67 AM1 Induces Proliferation of PD-1+ Effector CD8+ T Cells AM1 monotherapy induction of KI67 + PD-1 + LAG3 + CD8 + T cells coincides with tumor shrinkage Iso Week 4 Week 17 Week 21 Wk 4 Wk 17 Wk PD-1+ Effector T cells Iso PD-1 Renal Cell Carcinoma Patient FACS analysis of CD8+ T cells (blood) Dose: 2 mg/kg AM1 Previous Therapies 1. Sutent +/- LY (CXCR4 peptide antagonist) (23mo) 2. ASONEP (mab anti-angiogenesis) (3mo) 2 patients with AM1 monotherapy analyzed: KI67+ PD1+ T cells +14% to +118% increased 8 91 Iso LAG LAG3+ Effector T cells 22

24 % C h a n g e in T u m o r b u r d e n ( ir R C ) AM1 Reduces of Treg Proliferation AM1 reduces proliferation of Foxp3+ T cells in the blood 1 5 Wk 8 Wk 4 Wk 16 Wk w e e k s Renal Cell Carcinoma Patient FACS analysis of CD4+ T cells (blood) PR (-56%) 2 mg/kg AM1 2 patients with AM1 monotherapy analyzed: KI67+ Foxp3+ T cells -89% to -9% decreased 23

25 P B M C : % P D 1 + C e lls P B M C : % K i6 7 + P D 1 + P B M C : F o x P 3 -C D 3 + / F o x P 3 + C D 3 + R a tio P B M C : K i6 7 + F o x P 3 -C D 3 + K i6 7 + F o x P 3 + C D 3 + R a tio AM1 Increases Blood Effector/Treg Ratio AM1 skews the patients immune system from a regulatory to an effector function 7 5 P B M C : P D 1 + C e lls 2 P B M C : P ro life ra tin g P D 1 + C e lls 7 5 P B M C : E ffe c to r/ S u p p re s o r C e lls P B M C : P ro life ra tin g E ffe c to r/s u p p re s o r c e lls 4 * ** D a y 1 1 m o > 2 m o D a y 1 1 m o > 2 m o D a y 1 1 m o > 2 m o D a y 1 1 m o > 2 m o 8 Patients Melanoma, RCC, GE, PDAC, NSCLC Reproducible in monotherapy or combination with FOLFOX or anti-pd-1 mab 24

26 Oligoclonal T cell Expansion in RCC Patients in Response to AM1 Monotherapy Day 29 Day 14 Clones P B M C P T B c M e ll C c T o u c n e ts ll c o u n ts Clonal analysis of peripheral T cells (TCR sequence, 73 patient analyzed) AM1 increase of T cell clones prior to tumor shrinkage T c e ll R e p e rto ire Day 29 Day 14 1 T c e ll R e p e rto ire 8 1 Day 29 Day 14 Expanded clones Expanded clones Day 1 Contracted clones Day 1 Contracted clones Day 29 Day 14 D a y 2 9 T im e P o in t T im e P o in t C o n tra c te d D a y 2 9 D a y D a y CEo xn ptra a cn te d ed d E x p a n d e d Adaptive Biotechnologies 25

27 AM1 Expands Tumor Infiltrating T cell Clones in Immuno-Insensitive Cancers Day 29 (count) C o Clones u n ts CRC patient s blood shows increase of unique tumor specific TCR clones in the blood 8 T c e ll c lo n e s Expanded clones 6 4 Expanded Clone Expanded Clone also found in tumor Contracted Clone Contracted Clone also found in tumor Stable Clone Contracted clones 2 Day 1 (count) 2 9 Total Tumor Day 29 D a y Adaptive Biotechnologies C o n tr a c te d E x p a n d e d C o n tra c te d, a ls o fo u n d in tu m o r 26

28 AM1 Monotherapy Increases PD-1 + CD8+ Effector Cells in Immuno-Insensitive Cancers AM1 increases the number of PD-1 + CD8 + effector cells in MSS CRC patient and thus may prime this tumor to become responsive to anti-pd-1 therapy Pre Treatment Day 6 of Treatment Liver metastasis Tumor Infiltrating Cytotoxic PD-1 + CD8 + T Cells (TILs) Granzyme B CD8 AM1 increases the number of PD-1 +, T-bet +, Granzyme +, pstat3 + CD8 + T cells in the tumor 27

29 AM1 Summary AM1 is a therapeutically active molecule with single agent activity AM1 has an acceptable safety profile AM1 primes tumors with activated PD1+ CD8+ effector cells immuno-sensitive cancers such as melanoma, RCC and NSCLC immuno-insensitive cancers such as CRC, PDAC and TNBC AM1 skews the immune system of cancer patients towards effector function Initiation of Ph2/3 registration studies with AM1 are planned for

30 Ongoing AM1 Ph1/Ph1b Studies Completed Enrollment Ongoing Enrollment Monotherapy Dose Escalation (n=33) Monotherapy Dose Expansion 1 Indications (n=111) Combo-Therapy Dose Escalation 7 Chemo SOC (n=65) Combo-Therapy Dose Escalation w/ 2 Anti-PD-1 Nivo/Pembro (n=29) PDAC 2 nd Line (n=3) FOLFOX + AM1 TNBC 1 st /2 nd Line (n=2) Gem/Carbo + AM1 Melanoma >2 nd Line (n=3) Anti-PD-1 Refractory Pembro/Nivo + AM1 NSCLC >2 nd Line (n=3) Nivo + AM1 RCC >2 nd Line (n=3) Nivo + AM1 29

31 Thanks We want to thank all patients and their relatives! Jeffrey R. Infante Johanna C. Bendell Todd M. Bauer Aung Naing Filip Janku Rivka Colen Nizar Tannir Sarah Cannon Research Institute / Tennessee Oncology, PLLC; Nashville, TN MD Anderson Cancer Center; Houston TX Peter Van Vlasselaer Melinda Whiteside John Mumm Ivan Chan Martin Oft ARMO BioSciences Inc.; Redwood City CA Kyriakos P. Papadopoulos Karen A. Autio Patrick A. Ott Deborah J. Wong Gerald S. Falchook Manish R. Patel Shubham Pant START Center for Cancer Care; San Antonio, TX Memorial Sloan-Kettering Cancer Center; New York, NY Dana-Farber Cancer Institute; Boston, MA University of California Los Angeles (UCLA); Los Angeles, CA Sarah Cannon Research Institute at HealthONE; Denver, CO Florida Cancer Specialists; Sarasota, FL Oklahoma University; Oklahoma City, OK 3