I L - 1 8 IF N F a s L T G F Clinical activity and safety ...

1 Clinical activity and safety of PEGylated human IL-10 (AM0010) in combination with anti-PD-1. Aung Naing1*, Kyriakos P. Papadopoulos2*, Jeffrey R. Infante3*, Deborah J. Wong6, Karen A. Autio4, Patrick A. Ott5, Gerald S. Falchook7, Manish Patel8, Shubham Pant9, Amita Patnaik2, Melinda Whiteside10, John B. Mumm10, Ivan H. Chan10, Johanna C. Bendell3, Todd M. Bauer3, Filip Janku1, Milind Javle1, Rivka Colen1, Nizar Tannir1, Peter Van Vlasselaer10 and Martin Oft10. 1 MD Anderson Cancer Center; 2 START Center for Cancer Care, San Antonio, TX; 3 Sarah Cannon Research Institute / Tennessee Oncology, PLLC; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 Dana-Farber Cancer Institute, Boston, MA; 6 University of California Los Angeles (UCLA), Los Angeles, CA; 7 Sarah Cannon Research Institute at HealthONE, Denver, CO; 8 Sarah Cannon Research Institute/Florida Cancer Specialists, 9.

2 Oklahoma University, 10 ARMO BioSciences, Redwood City CA. Background and Purpose Study Design and Eligibility Immune Activation by PEG-IL-10 in Patients is independent of anti-PD-1 Conclusion and Outlook AM0010 Monotherapy induces Phospho-STAT3. o IL-10 was cloned at DNAX/Schering-Plough in 1989 two functions AM0010. Monotherapy Monotherapy AM0010 - immune activation signature IL - 1 8 IF N g FasL TG Fb . * * in Intratumoral CD8+ T cells o CSIF (cytokine synthesis inhibitory factor) - anti-inflammatory . **. AM0010 + Pembrolizumab Summary **. Continuous Daily Subcutaneous Injection Dose Escalation Dose Expansion 2500 5. 50 15. oAM0010 treatment (20mg/kg) induced a comprehensive o B-TCGF (B cell derived T cell growth factor) - stimulates cytotoxic CD8+ T cells 3+3 Dose Escalation 1-40 mg/kg Cohorts immune signature in the serum of patients 2000 4 40.

3 T G F b ( n g /m L ). F a s L ( p g /m L ). 20 mg/kg IF N g ( p g /m L ). IL - 1 8 ( p g /m L ). o Schering-Plough sponsored several phase 3 studies with rHuIL-10 in immune mediated inflammatory Dose levels: 10 & 20 g/kg Th1 cytokines AM0010 3 30. 10. IFNg , IL-18 o19 patients with immune sensitive tumor types 1500. diseases (Psoriasis, Crohn's disease, RA) and liver fibrosis (n=16) 2 20. CD8+ T cells Dendritic cell stimulation: IL-4, GM-CSF 1000. o 5. rHuIL-10 transiently lowered TNFa and IL-1 in patients (-50% only) Pembrolizumab Pembrolizumab Pembrolizumab Growth factor for memory CD8+ T cells IL-7. 500 1 10 P-STAT3- P-STAT3+ (Melanoma, RCC, NSCLC) were enrolled for the o Signs of efficacy were observed but short T1/2 of rHuIL-10 limits its therapeutic efficacy 2mg/kg every three weeks + AM0010 + AM0010 0 0 0 0.

4 % STAT3+. treatment with PEG-IL-10 (10 or 20mg/kg qd) and o Increased Granzymes and IFNg were observed at higher doses (indicative of CD8+ T cell activity ) Dose Expansion CD8+ T cell activity FasL * * * * p < 0 .0 0 0 1 * p = 0 .0 2 * p = 0 .0 4 3 * * p = 0 .0 0 3 1. 100. 10-20 mg/kg C D 8 + p S T A T 3 - P re 9. 9. 9. 9. 1. 1. 1. 1. 2. 2. 2. 2. y y y % of CD8+ TILs pembrolizumab (2mg/kg q3w). y a y a y a y o 10 mg/kg a y C D 8 + p S T A T 3 - P o st a D. Uveal melanoma a a D. D. Immune suppression a D. ARMO BioSciences is developing AM0010, a PEGylated human IL-10 (PEG-rHuIL-10). D. TGF-b D. D. D. 75. Pre IL - 1 8 IF N g FasL TG Fb o High cure rate in animals with solid tumors and metastatic disease (PEG-IL-10 not rIL-10).

5 Key Eligibility in Pembrolizumab + AM0010 Cohorts oOther inflammatory cytokines were not significantly 2500 ** 5. **. 50 * 15 *. P-STAT3 - CD8 50. Acceptable tolerability profile (up to 12 months). o Induces activation, proliferation and survival of intratumoral CD8+ T cells altered o Expansion of tumor specific CD8+ T cells . 2000 4 40 25. oThe combination was tolerated at 10 and 20mg/kg IF N g ( p g /m L ). Tumor types: Melanoma, RCC, NSCLC (no prior anti-PD1 or anti-PD-L1 allowed). T G F b ( n g /m L ). IL - 1 8 ( p g /m L ). F a s L ( p g /m L ). oIL-10 immune activation signature is activated in all AM0010 + 3. 10. AM0010 no increase in irAEs 1500.

6 O 30 0. Treatment results in long-term anti-tumor immune memory patients with or without anti-PD-1 Anti-PD-1. t t re re os os -P. P. -P. P. 2. o +. 1000 20. T3. +. T3. Works in combination with chemotherapy T3. Encouraging Efficacy Profile T3. TA. (n=16) 5. TA.. TA. TA. Excluded prior Guillain-Barr syndrome and neuro-inflammatory diseases pS. pS. pS. pS. 1. 8+. 500 10. 8+. 8+. 8+. oAM0010 increases Phospho-STAT3 in tumor infiltrating D. D. oRCC (n=8): ORR 50%, DCR 100% at 16 weeks D. C. D. Day 225. C. C. C. o In this Ph1 Clinical study AM0010 was evaluated as single agent and in combination with SOC chemo and CD8+ T cells 0. * * * * p < 0 .0 0 0 1.

7 0. * * p = 0 .0 0 1 7. 0. * p = 0 .0 4 9. 0. 9. * p = 0 .0 1 7 2. 1. 9. 9. 9. 2. 1. 1. 1. oNSCLC (n=5): ORR 40%, DCR 80% at 16 weeks y 2.. 2. 2. y y y a y anti-PD-1 Allowed all other autoimmune diseases incl. RA, Crohn's disease, psoriasis a y a y a y a D. a D. a D. a D. D. D. D. D. Serum cytokine assays by Myriad RBM; IHC by Dr. Scott Rodig DFCI and Cr. Coya Tapiya MDACC; FACS analysis by Drs. Phil Wong, Jianda Yuan and Kong Shen, MSKCC P-STAT3 CD8. o Here we report on the cohorts of AM0010 in combination with Pembrolizumab. oMelanoma (n=6): ORR 33% (high rate of pseudo Background: Mechanism of Action Results progression?). Treatment Related Adverse Events AM0010 +pembrolizumab combo has durable efficacy in AM0010 or AM0010 + pembrolizumab combo induces sustained proliferation of PD-1+ Sustained Th1 / CD8+ T cell mediated immune activation Low levels of IL-10 are anti-inflammatory - high levels Most common TrAEs included fatigue (n=11; 57%), anemia oIncrease of activated tumor infiltrating CD8+ T cells expand antigen activated CD8+ T cells (11; 57%), thrombocyotopenia (10; 53%), maculopapular RCC, NSCLC and Melanoma patients CD8+ T effector cells in the peripheral blood of cancer patients rash (10; 53%), hypertriglyceridemia (9; 42%), anorexia (8.)

8 P B M C : P D 1 + C e lls P B M C : P r o life r a tin g o Increase of proliferating, PD-1+ CD8+ T cells P D 1 + C e lls Tumor antigen recognition by CD8+ T cells 37%) and pruritis (7; 37%) Best Response SD PR CR DCR 75. 20 o Oligoclonal expansion of novel T cells in systemic (TCR) induces PD-1 and the IL-10 receptor G3 TrAEs at 20mg/kg were anemia (3; 16%) or (SD, PR, CR: > 24 weeks) circulation P B M C : % P D 1 + C e lls thrombocytopenia (3; 16%), AST/ALT increase (2; 11%). P B M C : % K i6 7 + P D 1 +. on CD8+ T cells RCC (n=8) 4 2 2 5 50. 15. All G3/4 TrAEs were reversible and allowed AM0010. reintroduction NSCLC (n=5) 3 2 - 4 10. IL-10 activates CD8+ T cells ( Cytotoxic License ) Immune related TrAEs, such as colitis, pneumonitis or AM0010 + Mechanism Based Combinations with AM0010.

9 Melanoma (n=6) 2 2 - 2 pembrolizumab 25. 5. endocrine disorders were observed at frequency and severity expected in Pembrolizumab monotherapy P e m b r o H S p id e r S C A N. PEG-IL-10 induces cytotoxicity, proliferation and 100. 0 0. survival of CD8+ T cells and the persistence of o o o o 1. 1. m m m m y y a a 1. 2. 1. 2. D. D. >. >. antigen activated intratumoral CD8+ T cells G3/4 Treatment related adverse events AM0010 + pembrolizumab cohorts T u m o r B u rd e n (% ). 50. 8 Patients Melanoma, RCC, GE, PDAC, NSCLC . - Phosphorylation of the STAT1 and STAT3 RCC with AM0010 Monotherapy Combination AM0010 - Pembro Monotherapy or combination with FOLFOX or anti-PD-1 mAb Grade 1 Grade 2 Grade 3 Grade 4 0.

10 In a large Phase 1 study, 144 patients with advanced AM0010 Dose Number of Patients 10 g/kg 20 g/kg 10 g/kg 20 g/kg 10 g/kg 20 g/kg 10 g/kg 20 g/kg N=13 N=6 N=13 N=6 N=13 N=6 N=13 N=6. AM0010 and AM0010 + Analysis of unique TCR clones in the blood shows solid tumors have been treated with AM0010. monotherapy. Objective responses were observed in Hematopoietic AEs -5 0. pembrolizumab reduces proliferation appearance of previous not detected T cells by 3 weeks Anaemia 1 (8%) 3 (23%) 2 (33%) 2 (15%) 1 (17%). ocular melanoma, renal cell cancer (RCC) and Neutropenia 1 (8%) 1 (17%). -1 0 0. of Foxp3+ CD4+ T regulatory cells in treatment with AM0010 + pembrolizumab, but only after lymphoma, prolonged disease stabilization has been Thrombocytopenia 3 (23%) 3 (23%).