Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial

Abstract

BackgroundAvailability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone.MethodsIn this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts.ResultsOverall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC.ConclusionsCheckpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC.Trial registration numberNCT02475213.

Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts

“…One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with checkpoint inhibitor (CPI)-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC [ 178 ]. This phase I/II trial showed that combining Enoblituzumab with Pembrolizumab demonstrated acceptable safety and effect in patients with CPI-naïve HNSCC and NSCLC.…”

Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy

“…It was also reported that downregulated B7-H3 can reduce lipid synthesis via the SREBP-1/FASN signaling pathway in lung cancer [ 125 ]. T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected NK cells have shown significant antitumor activity in a preclinical model [ 126 ], and combined targeting of B7-H3 and PD-1 has resulted in promising response rates in clinical trials [ 127 ].…”

“…CD3 + T cell and B7-H3 bispecific antibodies and B7-H3-targeting CAR-T therapy have shown potent antimelanoma activity when investigated using in vivo and in vitro models [ 147 , 148 ], validating the great potential of B7-H3 in melanoma immunotherapy. Nevertheless, mechanistic studies and preclinical success have not yet been translated into a clinical benefit, and a poor response rate was observed in patients with melanoma who were treated with anti-B7-H3 and anti-PD-1 antibodies [ 127 ]. Clinical evaluations of multiple modalities in a larger cohort are still ongoing.…”

Advanced Acral Melanoma Therapies: Current Status and Future Directions

“…Additionally, the potential value of various new inhibitory immune checkpoints (BTLA [130][131][132], B7 family [133][134][135][136][137], IDO-1 [138,139], LAG-3 [140,141]) and costimulatory molecules (GITR [142][143][144][145], ICOS [146][147][148], OX40 [149][150][151], 4-1BB [152][153][154], CD40 [155,156], CD27 [157][158][159]) has been confirmed for melanoma treatments. The efficacy and safety of some inhibitory checkpoints and costimulatory molecules in melanoma treatments, alone or combined with ICIs, have been preliminarily elucidated in early clinical trials [160][161][162][163][164][165][166][167][168][169][170][171][172][173] and others are in progress (NCT04773951, NCT04137900, NCT02554812). Currently, no large-sample study comparing the expression levels of these immune checkpoints in AM and CM tissues is available.…”