tebotelimab (MGD013)

Dual blockade of LAG-3 and PD-1 with monoclonal antibodies relatlimab and nivolumab has improved PFS in advanced melanoma, leading to Food and Drug Administration approval for this indication. Concurrently, enthusiasm for targeting LAG-3 has been tempered by negative results in multiple indications, although novel approaches including LAG-3-directed bispecifics tebotelimab continue to demonstrate promise. In this review, we discuss the current understanding of LAG-3 in regulating antitumor immunity and the ongoing state of clinical development of LAG-3-directed agents in cancer.

Tebotelimab plus niraparib preliminarily demonstrated a tolerated and manageable safety profile and limited antitumor activity in patients with previously treated solid tumors.

The combination of nivolumab plus relatlimab is more efficacious compared to PD-1 inhibition alone, as has been previously seen with the combination of CTLA-4 inhibitor ipilimumab with nivolumab...Here, the authors review the mechanism of the LAG-3 pathway and its rationale as a target for anticancer therapy as well as currently available data regarding the use of LAG-3 agents in treating melanoma and other solid tumors. Other investigational agents that target LAG-3 via novel mechanisms are also reviewed.

P2/3, N=82, Completed, MacroGenics | Active, not recruiting --> Completed

P2/3; Trial completion date: Mar 2024 --> Jun 2025

P2/3; Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

The PD-1 × LAG-3 bispecific molecule tebotelimab is safe as a monotherapy and in combination with margetuximab.

P1, N=353, Completed, MacroGenics | Active, not recruiting --> Completed

Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma.

Tebotelimab demonstrated a manageable safety profile in pts with aHCC. Antitumor activity, mainly as disease stabilization, was observed in both the CPI-naïve setting and the CPI-experienced setting. No additional clinical trials are planned at this time.

P2, N=62, Terminated, MacroGenics | Trial completion date: Apr 2024 --> Jul 2022 | Recruiting --> Terminated | Trial primary completion date: Apr 2024 --> Jul 2022; Based on internal review of safety data