Emiltatug Ledadotin Generates Positive Initial Data in Advanced/Metastatic Solid Tumors

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Initial data from a phase 1 study (NCT05377996) evaluating emiltatug ledadotin (Emi-Le; XMT-1660) in patients with advanced/metastatic triple-negative breast cancer (TNBC), hormone receptor (HR)–positive/HER2-negative breast cancer, ovarian cancer, endometrial cancer, and adenoid cystic carcinoma type 1 were positive, showing a generally tolerable safety profile and early signs of efficacy.¹

Emi-Le is a homogeneous DAR 6 dolasynthen antibody-drug conjugate (ADC) that targets B7-H4.² The agent has also received a new fast track designation from the FDA for the treatment of patients with advanced or metastatic HER2-low or HER2-negative breast cancer who have previously received a topoisomerase-1–directed ADC.³ Patients with HR-positive, HER2-low/negative disease should have previously received or be ineligible for endocrine therapy. Previously, the agent received FDA fast track designation for the treatment of adult patients with advanced or metastatic recurrent TNBC.

At the December 13, 2024, data cutoff, patients in the overall population of the dose-escalation portion of the trial (n = 130) experienced no grade 4 or 5 treatment-related adverse effects (TRAEs).¹ Any-grade TRAEs (76.2%), grade 3 TRAEs (30.0%), TRAEs leading to treatment discontinuation (2.3%), TRAEs leading to dose reduction (9.2%), and TRAEs leading to dose delay (12.3%) were all reported.² Serious TRAEs occurred in 4.6% of patients; no dose-limiting neutropenia, neuropathy, ocular toxicity, interstitial lung disease, or thrombocytopenia were reported.¹

The confirmed overall response rate (ORR) at intermediate dose levels (38.1 mg/m² to 67.4 mg/m²) was 23% among efficacy-evaluable patients with B7-H4–high tumors (n = 26).² Patients with B7-H4–high TNBC (n = 13) also achieved a confirmed ORR of 23%. At doses at or above 76.2 mg/m², the confirmed ORR among efficacy-evaluable patients with B7-H4–high tumors (n = 9) was 22%, with 78% of patients achieving a tumor reduction in target lesions of at least 30%.

“We believe the initial safety, tolerability, and efficacy data for Emi-Le demonstrate a profile that is exciting and differentiated within both the B7-H4 field and the broader ADC landscape,” Martin Huber, MD, president and CEO of Mersana Therapeutics, stated in a news release.¹ “We have observed clinical activity across tumors, including in heavily pretreated patients with TNBC. These clinical data have led us to initiate expansion in patients with TNBC who have previously been treated with at least 1 topoisomerase-1–directed ADC, a population with very high unmet need.”

The first-in-human, multicenter phase 1 study of Emi-Le enrolled adult patients with recurrent or advanced solid tumors.⁴ Patients needed to have an ECOG performance status of 0 or 1, tumor tissue available for testing, and undergone MRI during the screening period or 30 days prior among patients with TNBC or a history of brain metastases.

Emi-Le monotherapy was administered intravenously at doses ranging from 7.2 mg/m² to 67.4 mg/m² every 3 weeks, 28.7 mg/m² to 44.5 mg/m² on days 1 and 8 every 4 weeks, or 28.7 mg/m² to 115.0 mg/m² every 4 weeks.² The median age of the overall population was 55.0 years. Patients had received a median of 4.5 prior lines of treatment (range, 0.0-15.0), including fam-trastuzumab deruxtecan-nxki (Enhertu; 27.7%), sacituzumab govitecan-hziy (Trodelvy; 53.1%), or both (20.8%).

The coprimary end points were the incidence of dose-limiting toxicities during the first cycle of treatment, incidence of adverse effects, and ORR per RECIST 1.1 criteria.⁴ Secondary end points included duration of response, as well as establishing the pharmacokinetic parameters of Emi-Le, including time of maximum observed plasma concentration, maximum observed plasma concentration, area under the concentration-time curve, systemic clearance, half-life, and trough concentration.

Additional safety data demonstrated that the most common any-grade TRAEs across the total population were increased aspartate aminotransferase (AST) levels (38%), proteinuria (31%), nausea (29%), and fatigue (28%). The most common grade 3 TRAEs were increased AST levels (14%) and proteinuria (9%).

In the first half of 2025, Mersana plans to continue enrollment to the expansion cohort of the phase 1 trial at a dose of 67.4 mg/m² every 4 weeks in patients with TNBC who have received prior therapy with at least 1 topoisomerase-1–directed ADC.¹ Also in 2025, the company plans to initiate enrollment to an expansion cohort at a second dose in this patient population and present additional clinical phase 1 data from the dose-escalation and backfill cohorts.

“In terms of both tolerability and clinical activity, these Emi-Le data are encouraging,” Erika Hamilton, MD, director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee, said in the news release. “It is notable that all the [patients with] TNBC who responded to Emi-Le had previously been treated with at least 1 topoisomerase-1–directed ADC. The results indicate that Emi-Le may help address an already substantial and growing need [for new treatments] among [patients with breast cancer who have received] topoisomerase-1[–directed therapy].”

References

1. Mersana Therapeutics announces positive initial clinical data from phase 1 clinical trial of emiltatug ledadotin (XMT-1660); initiation of expansion in triple negative breast cancer. News release. Mersana Therapeutics, Inc. January 10, 2025. Accessed January 10, 2025. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-positive-initial-clinical-data
2. Corporate presentation. Mersana Therapeutics, Inc. January 10, 2025. Accessed January 10, 2025. https://ir.mersana.com/static-files/a6b76e0c-b081-4f62-bdfc-b21f8f15bff0
3. Mersana Therapeutics announces additional FDA fast track designation granted to emiltatug ledadotin (XMT-1660). News release. Mersana Therapeutics, Inc. January 10, 2025. Accessed January 10, 2025. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-additional-fda-fast-track
4. A study of XMT-1660 in participants with solid tumors. ClinicalTrials.gov. Updated September 19, 2024. Accessed January 10, 2024. https://clinicaltrials.gov/study/NCT05377996