Emiltatug Ledadotin Elicits Responses in Aggressive Adenoid Cystic Carcinoma

Emiltatug ledadotin (Emi-Le), a B7-H4–directed antibody-drug conjugate (ADC), showcased antitumor activity with favorable tolerability in patients with clinicopathologically defined aggressive adenoid cystic carcinoma (ACC), according to data from an interim post hoc analysis of a phase 1 study (NCT05377996) presented at the 2026 ASCO Annual Meeting.¹

In this efficacy-evaluable cohort of patients with aggressive ACC (n = 32), the agent elicited an overall response rate (ORR) of 46.9% (95% CI, 29.1%-65.3%), which included 1 complete response (CR). The disease control rate (DCR) was 81.3% (95% CI, 63.6%-92.8%). Moreover, in the 14 responders, the median time to response (TTR) was 2.7 months (95% CI, 1.4-5.3), and the median duration of response (DOR) was 6.4 months (95% CI, 3.1-9.5).

The median progression-free survival (PFS) was 7.8 months (95% CI, 4.7-11.6), which was roughly quadruple the 2- to 3-month median historically reported for aggressive ACC, according to the presenting author, Glenn J. Hanna, MD. Hanna is director of the Center for Cancer Therapeutic Innovation (Early Drug Development Program) and the Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

In the broader molecularly and clinicopathologically defined ACC population (n = 45), the ORR was 35.6% (95% CI, 21.9%-51.2%), which included 1 CR. The DCR was 82.2% (95% CI, 67.9-92.0), and the median DOR was 7.4 months (95% CI, 3.1-not reached).

“Advanced metastatic ACC represents a high unmet need. There are no approved therapies currently, or preferred therapies, particularly for patients with a more aggressive ACC clinical pathologic phenotype,” Hanna said. “Emi-Le is a B7H4-directed ADC with a microtubule inhibitor payload that is showing promising phase 1 data in this hard-to-treat population, with a manageable safety profile, and the clinical activity was quite impressive.”

Why do these data matter for patients with aggressive ACC?

ACC is a rare cancer of the secretory glands that arises most often in the salivary glands, and no systemic therapies are approved or preferred for recurrent or metastatic disease.² Molecular subtyping has defined a distinct high-risk subset, designated ACC-I, which is characterized by activating NOTCH mutations, c-Myc overexpression, and/or low or negative p63 expression, and is linked with solid histology and poor prognosis. Approximately 30% to 40% of patients show this aggressive phenotype, which has carried a historical median PFS of 2 to 3 months and a median overall survival of approximately 3 years across prior trials.^2,3

“There remains a tremendous and high unmet need for this aggressive population,” Hanna noted.

Because molecular profiling is not always accessible or feasible, particularly at community centers or in patients with limited tissue, aggressive ACC can be identified clinicopathologically: by solid tumor morphology or high-grade transformation (HGT) on histology, plus recurrence or progression within 3 years of diagnosis and/or extrapulmonary sites of metastasis.

B7-H4, a member of the CD28/B7 family of immune co-inhibitory molecules, is a clinically validated target and negative prognostic factor that is highly expressed in ACC with limited expression in healthy tissue; high B7-H4 staining was linked with inferior survival in ACC (HR, 2.54; 95% CI, 1.05-6.18; P = .0123).⁴ “Emiltatug ledadotin, formerly XMT-1660, is a B7-H4–directed ADC with a proprietary auristatin F-HPA microtubule-inhibitor payload designed for controlled bystander effect, with a target-optimized drug-to-antibody ratio of 6 and allows for site-specific conjugation with a novel ADC platform,” Hanna said.⁵

How was the emiltatug ledadotin phase 1 trial designed?

The phase 1 study enrolled patients with recurrent, advanced, or metastatic solid tumor cohorts, including triple-negative breast cancer, hormone receptor–positive/HER2-negative breast cancer, endometrial cancer, ovarian cancer, and ACC-I. Patients are aged 18 years or older with an ECOG performance status of 0 or 1 and B7-H4 expression assessed retrospectively by immunohistochemistry.

Patients with ACC were required to have the following features: a histopathologic phenotype (solid tumor morphology), a clinical phenotype (less than 3 years to recurrence/progression or de novo metastatic disease with atypical sites), and/or activating NOTCH1-4 mutations, c-Myc positivity, or negative/low p63.

Doses from 7.2 to 115 mg/m² were evaluated, with maximum tolerated dose, safety, and tolerability as primary end points for the escalation phase of the study. The expansion phase, which is enrolling patients with TNBC and ACC-I, evaluates 67.4 mg/m² every 4 weeks (Q4W), a 44.5-mg/m² split-dose lead-in followed by 80 mg/m² Q4W, and 80 mg/m² Q4W. ORR, safety, and tolerability serve as primary end points. “We landed on 80 mg/m² monthly as the preferred dose,” Hanna said.

The preliminary analysis reported safety for all enrolled patients and antitumor activity for the ACC-specific cohort.¹

Among the 48 patients with ACC, 77.1% had solid tumor morphology, 77.1% had extrapulmonary metastasis, and 68.8% had progressed within 3 years of diagnosis. The median B7-H4 tumor proportion score (TPS) was 77.5% (range, 2%-100%) among 40 evaluated patients, and 66.7% harbored activating NOTCH1-4 mutations. Patients with ACC had received a median of 1 prior line of therapy (range, 0-3).

Of those in the overall population (n = 180), 88.3% were female, with a median age of 57.5 years. ”The patient demographics are as we would expect from this population,” Hanna noted.

For the post hoc analysis, a stricter clinicopathologic definition required both a histopathologic phenotype (solid/basaloid histology or HGT) and at least one clinical risk factor (progression within 3 years or extrapulmonary metastasis). Thirteen patients were excluded; 10 patients had unavailable histology, 2 did not have clinical phenotype criteria met, and 1 did not have histopathologic phenotype criteria met. This left 35 patients with aggressive ACC, and 32 were efficacy evaluable.

What was learned about emiltatug ledadotin response as it relates to B7-H4 expression in aggressive ACC?

"I'm happy to say that all responses have now been confirmed, including 1 CR," Hanna said. B7-H4 expression level did not clearly predict benefit. "Some patients with expression as low as 2% have evidence of durable and deep responses," he said.

What was the safety profile of emiltatug ledadotin?

Emiltatug ledadotin demonstrated a manageable safety profile across the full population of 180 patients. Any-grade treatment-related adverse effects (TRAEs) occurred in 88.9% of all patients and 100% of those with ACC, and grade 3 TRAEs occurred in 51.1% and 79.2%, respectively. There were no grade 4 or 5 TRAEs and no treatment-related deaths.

The most common TRAEs were transient aspartate aminotransferase elevations, which resolved to baseline or grade 1 by the subsequent dose, with no hepatic failure or Hy's law observed; asymptomatic and reversible proteinuria; and predominantly low-grade fatigue and nausea. There was no alopecia and no interstitial lung disease or pneumonitis, and rates of cytopenias, peripheral neuropathy, keratitis, and ocular toxicity were low relative to other ADCs, according to Hanna. Neutropenia, keratitis, and neuropathy occurred in 2.2%, 3.9%, and 2.8% of all patients, respectively.

In the ACC cohort (n = 48), TRAEs led to discontinuation in only 1 patient (2.1%), dose reduction in 45.8%, and dose delay in 56.3% of patients. Asymptomatic proteinuria, characterized on post hoc biopsy as glomerular podocytopathy without acute renal vascular injury, represented the leading cause of dose modification. After a protocol amendment introduced an updated monitoring and management plan, including renal-protective medications, proteinuria-related dose reductions decreased from 38.9% to 20% and delays from 50.0% to 6.7% among patients with ACC.

"Patients were easily managed and monitored with no subsequent long-term nephrotic syndrome, issues with creatinine elevation, and many patients have sustained dosing for many months, even beyond 1 year," Hanna said.

What are the next steps for emiltatug ledadotin in ACC?

The phase 2 EMBLEM-1 study (NCT05377996), a continuation of the phase 1 program, is enrolling patients with aggressive ACC and measurable disease per RECIST v1.1, with the phenotype confirmed by both histopathologic criteria (solid/basaloid histology or HGT) and clinical phenotype (progression within 3 years or extrapulmonary metastasis). Tissue is submitted for B7-H4 testing and molecular profiling.

The dosing regimen is emiltatug ledadotin 80 mg/m² (capped at 160 mg) Q4W, with ORR as the primary end point and DOR, DCR, PFS, overall survival, and safety as secondary end points.

"These findings certainly support advancement into phase 2 study,” Hanna concluded.

In May 2026, the FDA granted emiltatug ledadotin breakthrough therapy designation for the treatment of patients with locally advanced, recurrent, or metastatic ACC with solid histology or HGT, based on phase 1 results.⁶ The agent also carries FDA fast track designation in breast cancer, including HER2-low and HER2-negative disease previously treated with a topoisomerase-1 inhibitor ADC.

Disclosures: Hanna reported honoraria from the Massachusetts Medical Society; consulting or advisory roles with Adela, Astellas Pharma, AstraZeneca, Bicara Therapeutics, Boxer Capital, Bristol Myers Squibb, Coherus Biosciences, CorriXr, Curie.Bio, Elevar Therapeutics, Grey Wolf Therapeutics, Guardian Bio, InhibRx, KSQ Therapeutics, Kura Oncology, Merck, Naveris, Nextech Invest, OncoSwitch, Ottimo, Outrun, PDS Biotechnology, Pyxis, Regeneron, Remix Therapeutics, Replimune, Rgenta, Surface Oncology, TD Cowan, and Tubulis; institutional research funding from Actuate Therapeutics, Astellas Pharma, Bicara Therapeutics, Bristol Myers Squibb, Cellestia Biotech, Coherus Biosciences, Exelixis, Genentech, ImmunityBio, KSQ Therapeutics, Kura Oncology, Regeneron, Remix Therapeutics, Rgenta, and Secura Bio; and a relationship with Tubulis.

References

1. Hanna GJ, Rabinowits G, Attarian S, et al. Emiltatug ledadotin (Emi-Le), a B7-H4–directed antibody-drug conjugate (ADC), in patients with aggressive adenoid cystic carcinoma (ACC): phase 1 interim analysis. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 6010.
2. Ferrarotto R, Mitani Y, McGrail DJ, et al. Proteogenomic analysis of salivary adenoid cystic carcinomas defines molecular subtypes and identifies therapeutic targets. Clin Cancer Res. 2021;27(3):852-864. doi:10.1158/1078-0432.CCR-20-1192
3. Hanna GJ, Stathis A, Lopez-Miranda E, et al. A phase 1 study of the pan-Notch inhibitor CB-103 for patients with advanced adenoid cystic carcinoma and other tumors. Cancer Res Commun. 2023;3(9):1853-1861. doi:10.1158/2767-9764.CRC-23-0333
4. Sousa LG, Dawidowicz M, Bailey A, et al. Spatial immunoprofiling of adenoid cystic carcinoma reveals B7-H4 is a therapeutic target for aggressive tumors. Clin Cancer Res. 2023;29(16):3162-3171. doi:10.1158/1078-0432.CCR-23-0514
5. Toader D, Fessler SP, Collins SD, et al. Discovery and preclinical characterization of XMT-1660, an optimized B7-H4-targeted antibody-drug conjugate for the treatment of cancer. Mol Cancer Ther. 2023;22(9):999-1012. doi:10.1158/1535-7163.MCT-22-0786
6. Emiltatug ledadotin (Emi-Le) granted breakthrough therapy designation by the U.S. FDA for adenoid cystic carcinoma (ACC). News release. Servier. May 12, 2026. Accessed June 15, 2026. https://servier.mediaroom.com/2026-05-12-Emiltatug-Ledadotin-Emi-Le-Granted-Breakthrough-Therapy-Designation-by-the-U-S-FDA-for-Adenoid-Cystic-Carcinoma-ACC