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1 O4 First-in-Human Phase Dose Escalation and Expansion of a Novel Combination, Anti CSF- Receptor (cabiralizumab) Plus Anti PD- (nivolumab), in Patients With Advanced Solid Tumors Zev A. Wainberg, Sarina A. Piha-Paul, Jason Luke, 3 Edward J. Kim, 4 John A. Thompson, 5 Carolyn D. Britten, 6 Jennifer M. Johnson, 7 Nicklas Pfanzelter, 8 Michael Gordon, 9 Drew W. Rasco, F. Stephen Hodi, Amy Weise, Sandeep Inamdar, 3 Serena Perna, 4 Christy Ma, 3 Janine Powers, 3 Yeonju Lee, 3 Majid Ghoddusi, 3 Michael Carleton, 4 Hong Xiang, 3 Lei Zhou, 3 Helen Collins, 3 James J. Lee 5 UCLA Medical Center, Los Angeles, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; 3 University of Chicago Medical Center, Chicago, IL; 4 UC Davis Cancer Center, Sacramento, CA; 5 University of Washington, Seattle Cancer Center, Seattle, WA; 6 Medical University of South Carolina, Charleston, SC; 7 Sidney Kimmel Cancer Center, Jefferson University, Philadelphia, PA; 8 Rush University Medical Center, Chicago, IL; 9 Honor Health Research Institute, Scottsdale, AZ; South Texas Accelerated Research Therapeutics, San Antonio, TX; Dana-Farber Cancer Institute, Boston, MA; Barbara Ann Karmanos Cancer Institute, Detroit, MI; 3 FivePrime Therapeutics, South San Francisco, CA; 4 Bristol-Myers Squibb, Princeton, NJ; 5 University of Pittsburgh Cancer Institute, Pittsburgh, PA

2 FPA8-3 Presenter Disclosures Dr Wainberg has no relationships related to this presentation to disclose Outside the scope of this work, he has received consulting fees from FivePrime and Merck There will be discussion about the use of products for non FDA-approved indications in this presentation

3 FPA8-3 Rationale for Cabiralizumab in Combination With Nivolumab TAM survival Immunosuppressive factors CSF-R CSF- PD-L TAMs inhibit antitumor T-cell activity in the tumor microenvironment, In pancreatic and other cancers, high levels of TAMs are associated with poor prognosis 3-5 Signaling through the CSF- receptor promotes the maintenance and function of TAMs, PD- Tumor survival T-cell function CSF- = colony stimulating factor ; TAM = tumor-associated macrophage; PD- = programmed death-. Ries CH, et al. Cancer Cell 4;5: Cannarile M, et al. J ImmunoTher Cancer 7;5: Hu H, et al. Tumour Biol 6;37: Kurahara H, et al. J Surg Res ;67:e e9. 5. Goswami KK, et al. Cell Immunol 7;36:.

4 FPA8-3 Rationale for Cabiralizumab in Combination With Nivolumab TAM survival Immunosuppressive factors CSF-R Cabiralizumab CSF- PD- PD-L TAMs inhibit antitumor T-cell activity in the tumor microenvironment, In pancreatic and other cancers, high levels of TAMs are associated with poor prognosis 3-5 Signaling through the CSF- receptor promotes the maintenance and function of TAMs, Cabiralizumab is a humanized IgG4 mab that blocks CSF-R 6 and depletes TAMs T cell CSF- = colony stimulating factor ; TAM = tumor-associated macrophage; IgG = immunoglobulin G, mab = monoclonal antibody; PD- = programmed death-. Ries CH, et al. Cancer Cell 4;5: Cannarile M, et al. J ImmunoTher Cancer 7;5: Hu H, et al. Tumour Biol 6;37: Kurahara H, et al. J Surg Res ;67:e e9. 5. Goswami KK, et al. Cell Immunol 7;36:. 6. Bellovin D, et al. Cancer Res 7;77 (3 suppl) [abstract 599]).

5 FPA8-3 Rationale for Cabiralizumab in Combination With Nivolumab TAM survival Immunosuppressive factors CSF-R Restored T-cell function Cabiralizumab CSF- Nivolumab PD- Antitumor response TAMs inhibit antitumor T-cell activity in the tumor microenvironment, In pancreatic and other cancers, high levels of TAMs are associated with poor prognosis 3-5 Signaling through the CSF- receptor promotes the maintenance and function of TAMs, Cabiralizumab is a humanized IgG4 mab that blocks CSF-R 6 and depletes TAMs Preclinical data suggest that CSF-R inhibition synergizes with PD- blockade to enhance antitumor activity 7 CSF- = colony stimulating factor ; TAM = tumor-associated macrophage; IgG = immunoglobulin G, mab = monoclonal antibody; PD- = programmed death-. Ries CH, et al. Cancer Cell 4;5: Cannarile M, et al. J ImmunoTher Cancer 7;5: Hu H, et al. Tumour Biol 6;37: Kurahara H, et al. J Surg Res ;67:e e9. 5. Goswami KK, et al. Cell Immunol 7;36:. 6. Bellovin D, et al. Cancer Res 7;77 (3 suppl) [abstract 599]). 7. Zhu Y, et al. Cancer Res 4;74:

6 FPA8-3 First-in-Human Phase a/b Dose-Escalation Study of Cabiralizumab ± Nivolumab in Advanced Solid Tumors Monotherapy Dose Escalation in Advanced Solid Tumors (n = 4) Cabiralizumab IV QW mg/kg (n = 3) 6 mg/kg (n = ) 4 mg/kg (n = ) Confirm tolerability of 4 mg/kg Combination Dose Escalation in Advanced Solid Tumors (n = ) a Cabiralizumab IV QW Nivolumab IV QW mg/kg + 3 mg/kg (n = 3) mg/kg + 3 mg/kg (n = 4) 6 mg/kg + 3 mg/kg (n = ) 4 mg/kg + 3 mg/kg (n = 3) Cabiralizumab 4 mg/kg + Nivolumab 3 mg/kg Combination Dose Expansion in Advanced Solid Tumors in Disease-Specific Cohorts (n = 95) Pancreatic cancer (n = 33) Other solid tumors (n = 6) August, 7, cutoff Primary objectives: safety/tolerability, dose-limiting toxicities Secondary objectives: immunogenicity, PK, pharmacodynamics, preliminary antitumor activity b a Initiated after corresponding monotherapy doses were deemed tolerable. b Primary objective for expansion phase IV = intravenous; PK = pharmacokinetics; QW = every weeks 6

7 FPA8-3 Baseline Demographics and Prior Therapy Median age (range), years < 65 years, n (%) Cabiralizumab monotherapy (n = 4) 65.5 (48 88) (4) Cabiralizumab + nivolumab (n = 5) 64 (5 85) (54) Male, n (%) 3 (54) (49) ECOG performance status, n (%) Not reported 7 (9) 7 (7) 55 (7) 45 (7) 4 () (<) No. of prior regimens, n (%) 3 No. of prior regimens for metastatic disease, n (%) 3 ECOG = Eastern Cooperative Oncology Group 5 () (8) 7 (7) 7 (9) 6 (5) 3 (3) 8 (33) 7 (3) 47 (3) 58 (8) 93 (45) 77 (38) 8 (4) 44 () 56 (7) 7

8 FPA8-3 Cabiralizumab serum concentration after first dose (µg/ml) Cabiralizumab Demonstrated Target-Mediated Clearance and Low Immunogenicity Cabiralizumab serum concentration after first dose (µg/ml) Dose escalation (n = 34) Cabira mg/kg + NIVO (n = 4) Cabira 4 mg/kg (n = ) Cabira mg/kg (n = 3) Cabira 4 mg/kg + NIVO (n = 3) Cabira mg/kg + NIVO (n = 3) Cabira 6 mg/kg (n = ) Dose expansion (cabira 4 mg/kg + NIVO 3 mg/kg; pancreatic cohort vs other tumors) Other cancer (n = 56) Pancreatic cancer (n = 33) Day Day Cabiralizumab PK is similar when administered as a monotherapy or in combination with nivolumab PK of cabiralizumab 4 mg/kg QW approaches the linear dose range, suggesting saturation of target-mediated clearance Exposure with the cabiralizumab 4 mg/kg dose in the presence of nivolumab was similar across tumor types Cabiralizumab ± nivolumab demonstrated low immunogenicity (data not shown) Cabira = cabiralizumab; NIVO = nivolumab 8

9 FPA8-3 CD4 + CD6 ++ nonclassical monocytes/µl a in peripheral blood after first dose Cabiralizumab ± Nivolumab Depleted Circulating Monocytes in Patients With Advanced Solid Tumors CD4 + CD6 ++ nonclassical monocytes /µl a in peripheral blood after first dose 8 6 Dose escalation (n = 33) Cabira mg/kg + NIVO (n = 4) Cabira mg/kg (n = 3) Cabira mg/kg + NIVO (n = 3) Cabira 4 mg/kg (n = ) Cabira 4 mg/kg + NIVO (n = 3) Cabira 6 mg/kg (n = ) Dose expansion (cabira 4 mg/kg + NIVO 3 mg/kg; pancreatic cohort vs other tumors) 8 6 Other cancer (n = 43) Pancreatic cancer (n = 3) Day Day Decreases in levels of circulating nonclassical monocytes are a pharmacodynamic marker of cabiralizumab and have been observed with other CSF-R targeting agents -3 Cabiralizumab 4 mg/kg QW was the minimal dose required to consistently deplete circulating nonclassical monocytes throughout the dosing interval; results were similar with cabiralizumab 4 mg/kg + nivolumab Decreases in levels of nonclassical monocytes were similar across tumor types a Bars denote -sided standard deviation. Ries CH, et al. Cancer Cell 4;5: Gomez-Roca CA, et al. J Clin Oncol 5;33(suppl) [abstract 35]. 3. Anthony S, et al. J Clin Oncol ;9(5 suppl) [abstract 393]. 9

10 FPA8-3 Cabiralizumab ± Nivolumab Demonstrated a Tolerable Safety Profile Safety profile of the combination was generally consistent with that of nivolumab, and cabiralizumab 3 monotherapy The most common TRAEs were elevations in creatine kinase and serum liver enzymes (without elevation in bilirubin) These are believed to be secondary to cabiralizumab s depletion of Kupffer cells (macrophages) and were reported with other CSF-R targeting agents 4-6 Isolated enzyme elevations were not associated with other clinical sequelae Cabiralizumab monotherapy (n = 4) Cabiralizumab + nivolumab (n = 5) Any grade, n (%) Grade 3 4, n (%) Any grade, n (%) Grade 3 4, n (%) Any TRAE 5 (63) 3 (54) 84 (9) (49) AEs leading to discontinuation 3 (3) (8) 5 (7) (5) Clinical TRAEs ( 5% of pts treated with combination) Periorbital edema Fatigue Rash Pruritus Nausea Treatment-related laboratory abnormalities of interest Serum enzyme elevations a Pancreatic enzyme elevations b 5 () 7 (9) (4) (8) 3 (3) (4) 3 (3) (4) 9 (38) (8) 84 (4) 74 (36) 38 (9) 34 (7) 3 (5) 3 (5) 4 () Treatment-related deaths 3 (.5) c (<) (5) 8 (4) () 4 () 4 () a Includes AE terms indicative of elevated CPK, AST, ALT, and LDH. b Includes AE terms indicative of elevated amylase and lipase. c Includes pneumonitis in a patient with thyroid cancer (cabiralizumab mg/kg + nivolumab 3 mg/kg), and respiratory distress (n =, cabiralizumab 4 mg/kg + nivolumab) and acute respiratory distress (n =, cabiralizumab 4 mg/kg + nivolumab) in patients with lung cancer. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; LDH = lactate dehydrogenase; TRAE, treatment-related adverse event. Brahmer J, et al. N Engl J Med 5;373: Ferris RL, et al. N Engl J Med 6;375: Sankhala K, et al. J Clin Oncol 7;35(suppl) [abstract 78]. 4. Ries CH, et al. Cancer Cell 4; 5: Tap WD, et al N Engl J Med 5;373: Papadopoulos KP, et al Clin Cancer Res 7;3:

11 FPA8-3 Cabiralizumab ± Nivolumab Demonstrated a Tolerable Safety Profile Safety profile of the combination was generally consistent with that of nivolumab, and cabiralizumab 3 monotherapy The most common TRAEs were elevations in creatine kinase and serum liver enzymes (without elevation in bilirubin) These are believed to be secondary to cabiralizumab s depletion of Kupffer cells (macrophages) and were reported with other CSF-R targeting agents 4-6 Isolated enzyme elevations were not associated with other clinical sequelae Cabiralizumab monotherapy (n = 4) Cabiralizumab + nivolumab (n = 5) Any grade, n (%) Grade 3 4, n (%) Any grade, n (%) Grade 3 4, n (%) Any TRAE 5 (63) 3 (54) 84 (9) (49) AEs leading to discontinuation 3 (3) (8) 5 (7) (5) Clinical TRAEs ( 5% of pts treated with combination) Periorbital edema Fatigue Rash Pruritus Nausea Treatment-related laboratory abnormalities of interest Serum enzyme elevations a Pancreatic enzyme elevations b 5 () 7 (9) (4) (8) 3 (3) (4) 3 (3) (4) 9 (38) (8) 84 (4) 74 (36) 38 (9) 34 (7) 3 (5) 3 (5) 4 () Treatment-related deaths 3 (.5) c (<) (5) 8 (4) () 4 () 4 () a Includes AE terms indicative of elevated CPK, AST, ALT, and LDH. b Includes AE terms indicative of elevated amylase and lipase. c Includes pneumonitis in a patient with thyroid cancer (cabiralizumab mg/kg + nivolumab 3 mg/kg), and respiratory distress (n =, cabiralizumab 4 mg/kg + nivolumab) and acute respiratory distress (n =, cabiralizumab 4 mg/kg + nivolumab) in patients with lung cancer. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; LDH = lactate dehydrogenase; TRAE, treatment-related adverse event. Brahmer J, et al. N Engl J Med 5;373: Ferris RL, et al. N Engl J Med 6;375: Sankhala K, et al. J Clin Oncol 7;35(suppl) [abstract 78]. 4. Ries CH, et al. Cancer Cell 4; 5: Tap WD, et al N Engl J Med 5;373: Papadopoulos KP, et al Clin Cancer Res 7;3:

12 FPA8-3 Rationale for Targeting CSF-R in Pancreatic Cancer Pancreatic cancer is associated with high TAM infiltration and poor prognosis, It typically presents as metastatic disease with a -year survival rate of 7%-3% 3 and a 5-year survival rate of %-3% 4,5 Approximately 95%-99% of patients have microsatellite stable (MSS) pancreatic cancer, 6-8 lack response to anti PD-/L therapy, 5,9 and are in need of new treatment options Combination of cabiralizumab and nivolumab may benefit patients with pancreatic cancer by simultaneous reduction of TAMs and inhibition of PD- signaling. Hu H, et al. Tumour Biol 6;37: Kurahara, et al. J Surg Res ;67:e e9. 3. Von Hoff DD, et al. N Engl J Med 3;369: American Cancer Society. Pancreatic cancer. Accessed October, Foley K, et al. Cancer Lett 6;38; Goggins M, et al. Am J Pathol 998; Luttges J, et al. Mod Pathol 3;6: Laghi L, et al. PLOS One ;7:e Brahmer JR, et al. N Engl J Med ;366;

13 FPA8-3 Pancreatic Cancer Cohort Baseline Demographics and Safety Patient demographics and the safety profile in the pancreatic cohort was similar to those in all patients treated with cabiralizumab + nivolumab Baseline demographics and prior therapy Median age (range), years < 65 years, n (%) Cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Pancreatic cancer (n = 33) a 64 (37 85) 7 (5) Male, n (%) 7 (5) ECOG performance status, n (%) No. of prior regimens, n (%) 3 No. of prior regimens for metastatic disease, n (%) 3 3 (39) 9 (58) (3) (3) b 3 (9) 4 (4) 5 (45) 7 () 4 () (36) (3) a Of 33 patients, 3 were response evaluable. b Patient was ineligible or refused standard therapy. 3

14 FPA8-3 Pancreatic Cancer Cohort Baseline Demographics and Safety Patient demographics and the safety profile in the pancreatic cohort was similar to those in all patients treated with cabiralizumab + nivolumab Baseline demographics and prior therapy Median age (range), years < 65 years, n (%) Cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Pancreatic cancer (n = 33) a 64 (37 85) 7 (5) Male, n (%) 7 (5) ECOG performance status, n (%) No. of prior regimens, n (%) 3 No. of prior regimens for metastatic disease, n (%) 3 3 (39) 9 (58) (3) (3) b 3 (9) 4 (4) 5 (45) 7 () 4 () (36) (3) Safety summary Cabiralizumab 4 mg/kg + nivolumab 3 mg/kg Pancreatic cancer (n = 33) a Any grade n (%) Grade 3/4 n (%) Any TRAE 3 (94) (6) AEs leading to discontinuation 3 (9) 3 (9) Clinical TRAEs in 5% of patients Fatigue Periorbital edema Rash Vomiting Hyponatremia Diarrhea Rash maculopapular Treatment-related laboratory abnormalities of interest Serum enzyme elevations c Pancreatic enzyme elevations d 4 (4) (3) 7 () 7 () 6 (8) 5 (5) 5 (5) 7 (5) (6) Treatment-related deaths (3) 3 (9) (3) 3 (9) (33) (3) a Of 33 patients, 3 were response evaluable. b Patient was ineligible or refused standard therapy. c Includes AE terms indicative of elevated CPK, AST, ALT, and LDH. d Includes AE terms indicative of elevated amylase and lipase 4

FPA8-3 Deep and Durable Responses Observed in Patients With Pancreatic Cancer Best change in tumor burden over time in efficacy-evaluable patients treated with cabiralizumab 4 mg/kg + nivolumab 3

75+, 68+, 58, and 47+ days Adjudicated by BIRC as PR All 4 confirmed responses were observed in patients with MSS disease, who historically have not shown benefit with anti PD-/L therapy, Responses

15 FPA8-3 Deep and Durable Responses Observed in Patients With Pancreatic Cancer Best change in tumor burden over time in efficacy-evaluable patients treated with cabiralizumab 4 mg/kg + nivolumab 3 mg/kg (n = 3) a In this heavily pretreated population, durable clinical benefit was observed in 5 patients (6%) Confirmed ORR = % (Updated confirmed ORR = 3%) Duration of treatment for responders = 75+, 68+, 58, and 47+ days Adjudicated by BIRC as PR All 4 confirmed responses were observed in patients with MSS disease, who historically have not shown benefit with anti PD-/L therapy, Responses were accompanied by steep declines in levels of the pancreatic tumor marker CA9-9 over baseline a Plot shows 3 efficacy-evaluable patients; patients discontinued treatment early due to AEs before disease evaluation. BIRC = blinded independent review committee; ORR = objective 5 response rate; PR = partial response; SLD = sum of longest diameters. Overman M et al. Ann Oncol. 6;7:49-6 [abstract 479P].. Le DT, et al. N Engl J Med 5;37;59 5.

Patient achieved a partial response with a best change in tumor burden of 5% CA9-9 levels declined by 99% from baseline Response is ongoing Images

16 FPA8-3 Durable Response in the Liver of a Heavily Pretreated Patient With MSS Pancreatic Cancer Pt A Baseline (October 6) June 7 58-year-old male patient who received 3 prior chemotherapy regimens Neoadjuvant FOLFIRINOX Gemcitabine + nabpaclitaxel 5-FU + leucovorin + liposomal irinotecan Patient achieved a partial response with a best change in tumor burden of 5% CA9-9 levels declined by 99% from baseline Response is ongoing Images provided by James Lee from the University of Pittsburgh Cancer Institute. 5-FU = 5-fluorouracil; FOLFIRINOX = leucovorin + fluorouracil + irinotecan + oxaliplatin 6

63-year-old male patient who received 4 prior chemotherapy regimens Adjuvant FOLFIRINOX FOLFIRINOX Capecitabine

17 FPA8-3 Durable Response in the Lung of a Heavily Pretreated Patient With MSS Pancreatic Cancer Pt A Baseline (February 7) July 7 Images provided by Jennifer Johnson from Thomas Jefferson University Hospital. 63-year-old male patient who received 4 prior chemotherapy regimens Adjuvant FOLFIRINOX FOLFIRINOX Capecitabine Gemcitabine + nabpaclitaxel Patient achieved a partial response with a best change in tumor burden of 5% CA9-9 levels declined by 96% from baseline Response is ongoing 7

18 FPA8-3 Conclusions Cabiralizumab is a new immunotherapeutic agent that targets TAMs in the immunosuppressive microenvironment Cabiralizumab with or without nivolumab demonstrated: Tolerable safety profile that is comparable to either monotherapy Dose-dependent reduction of circulating CD4 + CD6 ++ nonclassical monocytes, reaching maximum at 4 mg/kg QW when clearance approaches linear dose range Preliminary evidence of durable clinical benefit with cabiralizumab plus nivolumab was observed in heavily pretreated patients with advanced MSS pancreatic cancer Further cohort expansion is ongoing as well as additional biomarker analyses These data support further study of cabiralizumab plus nivolumab ± chemotherapy in pancreatic cancer (NCT33366) 8

19 FPA8-3 Acknowledgments The patients and families who made this trial possible The clinical study teams who participated in this trial Ago Ahene (FivePrime Therapeutics) for immunogenicity analyses; David Leung (Bristol-Myers Squibb) for assistance with imaging; Urvi Aras (Bristol-Myers Squibb) for review and scientific input FivePrime Therapeutics, Inc. (South San Francisco, CA), Bristol-Myers Squibb (Princeton, NJ), and ONO Pharmaceutical Company, Ltd. (Osaka, Japan) All authors contributed to and approved the presentation; writing and editorial assistance was provided by Jillian Brechbiel of Chrysalis Medical Communications, Inc, funded by Bristol-Myers Squibb 9

More cancer patients are being treated with immunotherapy, but

More cancer patients are being treated with immunotherapy, but Bristol-Myers Squibb and Five Prime Present Phase 1a/1b Data Evaluating Cabiralizumab (anti-csf-1 receptor antibody) with Opdivo (nivolumab) in Patients with Advanced Solid Tumors PRINCETON, N.J. & SOUTH