Phase 1 study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients with metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (MCRPC).

Abstract

2548 Background: Tumor-associated macrophages (TAM) correlate with increased invasiveness, growth, and immunosuppression. Activation of CSF-1R results in proliferation, differentiation, and migration of monocytes/macrophages. CSF-1R inhibition with LY3022855 (LY), a human immunoglobulin G subclass 1 (IgG1) monoclonal antibody (mAB), may have favorable anti-tumor effects. We evaluated the safety and clinical response of LY monotherapy. Methods: Patients (pts) with advanced refractory MBC and MCRPC received LY intravenously in 6-week cycles in cohorts: A) 1.25 mg/kg every 2 weeks [Q2W]; B) 1.0 mg/kg on Weeks 1, 2, 4, and 5; C) 100 mg once weekly; D)100 mg Q2W. MCRPC pts were enrolled in cohorts A and B; MBC pts were enrolled in all cohorts. Anti-tumor activity was assessed using RECIST v1.1 by radiological imaging every 6 weeks. Results: Thirty-four pts (22 MBC; 12 MCRPC) received ≥1 dose of LY. Median age was 57.0 years (range: 32.0–81.0) for MBC pts and 72.5 years (range: 58.0–84.0) for MCRPC pts. Baseline Eastern Cooperative Oncology Group performance status was 0 (n = 13, 38.2%), 1 (n = 18, 52.9%), or 2 (n = 3, 8.8%). MBC pts were hormone receptor (HR) positive (n = 20), HR negative (n = 1), or unknown (n = 1); 3 MBC pts received concurrent hormone therapy. Common treatment-related adverse events of any grade were fatigue (38.2%), decreased appetite (26.5%), nausea (26.5%), increased lipase (23.5%), and increased creatine phosphokinase (20.6%). No complete or partial response was observed. Stable disease (SD) was observed in 5/22 MBC pts (duration 82–302 days) and 3/7 evaluable MCPRC pts (duration 50–124 days). Two MBC pts (9%; Cohort A) had durable SD > 9 months and 1 pt had palpable reduction in a nontarget neck mass. Circulating CSF1 and IL-34 increased at Day 8 suggestive of target engagement. Pharmacokinetics of LY were consistent with other IgG1 mAbs. Conclusions: LY3022855 was well tolerated and showed evidence of target engagement. Clinically meaningful SD > 9 months was observed in 2 MBC pts. Tumor biomarker analyses are underway. Clinical trial information: NCT02265536.

Targeting Innate Immunity in Cancer Therapy

“…Synergy in combination with anti-PD-1 and anti-CTLA-4 therapy has also been demonstrated [201]. Clinical trials of antibodies and small molecule inhibitors targeting CSF-1R are ongoing as monotherapy, and in combination with chemotherapy and ICI [197,202,203].…”

“…Multiple therapeutic strategies have been found to drive polarization of protumorigenic M2 TAMs towards antitumor M1 TAMs, which include activation of CD40, TLR3, TLR4, TLR7/8 and TLR9 [89,90,151,155,197], covered in prior sections. Here, we discuss additional strategies being pursued in clinical trials.…”

Macrophage reprogramming for therapy

“…196,197 TAMs repolarization to produce inflammatory mediators is currently being evaluated in a number of clinical trials, examples of which are summarized in Table 1. [198][199][200][201][202][203][204][205][206] Several strategies to target TAMs have been adopted, and we will describe common ones below.…”

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors

“…LY3022855 is a novel, recombinant, immunoglobulin G sub-class1, human monoclonal antibody (mAb) which prevents binding of CSF-1 and IL-34 to CSF-1R, and inhibits CSF-1R activation for tumor regulation and growth [13,14]. Preclinical studies suggested that CSF-1R blockade with LY3022855 modulates the TME in mouse cancer models [15].…”

“…Preclinical studies suggested that CSF-1R blockade with LY3022855 modulates the TME in mouse cancer models [15]. A previous phase 1 study of LY3022855 monotherapy in patients with metastatic breast cancer (MBC) demonstrated good tolerability and target engagement activity, with two patients achieving stable disease (SD) for over nine months [14]. Blockade of PD-1/PD-L1 and CTLA-4 has shown anti-tumor activity in solid tumors [16], which includes promising anti-tumor activity of PD-1/PD-L1 in a subset of patients with NSCLC [17,18], and limited anti-tumor activity of PD-1/PD-L1 alone or in combination with other checkpoint inhibitors in OC in preclinical setting [19].…”