About Emiltatug ledadotin
Emiltatug ledadotin, developed by Mersana Therapeutics targets the B7-H4 protein, which is commonly overexpressed in several cancers, including breast, endometrial, and ovarian cancer. The drug features a precise drug-to-antibody ratio, enhancing its potential to selectively target cancer cells. Positive initial clinical data from a Phase 1 trial’s dose-escalation and backfill cohorts showed that emiltatug ledadotin was generally well tolerated, with no grade 4 or 5 treatment-related adverse events (TRAEs) reported in patients with advanced or metastatic triple-negative breast cancer (TNBC).
The Phase 1 trial, with a data cutoff date of December 13, 2024, included 130 patients who had advanced or metastatic TNBC, HR-positive/HER2-negative breast cancer, ovarian cancer, endometrial cancer, and adenoid cystic carcinoma type 1. These patients were heavily pretreated, having received up to 15 prior lines of therapy, with a median of 4.5 lines. Notably, around 92% of the patients with TNBC had previously been treated with at least one topoisomerase-1 inhibitor antibody-drug conjugate (ADC). Among 103 patients with known B7-H4 tumor expression, approximately 44% had a tumor proportion score of 70% or higher, making them eligible for treatment with emiltatug ledadotin.
At intermediate doses (38.1 mg/m² to 67.4 mg/m²), the trial reported a confirmed objective response rate (ORR) of 23% across all B7-H4 high tumors and 23% in B7-H4 high TNBC. These responses were observed in patients who had been pretreated with at least one topoisomerase-1 inhibitor. The most common treatment-related adverse events were transient increases in aspartate aminotransferase, reversible proteinuria, nausea, and fatigue. There were no cases of dose-limiting treatment-related neutropenia, neuropathy, ocular toxicity, interstitial lung disease, or thrombocytopenia. Following these promising results, a dose of 67.4 mg/m² every four weeks was selected for further expansion in patients with TNBC who have received 1 to 4 prior lines of treatment.
About the Trial
As of December 13, 2024, the dose escalation portion of the Phase 1 clinical trial for Emi-Le (XMT-1660) enrolled 130 patients across multiple advanced/metastatic cancers, including triple-negative breast cancer (TNBC), hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancer, ovarian cancer, endometrial cancer, and adenoid cystic carcinoma type 1. The enrolled patients were heavily pretreated, with a median of 4.5 prior therapy lines, including patients who had previously received at least one topo-1 antibody-drug conjugate (ADC). Notably, 44% of patients with known B7-H4 tumor expression had a tumor proportion score of 70% or higher, which Mersana has identified as “B7-H4 high.”
Emi-Le was generally well tolerated, with no Grade 4 or 5 treatment-related adverse events (TRAEs) reported. Common adverse events included transient increases in aspartate aminotransferase (AST), reversible proteinuria, low-grade nausea, and fatigue. Notably, no dose-limiting neutropenia, neuropathy, ocular toxicity, interstitial lung disease, or thrombocytopenia were observed, which the company believes differentiates Emi-Le from many other ADCs in clinical development or on the market. TRAEs leading to treatment discontinuation, dose reduction, and delays were relatively low, with 2.3%, 9.2%, and 12.3% of patients experiencing these effects, respectively.
At intermediate doses (38.1 mg/m2 to 67.4 mg/m2), the confirmed objective response rate (ORR) was 23% in evaluable patients with B7-H4 high tumors and 23% in patients with B7-H4 high TNBC who had been treated with at least one prior topo-1 ADC. This response rate is particularly notable when compared to the results seen in the ASCENT Phase 3 trial of sacituzumab govitecan, a topo-1 ADC, which showed an ORR of approximately 5% with chemotherapy in relapsed/refractory TNBC.
Given the promising clinical activity observed in this early-stage trial, Mersana has advanced a dose of 67.4 mg/m2 of Emi-Le every four weeks into an expansion cohort for patients with TNBC who have received one to four prior treatments, including at least one topo-1 ADC. This expansion cohort aims to further evaluate the potential of Emi-Le as a treatment option for patients with difficult-to-treat cancers, particularly those with B7-H4 high tumor expression.
For Further Reading, “A Study of XMT-1660 in Participants With Solid Tumors.”