Emiltatug ledadotin

EMBLEM-1 is the phase 2 part of the NCT05377996 protocol and had reported no results as of the June 29, 2026 registry update. Public information on the design comes from the registry record, which covers all three study parts, and from a conference report of the ASCO 2026 presentation. The planned EMBLEM-1 sample size, the prespecified ORR threshold, the use of blinded independent central review, and the statistical analysis plan are not public; the registry lists investigator-assessed ORR and an estimated enrollment of 360 participants for the entire phase 1/2 study. The single-arm design without a comparator means time-to-event outcomes such as PFS and OS cannot be attributed to treatment, a limitation noted in FDA endpoint guidance. Eligibility requires both a histopathologic phenotype (solid/basaloid histology or high-grade transformation) and a clinical phenotype, which matches the population in the May 2026 FDA breakthrough therapy designation, so results would not apply to non-aggressive ACC. The registry exclusion criteria remove participants with prior auristatin-based or B7-H4-targeted therapy, untreated CNS metastases, clinically significant liver or cardiovascular disease, and active keratitis.

The ASCO 2026 abstract (data cut-off October 1, 2025) reports 221 participants dosed, 35 with ACC, and 25 evaluable participants with ACC. The oral presentation at the same meeting reports 180 participants in the dose escalation and backfill cohorts, 48 with ACC, 45 evaluable participants with ACC, and 32 evaluable participants in the post hoc aggressive ACC subset. The accessible sources do not state the data cut-off of the oral presentation and do not explain why the total count is lower (180 compared with 221) while the ACC count is higher (48 compared with 35).

The December 13, 2024 slide lists columns in the order Total (N=130), ACC-I (N=7), endometrial (N=12), ovarian (N=14), HR+/HER2- breast cancer (N=34), and TNBC (N=63). Read in that order, the 7 participants with ACC-I had a median age of 55 years and a median of 0 prior lines of therapy (range 0 to 3), and none had received a prior topoisomerase-1 inhibitor ADC.

Across four interim reports, the number of evaluable participants with ACC increased from 9 to 45. At the March 8, 2025 data cut-off, ORR was 56% (5 of 9 evaluable participants with ACC-1). At the October 1, 2025 data cut-off, ORR was 40% (10 of 25; 9 confirmed and 1 unconfirmed) and DCR was 76% (19 of 25), with median PFS not reached. In the ASCO 2026 oral presentation, ORR in all evaluable participants with ACC (n=45) was 35.6% (95% CI, 21.9% to 51.2%), DCR was 82.2%, and median DoR was 7.4 months. In the post hoc aggressive ACC subset (solid/basaloid histology or high-grade transformation plus a clinical risk factor; n=32), ORR was 46.9% (95% CI, 29.1% to 65.3%) with 1 complete response, DCR was 81.3% (95% CI, 63.6% to 92.8%), median time to response was 2.7 months, median DoR was 6.4 months (95% CI, 3.1 to 9.5), and median PFS was 7.8 months (95% CI, 4.7 to 11.6). The investigator reported that B7-H4 expression level did not clearly predict benefit. All analyses are single-arm, with investigator-assessed response, and the ORR point estimates differ by data cut-off and by population definition.

Safety was reported for all enrolled participants across tumor types, with limited ACC-specific detail. In the ASCO 2026 presentation (n=180), the most common TRAEs were AST increase (56%), proteinuria (54%), fatigue (42%), and nausea (33%); grade 3 AST increase occurred in 20% and grade 3 proteinuria in 23%, no grade 4 or 5 TRAEs or treatment-related deaths were reported, and 3.9% discontinued treatment for TRAEs. Any-grade TRAEs occurred in 88.9% of all participants and 100% of participants with ACC, and grade 3 TRAEs in 51.1% and 79.2%, respectively. In the ACC cohort (n=48), TRAEs led to discontinuation in 1 participant (2.1%), dose reduction in 45.8%, and dose delay in 56.3%. The ASCO 2026 abstract (safety set of 221 participants, data cut-off October 1, 2025) reports lower frequencies: proteinuria 49.8%, AST increase 49.3%, fatigue 41.2%, grade 3 AST increase and grade 3 proteinuria 17.6% each, and discontinuation for TRAEs 3.6%. At the December 13, 2024 data cut-off (n=130), frequencies were lower again (AST increase 38%, proteinuria 31%) and 5 dose-limiting toxicities were reported, with 115 mg/m2 considered a non-tolerated dose.

The ACC evidence comes from dose escalation and backfill cohorts of a first-in-human, single-arm, open-label phase 1 study without a comparator, and response was assessed by the investigator per the registry primary outcome definition; independent central review was not reported. The aggressive ACC result (ORR 46.9%, n=32) comes from a post hoc analysis in which 13 of 48 participants with ACC were excluded, 10 of them because histology was unavailable, which introduces selection risk. Participants with ACC received doses of 57.4 to 89 mg/m2 on Q3W or Q4W schedules, so results do not describe a single regimen, and the EMBLEM-1 dose (80 mg/m2 capped at 160 mg Q4W) was applied only partly in these cohorts. Reported values differ between sources: the ASCO 2026 abstract (October 1, 2025 data cut-off) reports 221 participants dosed, 35 with ACC, and ORR 40% in 25 evaluable participants, while the oral presentation reports 180 participants, 48 with ACC, and ORR 35.6% in 45 evaluable participants, and the presentation data cut-off is not stated in the accessible sources. Safety frequencies also differ (proteinuria 49.8% compared with 54%; grade 3 proteinuria 17.6% compared with 23%). Sources disagree on whether the 35.6% and 46.9% ORR include unconfirmed responses, and a patient-directed report describes PFS approaching 8 to 9 months, compared with the 7.8 months reported by the sponsor. The comparison with a historical median PFS of 2 to 3 months is an external comparison. Median follow-up, OS, ACC-specific adverse event frequencies by grade, and health-related quality of life have not been reported, the slides are not publicly available, and no peer-reviewed full publication has been identified. A protocol amendment on proteinuria management changed dose reduction and delay rates during the study, so safety outcomes before and after the amendment are not directly comparable.