Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors

Abstract

BackgroundTo determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.Patients and methodsPatients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose.ResultsOverall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30–86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies.ConclusionsThe recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations.Trial registration numberNCT02713529

The Role of Macrophages in Cancer Development and Therapy

“…However, results from these studies vary significantly among drugs, cancer types, and combination therapies [ 78 , 79 ]. No sufficient anticancer activity with the use of monoclonal antibodies as a single-agent treatment has been achieved thus far for most of them [ 80 , 81 ].…”

“…Many therapeutic strategies focus on the depletion of TAMs. However, many of these approaches were not fully successful in clinical studies, especially as single-agent therapy [ 80 , 81 ]. TAM depletion may be effective as a combination therapy with chemo, radio, or immunotherapy.…”

Immune Therapy Resistance and Immune Escape of Tumors

“…In order to contrast their activity, many different strategies have been attempted in murine models as well as clinical trials either alone or in combination with other approaches, including iCPI. Strategies have been applied to reduce their expansion by interfering with the colony-stimulating factor (CSF)-1/CSF1R pathway using antibodies or small molecule inhibitors [ 88 , 89 , 90 , 91 ] or to block their recruitment by targeting the CCL2/CXCR2 [ 92 ] as well as the CXCL12/CXCR4 axis [ 93 , 94 ]. Interestingly, the removal of MDSC can result in tumor evasion by enhanced accumulation of Treg [ 95 ] or TAN [ 96 ].…”

Therapeutic Approaches Targeting the Natural Killer-Myeloid Cell Axis in the Tumor Microenvironment

“…However, because myeloid cells, and particularly macrophages, play an important role in assisting NK-and T-cell activation, it is important to target the right population of cells. Moreover, given that these are essential cell types, translation to a clinical setting may be limited by tolerability, as observed in studies targeting the CSFR1 axis with antibodies or small molecules (80,111,112), which resulted in increased liver enzymes and induction of periorbital edema. Less toxicity was observed when the alternate macrophage regulating receptor CCR2 was targeted (113)(114)(115).…”

“…Subcutaneous models are limited because they do not reflect the variations observed in the tissue of residence, and the speed of cell growth in these models does not enable elucidation of the longer-term consequences of the treatment strategy. As shown in Table 1, most clinical studies have taken a standard approach in which the myeloid therapy is co-administered with the checkpoint inhibitor or chemotherapy and then dosing is maintained chronically (80,(111)(112)(113)115). This approach has a number of drawbacks.…”