Abstracts J Immunother : first published as 10.1136/jitc-2020-SITC2020.0392 on 9 November 2020. Downloaded from

Abstract 391 Table 1 Frequency of patients with a TEAE related 5. No patient experienced a Dose Limiting Toxicity. No grade to SAR44100* by dose group and grade 3, 4 or 5 adverse events related to study treatment were reported. Adverse events related to study treatment in two or more subjects in both treatment groups combined were nonse- rious grade 1 or 2 fatigue (43%;10/23), vomiting (17%; 4/ 23), nausea (13%;3/23); local injection site reaction (11.7%, 2/23); and chills, diarrhea, and rash were reported as 9% (2/ 23), respectively (table 1 and 2). In some patients, increases in plasma IP10 and IFN gamma and CD8+ infiltration in tumor biopsies were observed. Conclusions SAR441000 administered as monotherapy and in combination with cemiplimab was generally well tolerated. An immunomodulatory effect is suggested by downstream effector cytokines and T cell infiltration. These data support further clinical evaluation of SAR441000. Ethics Approval The study was approved by each participating Institution’s Ethics or Institutional Review Board(s).

REFERENCE Abstract 391 Table 2 Frequency of patients with a TEAE related 1. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov 2014;13:759–780. to study treatment (SAR441000+cemiplimab) * by dose group and grade http://dx.doi.org/10.1136/jitc-2020-SITC2020.0391

392 PHASE 1 STUDY OF CI-8993 ANTI-VISTA ANTIBODY IN PATIENTS WITH ADVANCED SOLID TUMOR MALIGNANCIES 1Elizabeth Martinez, 2Jason Faris*, 3Reinhard Von Roemeling, 3Steven Angelides, copyright. 4Melissa Johnson. 1Curis Inc, Durham, NC, USA; 2Dartmouth-Hitchcock, Norris Cotton Cance, Lebanon, NH, USA; 3Curis, Ridgefield, CT, USA; 4Tennessee Oncology, Nashville, TN, USA

Background VISTA (V-domain Ig suppressor of T cell activa- interferon alpha-2b, granulocyte-macrophage colony-stimulating tion) is a key negative regulator, locking factor, and interleukin-15 sushi that we have identified as T cells in a quiescent state, unlike PD1 and CTLA4, which mediators of tumor regression across different murine tumor are expressed on activated T cells. Preclinically, VISTA mono- models. Local intratumoral administration of SAR441000 in clonal antibody treatment increased the number of tumor-spe- immunocompetent mice, mediates successful antitumor immun- cific T cells in the periphery, and enhanced the infiltration, ity leading to tumor eradication. Effective antitumor activity proliferation and effector function of tumor-reactive T cells of these cytokines involved multiple immune cell populations within the tumor microenvironment (TME). VISTA blockade http://jitc.bmj.com/ and was accompanied by intratumoral interferon gamma alters the suppressive feature of the TME by decreasing the induction, systemic antigen-specific T-cell expansion, increased presence of monocytic myeloid-derived suppressor cells and granzyme B+ T-cell infiltration, and formation of immune increasing the presence of activated dendritic cells (DCs) memory. Antitumor activity extended beyond the treated within the TME leading to enhanced T cell mediated immun- lesions and inhibited growth of non-injected distant tumors. ity. VISTA monoclonal antibody administration as a monother- Combining the mRNAs with checkpoint inhibitors enhanced apy has been shown to suppress the growth of both on September 28, 2021 by guest. Protected antitumor responses in both injected and non-injected tumors, transplantable and inducible in preclinical models. improving survival and tumor regression in mice. Based on CI-8993 is a first-in-class, fully human immunoglobulin (Ig) these preclinical observations a clinical study was initiated. G1k monoclonal antibody (mAb) against the VISTA . Methods In a phase 1 dose escalation study, patients with Prior human clinical evaluation of CI-8993 demonstrated tar- advanced solid tumors were treated with weekly intratumoral get-related clinical findings and pharmacodynamic activity at administration of SAR441000 monotherapy and in combina- 0.15 mg/kg. tion with fixed dose of cemiplimab 350 mg. Plasma samples Methods This phase 1 study is being conducted in the USA for cytokine analysis and tumor biopsies were collected at (NCT04475523) and is designed as a 3+3 dose escalation baseline and throughout the study to characterize the PK/PD study beginning at 0.15 mg/kg. Patients with solid tumor profile of SAR441000, immune cell tumor infiltration by malignancy (non-) that is metastatic or unresectable immunohistochemistry and the presence of corresponding and considered relapsed and/or refractory to prior therapy tumor proinflammatory signatures by RNA sequencing. will be included, excluding prior CAR-T therapy or allogenic Results As of July 2020, 17 patients received SAR441000 transplant. Patients will be treated with an initial step-dose of monotherapy (melanoma 7, breast 4, sarcoma 2, Cutaneous CI-8993 by IV infusion, followed by every 2 weeks of a full Squamous Cell 2, Basal Cell 1, and Merkel Cell 1) at dose dose, until disease progression or toxicity. Efficacy, pharmaco- levels 1 through 7. Six patients received SAR441000 in com- kinetics, pharmacodynamic and safety endpoints will be moni- bination therapy (melanoma 3, breast 3) at dose levels 4 and tored and reported.

A238 J Immunother Cancer 2020;8(Suppl 3):A1–A559 Abstracts J Immunother Cancer: first published as 10.1136/jitc-2020-SITC2020.0392 on 9 November 2020. Downloaded from

Results N/A Conclusions BMS-986218 monotherapy demonstrated an Conclusions N/A acceptable safety profile and signs of clinical benefit in this Ethics Approval The study was approved by Dartmouth-Hitch- heterogeneous patient population with select advanced . cock, Norris Cotton Cancer Center Ethics Board, approval Preliminary pharmacodynamic activity was consistent with number IRB00012031The study was approved Sarah Cannon enhanced effects of CTLA-4 blockade. Data from continuing Caner Research Institute, approval number IORG0000689 dose escalation of BMS-986218 ± NIVO along with preclini- cal results provide support for ongoing monotherapy expan- http://dx.doi.org/10.1136/jitc-2020-SITC2020.0392 sions and for BMS-986218 + NIVO expansions in patients with advanced cancer. Acknowledgements The authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New 393 FIRST-IN-HUMAN PHASE 1/2A STUDY OF THE NOVEL York, NY, USA, for his contributions to the study. – NONFUCOSYLATED ANTI CTLA-4 MONOCLONAL Trial Registration NCT03110107 ANTIBODY BMS-986218 ± NIVOLUMAB IN ADVANCED Ethics Approval This study was approved by the WCG Inde- SOLID TUMORS: INITIAL PHASE 1 RESULTS pendent Review Board, approval number 20170464 1Claire Friedman*, 2Paolo Ascierto, 3Diwakar Davar, 4Mark O’Hara, 5Ronnie Shapira- Frommer, 6Matthew Dallos, 7Vivek Khemka, 7Lee James, 7Bruce Fischer, 7Shilpa Demes, REFERENCE 7Li Li, 7Martin Kozicki, 7Palanikumar Ravindran, 7Ke Xu, 7Georgia Kollia, 1. Engelhardt J, Akter R, Valle J, et al. Preclinical characterization of BMS-986218, a – 7Jacqueline Shoukry, 7Mona Yunan, 7Ashish Massey, 8Martin Gutierrez. 1Memorial Sloan novel nonfucosylated anti CTLA-4 antibody designed to enhance antitumor activ- 2 ity. Presented at the American Association for Cancer Research (AACR) Virtual Kettering Cancer Center, New York, NY, USA; Istituto Nazionale Tumori IRCCS Fondazi, Annual Meeting II; June 22–24, 2020 [poster 4552]. Napoli, Italy; 3University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 4University of 5 Pennsylvania, Philadelphia, PA, USA; Sheba Medical Center, Tel HaShomer, Israel; http://dx.doi.org/10.1136/jitc-2020-SITC2020.0393 6Columbia University Medical Center, New York, NY, USA; 7Bristol Myers Squibb, Lawrenceville, NJ, USA; 8Hackensack University Medical Center, Hackensack, NJ, USA

Background CTLA-4 pathway blockade with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for – several cancers. A nonfucosylated version of IPI, BMS-986218, 394 INTERLEUKIN-8 NEUTRALIZING MONOCLONAL was developed to increase the effects of CTLA-4 blockade and ANTIBODY BMS-986253 PLUS NIVOLUMAB (NIVO) IN – – enhance intratumoral regulatory T-cell depletion via its BIOMARKER-ENRICHED, PRIMARILY ANTI PD-(L)1 increased affinity for Fcg receptors (FcgR, CD16) on natural EXPERIENCED PATIENTS WITH ADVANCED CANCER: copyright. killer T cells and macrophages, resulting in enhancement of INITIAL PHASE 1 RESULTS antibody-dependent cellular cytotoxicity. Preclinical data sup- 1Diwakar Davar, 2Matteo Simonelli, 3Martin Gutierrez, 4Emiliano Calvo, 5Jason Melear, ported the mechanism of action of BMS-986218 and demon- 6Sarina Piha-Paul, 5Donald Richards, 7Matthew Dallos, 8Janaki Parameswaran, strated greater antitumor activity in an MC38 tumor model vs 8Vinit Kumar, 8Xiaochen Zhao, 8Santanu Dutta, 9Ignacio Melero*. 1University of Pittsburgh 2 IPI.1 Here, we present initial results from the first-in-human Medical Center, Pittsburgh, PA, USA; Humanitas University; Humanitas Cancer Center – Humanitas Research Hospital, Milan, Italy; 3Hackensack University Medical Center, phase 1/2a trial of BMS-986218 ± NIVO in previously 4 treated patients with advanced cancer (NCT03110107). Hackensack, NJ, USA; START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain; 5Texas Oncology, US Oncology Research, Austin, TX, USA; 6The University of Methods Patients with 1 prior therapy received BMS-986218 7 – Texas, MD Anderson Cancer Center, Houston, TX, USA; Columbia University Medical 2 70 mg intravenously Q4W. Safety, tolerability, pharmacoki- Center, New York, NY, USA; 8Bristol Myers Squibb, Princeton, NJ, USA; 9Universidad de netics, and pharmacodynamics were evaluated. Navarra, Pamplona, Spain Results As of December 12, 2019, 65 patients (median age, http://jitc.bmj.com/ 61 years [range, 24–85 years]) received BMS-986218 mono- Background Interleukin 8 (IL-8) is a C-X-C chemokine that therapy. TRAEs occurred in 52% of patients; most were grade exerts protumorigenic effects in the tumor microenvironment, 1–2. The most common (10%) TRAEs (any grade; grade 3) including recruiting immunosuppressive PMN-MDSCs and pro- – were pruritus (12%; 0%) and diarrhea (11%; 3%). Eight moting angiogenesis.1 3 Elevated serum IL-8 (sIL-8) is a nega- patients (12%) had grade 3 TRAEs; most resolved with proto- tive prognostic indicator in patients with solid tumors and col-defined management. No grade 4 TRAEs were reported; 1 may have predictive value in patients treated with immuno- on September 28, 2021 by guest. Protected grade 5 TRAE (pneumonitis; 2 mg) occurred. Seven patients therapies.245BMS-986253, a fully human-sequence IgG1k (11%) discontinued treatment due to TRAEs; 4 dose-limiting anti–IL-8 monoclonal antibody, binds IL-8 and prevents signal- toxicities occurred. The maximum tolerated dose has not been ing through CXCR1/CXCR2 and has been shown to be safe reached. BMS-986218 exposure increased dose proportionally, in patients with advanced cancers.3 We present initial results and the half-life was »2 weeks. Increased levels of serum che- of BMS-986253 + NIVO from a phase 1/2a trial in patients mokine ligands 9 and 10 and interferon-g indicate that phar- with advanced cancers who had detectable sIL-8 levels, the macodynamic changes occurred at the lowest dose tested (2 majority of whom had progressed on/after prior anti–PD-(L)1 mg [»0.03 mg/kg]), similar to previous findings with IPI 3 (NCT03400332). mg/kg, and at higher doses (40–70 mg [»0.06–1 mg/kg]), con- Methods During safety evaluation/dose exploration, patients sistent with findings with IPI 10 mg/kg. In a subset of patients with advanced metastatic solid tumors (melanoma, NSCLC, with paired biopsies, BMS-986218 was associated with an SCCHN, RCC, or UCC) and detectable sIL-8 (>10 pg/mL at increased signature linked to CD8+ T-cell infiltration screening) received BMS-986253 600 (n=16), 1200 (n=15), and inflammation. In a highly heterogeneous population, as or 2400 mg (n=18) Q4W, or 1200 (n=12) or 2400 mg part of dose escalation, BMS-986218 monotherapy treatment (n=59) Q2W, + NIVO 480 mg intravenously Q4W. Safety, was associated with clinical activity in some patients. Updated pharmacokinetics, pharmacodynamics, and preliminary antitu- data based on a September 2020 data cutoff will be mor activity were evaluated (investigator-assessed, RECIST presented. v1.1).

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