Mersana Therapeutics' emiltatug ledadotin (Emi-Le; XMT-1660), an antibody-drug conjugate (ADC) targeting B7-H4, has shown promising initial clinical data in a Phase 1 trial, leading to Fast Track designation from the U.S. Food and Drug Administration (FDA) for advanced or metastatic HER2-low or HER2-negative breast cancer, including triple-negative breast cancer (TNBC). The trial, which included 130 patients with various advanced/metastatic cancer types, demonstrated a well-tolerated safety profile and encouraging efficacy, particularly in heavily pre-treated TNBC patients. These findings suggest that Emi-Le could address a significant unmet need in patients with limited treatment options.
Phase 1 Trial Results: Safety and Efficacy
The Phase 1 trial evaluated various doses and dosing schedules of Emi-Le. Notably, no Grade 4 or 5 treatment-related adverse events were reported. Common side effects included reversible proteinuria and low-grade nausea and fatigue. At intermediate dose levels (38.1 mg/m2 to 67.4 mg/m2), patients with B7-H4 high tumors exhibited a 23% confirmed objective response rate (ORR). In the subset of patients with B7-H4 high TNBC who had previously been treated with at least one topoisomerase-1 (topo-1) ADC, the ORR was also 23%.
Erika Hamilton, M.D., Director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee, noted, "In terms of both tolerability and clinical activity, these Emi-Le data are encouraging. It is notable that all the TNBC patients who responded to Emi-Le had previously been treated with at least one topo-1 ADC. The results indicate that Emi-Le may help address an already substantial and growing need among topo-1 experienced breast cancer patients for new treatments."
Comparison to Standard of Care
In the ASCENT Phase 3 clinical trial of sacituzumab govitecan, a topo-1 ADC, the ORR with standard-of-care single-agent chemotherapy in relapsed/refractory TNBC was approximately 5%, with progression-free survival of approximately seven weeks. The 23% ORR observed with Emi-Le in a similar patient population suggests a potential improvement over existing treatments.
Ongoing Development and Future Milestones
Mersana is continuing enrollment in an expansion cohort at a dose of 67.4 mg/m2 every four weeks in patients with TNBC who have received one to four prior treatment lines, including at least one prior topo-1 ADC. The company also plans to initiate enrollment in an expansion cohort at a second dose in the same patient population and present additional Phase 1 clinical data from dose escalation and backfill cohorts in 2025.
FDA Fast Track Designation
The FDA's Fast Track designation is intended to expedite the development and review of new drugs that treat serious conditions and fill unmet medical needs. This designation for Emi-Le underscores its potential to provide a meaningful benefit to patients with advanced breast cancer who have limited treatment options.
Implications for B7-H4-Targeted Therapy
Emiltatug ledadotin (XMT-1660) targets B7-H4, a protein overexpressed in various cancers, making it a promising target for ADC therapy. The initial data from the Phase 1 trial suggest that Emi-Le has a differentiated safety and tolerability profile compared to other ADCs, with no reported dose-limiting treatment-related neutropenia, neuropathy, ocular toxicity, interstitial lung disease, or thrombocytopenia. This favorable profile, combined with the observed clinical activity, supports further development of Emi-Le as a potential treatment option for patients with B7-H4-expressing tumors.
