Emiltatug ledadotin (Emi-Le)

Emiltatug ledadotin (Emi-Le, XMT-1660) is an investigational B7-H4-directed ADC with an auristatin F-HPA microtubule inhibitor payload at a drug-to-antibody ratio of 6. It is not approved in any jurisdiction. The FDA granted Breakthrough Therapy designation in May 2026 for locally advanced, recurrent or metastatic ACC with solid histology or high-grade transformation, and the phase 2 EMBLEM-1 part of NCT05377996 is enrolling, with an estimated primary completion date of February 2027 for the overall study. No biologics license application has been identified.

Treatment options for the target population are limited. ACC-I, which is enriched for solid histology, has a median overall survival of 3.44 years compared with 23.2 years for ACC-II, and in the axitinib plus avelumab phase II trial median overall survival was 11.3 months for ACC-I compared with 36 months for ACC-II; no systemic therapy is approved for recurrent or metastatic ACC; and the pooled objective response rate with VEGFR inhibitors is 6%. In one 1:1 matched series of 23 pairs, high-grade transformation was associated with a 3-year mortality of 34.8% compared with 4.3% in non-transformed ACC.

The efficacy evidence is limited to interim phase 1 data. In 45 evaluable participants with ACC, the objective response rate was 35.6%; in a post hoc subset of 32 evaluable participants with aggressive ACC, it was 46.9%, with a median progression-free survival of 7.8 months. These rates are numerically higher than the response rates of 0% to 21.7% reported in the lenvatinib, axitinib, axitinib plus avelumab, sorafenib, and rivoceranib studies in recurrent or metastatic ACC, the highest of which was a real-world lenvatinib cohort (10 of 46 evaluable participants, 21.7%). Objective response rate may understate the activity of the comparators: in the only randomized trial, axitinib produced an objective response rate of 0.0% while raising the 6-month progression-free survival rate to 73.0% from 23.0% with observation. The phase 1 data are single-arm, investigator-assessed, partly post hoc, drawn from doses of 57.4 to 89 mg/m2 rather than the phase 2 dose, and not published in a peer-reviewed journal. The main toxicities are proteinuria and transient AST increase. Grade 3 treatment-related adverse events occurred in 79.2% of participants with ACC, and dose reductions and delays were frequent (45.8% and 56.3%), although discontinuation was uncommon (2.1%). A protocol amendment for proteinuria monitoring and renal-protective medications reduced proteinuria-related dose modifications. Hematologic, ocular, and neuropathic toxicities were infrequent.

The sources disagree on several points that affect interpretation. The ASCO 2026 abstract (October 1, 2025 data cut-off) reports 221 participants dosed, 35 with ACC, 25 evaluable, and an objective response rate of 40%, whereas the oral presentation reports 180 participants, 48 with ACC, 45 evaluable, and 35.6%, without a stated data cut-off. Safety frequencies differ between the two (proteinuria 49.8% compared with 54%; grade 3 proteinuria 17.6% compared with 23%; discontinuation 3.6% compared with 3.9%). Conference reports differ on whether the 35.6% and 46.9% rates include unconfirmed responses, and a patient-directed report gives progression-free survival as approaching 8 to 9 months rather than 7.8 months. Sources give the historical median overall survival in aggressive ACC as approximately 3 years or as 2 to 3 years. In the comparator literature, Ma et al. label the same high-grade transformation mortality figure of 34.8% (8 of 23) as a 3-year rate in their results and as a 5-year rate in their discussion, and their abstract rounds it to 35.0%.

The main evidence gaps for a P&T committee are the absence of EMBLEM-1 results, sample size, and response threshold; overall survival and health-related quality of life data; independent central review; ACC-specific adverse event frequencies by grade; and baseline characteristics of the post hoc subset, from which 10 of 48 participants were excluded because histology was unavailable. The comparator evidence carries a matching gap: apart from the axitinib plus avelumab trial, which reported ACC-I and ACC-II separately, no comparator trial reports efficacy by histologic or molecular subtype, and the randomized axitinib trial states that it did not capture detailed information on pathologic subtype, so the historical response and survival rates used as benchmarks come from populations that were not selected for solid histology or high-grade transformation. The one ACC-specific quality of life cohort tested NOTCH1 status, primary site, sex, age, recurrence status, and type of recurrence as predictors of utility, but not histologic subtype. B7-H4 expression did not clearly predict response, and no B7-H4 threshold has been described for EMBLEM-1 enrollment, so eligibility would rest on histologic and clinical criteria; interobserver agreement for traditional solid-component grading systems is moderate (kappa 0.393 and 0.433). No price, budget impact model, or health technology assessment exists, and the only product-level revenue projections are company forecasts. A formulary decision would therefore depend on EMBLEM-1 results, the approved label and dose, and the launch price.