First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors

PURPOSE: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab. EXPERIMENTAL DESIGN: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated. RESULTS: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation. CONCLUSIONS: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent

IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials

IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials

Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor TypesDeterminants of Pembrolizumab Response in Solid Tumors

PurposeTo explore relationships between biological gene expression signatures and pembrolizumab response.Experimental designRNA-sequencing data on baseline tumor tissue from 1,188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of 11 prespecified gene expression signatures [18-gene T-cell-inflamed gene expression profile (TcellinfGEP), angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell (gMDSC), monocytic myeloid-derived suppressor cell (mMDSC), stroma/epithelial-to-mesenchymal transition (EMT)/TGFβ, and WNT] were evaluated for their relationship to objective response rate (per RECIST, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and TcellinfGEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the TcellinfGEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-TcellinfGEP consensus signatures for negative association [except proliferation (hypothesized positive association)] with response was adjusted for multiplicity.ResultsCovariance patterns of the 11 signatures (including TcellinfGEP) identified in Merck-Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA-sequencing data from pembrolizumab trials. TcellinfGEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGFβ were negatively associated with response to pembrolizumab monotherapy.ConclusionsThese findings suggest that features beyond IFNγ-related T-cell inflammation may be relevant to anti-programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations. See related commentary by Cho et al., p. 1479