The FDA granted a new fast track designation to emiltatug ledadotin for the treatment of advanced or metastatic breast cancer, specifically targeting patients with HER2-low or HER2-negative disease, including triple-negative breast cancer.
This designation applied to patients who had previously received a topoisomerase-1 inhibitor antibody-drug conjugate (ADC). Additionally, hormone-receptor positive patients needed to have either received prior endocrine therapy or be ineligible for such treatment. The FDA had previously granted fast track designation to emiltatug ledadotin for adult patients with advanced or metastatic recurrent TNBC.
Martin Huber, President and Chief Executive Officer of Mersana Therapeutics, added:
“Topoisomerase-1 inhibitor ADCs are rapidly becoming the standard of care for metastatic TNBC and hormone-receptor positive breast cancer, and an increasing amount of research shows that these patients are exceedingly difficult to treat thereafter. This growing population is a primary focus for us as we advance the development of Emi-Le. We are excited to announce this additional fast track designation and the initial clinical data from our ongoing phase 1 clinical trial that were press released separately this morning.”
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.”