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

Background: Availability 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.

Methods: In 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.

Results: Overall, 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.

Conclusions: Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC.

Trial registration number: NCT02475213.

Keywords: clinical trials as topic; drug therapy, combination; head and neck neoplasms; immunotherapy; lung neoplasms.

Figure 1

Trial design. HNSCC, head and neck squamous cell carcinoma; NSCLC, non–small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1.

Figure 2

B7-H3 staining. (A) HNSCC PR 2+/3+ membrane/epithelial staining, specifically HNSCC anti-PD-1/PD-L1–naïve patient #17; (B) NSCLC PR 3+ membrane staining, specifically NSCLC anti-PD-1/PD-L1–naïve, PD-L1 TPS <1% patient #12. Arrows indicate endothelial staining; arrowheads indicate membrane staining. B7-H3 positivity was defined as ≥2+ membrane staining (with or without cytoplasmic staining) in ≥10% of cancer cells and/or extensive staining (2+ and/or 3+) in ≥25% of associated tumor vasculature. HNSCC, head and neck squamous cell carcinoma; NSCLC, non–small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PR, partial response; TPS, tumor positivity score.

Figure 3

Pharmacokinetics of enoblituzumab after 2-hour intravenous infusions of 3–15 mg/kg QW. (A) Serum concentration–time profiles (semi-log scale). (B) Serum trough concentrations. Symbols and error bars represent arithmetic means and SDs, respectively. The duration of time between C1 and C2 was 6 weeks. C, cycle; D, day; QW, once weekly.

Figure 4

Antitumor activity and DOR in target lesions of response-evaluable patients with HNSCC or NSCLC. The best percent change in target lesion tumor burden from baseline in patients with (A) HNSCC anti-PD-1/PD-L1–naïve, (C) HNSCC post anti-PD-1/PD-L1, (E) NSCLC anti-PD-1/PD-L1–naïve, PD-L1 TPS <1%, and (G) NSCLC post anti-PD-1/PD-L1. The tumor burden (assessed as the longest linear dimension) over time in patients with (B) HNSCC anti-PD-1/PD-L1–naïve, (D) HNSCC post anti-PD-1/PD-L1, (F) NSCLC anti-PD-1/PD-L1–naïve, PD-L1 TPS <1%, and (H) NSCLC post anti-PD-1/PD-L1. B7-H3 expression status at baseline for each patient is indicated (P: B7-H3 positive; N: B7-H3 negative; U: B7-H3 expression status unknown). *Unless noted, patients are in the expansion or dose-escalation cohort at 15 mg/kg enoblituzumab plus 2 mg/kg pembrolizumab. All patients received at least one dose and had at least one postbaseline tumor evaluation. †Treatment ongoing. ‡These patients received 10 mg/kg enoblituzumab+2 mg/kg pembrolizumab. §These patients received 3 mg/kg enoblituzumab plus 2 mg/kg pembrolizumab. HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; NSCLC, non–small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; TPS, tumor positivity score.

Figure 5

Overall survival Kaplan-Meier curves for patients with HNSCC or NSCLC (safety population). HNSCC, head and neck squamous cell carcinoma; NSCLC, non–small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1.