Emiltatug ledadotin

Adenoid cystic carcinoma (ACC) is a malignancy of the secretory glands that arises most often in the salivary glands and accounts for approximately 1% of head and neck malignancies. Reported incidence is 3 to 4.5 per million, and approximately 1,200 to 1,300 new cases are diagnosed per year in the United States; Servier states that more than 200,000 people have ACC worldwide. No population registry reports the incidence or prevalence of ACC with solid histology or high-grade transformation. Institutional series indicate the size of the aggressive subgroup: the ACC-I molecular subtype accounted for 20 of 54 tumors (37%) in a proteogenomic cohort, solid-type histology was present in 27.5% of cases in one institutional series, and high-grade transformation was identified in 23 of 412 cases (5.6%) in another. Day One Biopharmaceuticals states that up to 40% of patients have the aggressive form.

Survival is shorter in the aggressive subgroup than in ACC overall. In SEER (3,026 head and neck cases), 5-, 10-, and 15-year survival for ACC overall was 90.3%, 79.9%, and 69.2%. In the proteogenomic cohort, median overall survival was 3.44 years for ACC-I and 23.2 years for ACC-II; a 2026 meta-analysis of 247 participants from 5 cohorts reported a pooled hazard ratio for death of 3.88 (95% CI 2.55 to 5.90) for ACC-I versus 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. In the original histologic grading series, 15-year survival was 5% for predominantly solid (grade III) tumors compared with 39% for grade I tumors. NOTCH1-mutant tumors, which are enriched for solid histology, had a median overall survival of 30 months compared with 122 months for wild-type tumors. High-grade transformation has been compared directly with non-transformed ACC in one 1:1 matched series of 23 pairs: mortality was 47.8% (11 of 23) versus 8.7% (2 of 23), 3-year mortality was 34.8% (8 of 23) versus 4.3% (1 of 23), median progression-free survival was 18.0 versus 37.0 months, and median survival after distant metastasis was 8.0 versus 16.5 months, although median follow-up was shorter in the transformed group (29.0 versus 39.0 months). Distant metastasis occurred in 78.3% of transformed cases, and in an earlier 9-participant series 5 died within 5 years, with a median overall survival of 12 months. Among solid-type tumors with distant metastases, 17 of 28 (61%) involved multiple organs. Company sources report a median progression-free survival of 2 to 3 months in aggressive ACC; the median overall survival is given as approximately 3 years in the 2026 Form 10-K and the ASCO 2026 abstract and as 2 to 3 years in a 2025 Mersana announcement.

No systemic therapy is approved by the FDA for recurrent or metastatic ACC. In a meta-analysis of 17 studies of VEGFR inhibitors (560 participants), the pooled objective response rate was 6%. In the only randomized comparator trial, 60 participants with recurrent or metastatic ACC progressing within the previous 9 months were allocated to axitinib or observation and 54 were evaluable: the 6-month progression-free survival rate was 73.0% with axitinib and 23.0% with observation, median progression-free survival was 10.8 versus 2.8 months (hazard ratio 0.25, 95% CI 0.14 to 0.48), and the disease control rate was 100.0% versus 51.9%, but the objective response rate was 0.0% in both groups and median overall survival was not reached with axitinib compared with 27.2 months with observation (P = 0.226). In a real-world cohort of 51 participants treated with lenvatinib at 17 Italian sites, the objective response rate was 21.7% among 46 evaluable participants, median progression-free survival was 14.8 months, and median overall survival was 16.1 months. Outcomes of ACC-I were worse than those of ACC-II across pooled systemic treatment categories in a real-world cohort (hazard ratio 3.06), and with axitinib plus avelumab, median progression-free survival was 1.8 months in ACC-I compared with 11.4 months in ACC-II.

Humanistic and economic burden data specific to aggressive ACC were not identified. The only ACC-specific health-related quality of life study (EQ-5D-5L; 161 participants, 563 questionnaires) reported a median EQ-5D value of 0.81 and a mean of 0.79, below the age-matched general population mean of 0.86, with a median visual analogue scale score of 70; a decrease in value from 1 to 0 was associated with an eightfold increase in the risk of death. Quality of life decreased significantly over time in that cohort, and no clinical variable tested, including NOTCH1 status, primary site, sex, age, and pattern of recurrence, predicted the decline; results were not reported by histologic subtype. No ACC-specific cost-of-illness study was identified. The closest United States estimate comes from claims data for oral cavity, oropharyngeal, and salivary gland cancers combined, in which total healthcare spending in the year after diagnosis was $79,151 in the commercially insured population. In a pilot survey in head and neck cancer, high financial toxicity was reported by 44.4% of caregivers and 25.9% of participants with cancer.

All clinical data for emiltatug ledadotin in ACC come from interim analyses of the dose escalation and backfill cohorts of NCT05377996, a first-in-human, open-label, single-group phase 1/2 study. There is no randomized or concurrent comparator, responses were assessed by investigators, and independent central review has not been reported. Results are available only as a congress abstract, a sponsor press release, conference news reports, and earlier company disclosures; no peer-reviewed full publication was identified. Participants with ACC received 57.4 to 89 mg/m2 every 3 or 4 weeks, which differs from the single regimen selected for phase 2 (80 mg/m2 every 4 weeks, capped at 160 mg).

The two ASCO 2026 sources report different data sets. The abstract (data cut-off October 1, 2025) reports 221 participants dosed across tumor types, 35 with ACC (median age 58 years, 57% female, median 1 prior line of therapy), and 25 evaluable participants with ACC, in whom the objective response rate was 40% (10 of 25; 9 confirmed and 1 unconfirmed), the disease control rate was 76% (19 of 25), and median progression-free and overall survival had not been reached. The oral presentation on June 1, 2026 reports 180 participants in dose escalation and backfill and 48 with ACC; in 45 evaluable participants with ACC, the objective response rate was 35.6% (95% CI 21.9% to 51.2%) with 1 complete response, the disease control rate was 82.2%, and the median duration of response was 7.4 months. The data cut-off of the oral presentation is not stated in the accessible sources, and the lower total count (180 compared with 221) with a higher ACC count (48 compared with 35) is not explained. At the earlier March 8, 2025 data cut-off, the objective response rate was 56% (5 of 9 evaluable participants with ACC-1).

The analysis closest to the target population is post hoc. A stricter definition of aggressive ACC required a histopathologic phenotype (solid or basaloid histology, or high-grade transformation) and at least one clinical risk factor. Of 48 participants with ACC, 13 were excluded (10 because histology was unavailable), leaving 35, of whom 32 were evaluable. In these 32 participants, the objective response rate was 46.9% (95% CI 29.1% to 65.3%) with 1 complete response, the disease control rate was 81.3% (95% CI 63.6% to 92.8%), the median time to response was 2.7 months, the median duration of response was 6.4 months (95% CI 3.1 to 9.5), and the median progression-free survival was 7.8 months (95% CI 4.7 to 11.6). A patient-directed news report described progression-free survival “approaching eight to nine months”. Sources disagree on response confirmation: the investigator was quoted as saying that “all responses have now been confirmed”, whereas another conference report described the 35.6% and 46.9% rates as combined confirmed and ongoing unconfirmed responses. B7-H4 expression (median tumor proportion score 77.5% in 40 evaluated participants) did not clearly predict benefit, and responses occurred with expression as low as 2%. Overall survival, health-related quality of life, and response by dose level have not been reported.

The safety data also differ by source. In the abstract safety set (221 participants), the most common treatment-related adverse events were proteinuria (49.8%), transient AST increase (49.3%), and fatigue (41.2%); grade 3 AST increase and grade 3 proteinuria each occurred in 17.6%, 3.6% discontinued treatment because of treatment-related adverse events, and no treatment-related deaths occurred. In the oral presentation (180 participants), the corresponding rates were AST increase 56%, proteinuria 54%, fatigue 42%, and nausea 33%, with grade 3 AST increase in 20%, grade 3 proteinuria in 23%, no grade 4 or 5 events, and discontinuation in 3.9%. Any-grade treatment-related adverse events occurred in 88.9% of all participants and 100% of participants with ACC, and grade 3 events in 51.1% and 79.2%, respectively. Among the 48 participants with ACC, treatment-related adverse events led to discontinuation in 1 (2.1%), dose reduction in 45.8%, and dose delay in 56.3%. Proteinuria, characterized on post hoc biopsy as glomerular podocytopathy, was the leading cause of dose modification; after a protocol amendment that added monitoring and renal-protective medications, proteinuria-related dose reductions decreased from 38.9% to 20% and delays from 50.0% to 6.7% among participants with ACC. AST elevations resolved to baseline or grade 1 by the next dose, with no hepatic failure or Hy's law cases. Neutropenia (2.2%), keratitis (3.9%), and neuropathy (2.8%) were infrequent, and no alopecia or interstitial lung disease was reported. Earlier in dose escalation, responses in several participants at high doses were not confirmed after proteinuria-related dose delays, and 115 mg/m2 was considered a non-tolerated dose.

Historical outcomes in recurrent or metastatic ACC provide the only context for these results. A meta-analysis of 17 VEGFR inhibitor studies (560 participants) reported a pooled objective response rate of 6%. Individual studies reported 15.6% (5 of 32 evaluable participants) and 11.5% (3 of 26) with lenvatinib and 21.7% (10 of 46) in a real-world lenvatinib cohort of 51 participants; 9.1% (3 of 33) with axitinib in ACC and 8% (2 of 26) with axitinib in a single-center trial in salivary gland carcinomas that did not meet its primary endpoint; 18% with axitinib plus avelumab (28 evaluable participants); 15.3% by investigator and 9.7% by blinded independent review with rivoceranib (72 evaluable participants); and 11% (2 of 19 evaluable participants) with sorafenib. In the randomized trial of axitinib versus observation (60 participants allocated, 54 evaluable), the objective response rate was 0.0% in both groups while the 6-month progression-free survival rate was 73.0% versus 23.0%, the disease control rate was 100.0% versus 51.9%, and median progression-free survival was 10.8 versus 2.8 months (hazard ratio 0.25); median overall survival was not reached with axitinib and was 27.2 months with observation (P = 0.226). Median progression-free survival in the other comparator studies ranged from 5.5 months (axitinib in salivary gland carcinomas) to 17.5 months (the 32-participant lenvatinib phase II trial), and reported median overall survival was 16.1 months in the real-world lenvatinib cohort, 19.6 months with sorafenib, 26.2 months with axitinib in salivary gland carcinomas, and 27 months in the 26-participant lenvatinib phase II trial. With axitinib plus avelumab, median progression-free survival in ACC-I was 1.8 months. Higher response rates were reported with apatinib in a single-arm trial in China (46.2% in 65 evaluable participants) and with CAP chemotherapy (25%). Toxicity in these comparator studies was frequent: grade 3 adverse events occurred in approximately half of participants in the 26-participant lenvatinib phase II trial and in 13 of 23 participants (57%) receiving sorafenib; dose reductions were required in 24 of the 28 participants enrolled in that lenvatinib trial, in 74% of participants receiving sorafenib, and in 32 of 51 participants (63.6%) in the real-world lenvatinib cohort; and median dose intensity with axitinib in salivary gland carcinomas was 59%. None of these studies restricted enrollment to aggressive ACC, and apart from the subtype analysis of the axitinib plus avelumab trial none reported efficacy by histologic or molecular subtype; the randomized axitinib trial states that it did not capture detailed information on pathologic subtype. Response assessment methods also differed, so comparisons with the phase 1 results are indirect.

EMBLEM-1, the phase 2 part of NCT05377996, enrolls participants with aggressive ACC and measurable disease per RECIST v1.1 who meet both the histopathologic and clinical criteria, and administers 80 mg/m2 (capped at 160 mg) every 4 weeks. The primary endpoint is investigator-assessed objective response rate, with duration of response, disease control rate, progression-free survival, overall survival, and safety as secondary endpoints. EMBLEM-1 has reported no results, its planned sample size and statistical hypotheses are not public, and the registry lists an estimated enrollment of 360 participants for the entire study and an estimated primary completion date of February 2027.

No price, budget impact model, cost-effectiveness analysis, or health technology assessment of emiltatug ledadotin was identified. Because no systemic therapy is approved for recurrent or metastatic ACC, there is no approved comparator whose price could anchor a budget impact estimate, a point also noted by a market research publisher. The displaced therapies would be off-label oral VEGFR tyrosine kinase inhibitors, whose reported treatment durations were a median of 5.9 months in a real-world lenvatinib cohort of 51 participants, 9.1 months in a 28-participant lenvatinib phase II trial, and 11.8 months with sorafenib, and whose administered dose is frequently below the labeled dose: dose reductions were required in 32 of 51 participants (63.6%) in the real-world lenvatinib cohort, in 24 of the 28 participants in that lenvatinib trial, and in 74% of participants receiving sorafenib, and only 16 of 51 participants (31.37%) in the real-world cohort started lenvatinib at the full 24 mg dose. No cost of these regimens in ACC was identified.

Population size is described only at the level of ACC overall. Company documents state an annual United States incidence of approximately 1,300 patients, including both frontline and relapsed ACC, and state that up to 40% of patients have the aggressive form; a genomic study describes approximately 1,200 cases per year. Servier states that more than 200,000 people have ACC worldwide. No source reports the number of people in the United States with locally advanced, recurrent, or metastatic ACC with solid histology or high-grade transformation who would be eligible for treatment.

The only product-level revenue projections are company forecasts. Mersana management forecasts prepared for the tender offer, risk-adjusted and limited to ACC-1 with direct United States sales and licensing outside the United States, projected no revenue through 2027, revenue of $145 million in 2028 rising to $230 million in 2042, and $115 million in 2043 and $57 million in 2044. A discounted cash flow analysis of these forecasts implied an equity value of $8 to $11 per share, compared with the upfront consideration of $25 per share. Contingent value right payments are tied to annual net sales of Emi-Le of at least $100 million by 2032, $200 million by 2035, and $300 million by 2037. Day One described a combined revenue opportunity of more than $1 billion across 3 indications without a separate figure for Emi-Le. Market research publishers estimated the ACC market at USD 178.2 million in the seven major markets in 2025, USD 164.0 million in the seven major markets in 2023, and USD 182.30 million globally in 2025.

Pricing analogues are indirect. In a study of injectable cancer drug prices, the median monthly price was US$14,950 in 2023, and launch prices were 120% higher for orphan than for non-orphan drugs (p = 0.051), with no consistent association between price and clinical benefit. Of 11 ADCs approved by the FDA since 2011, most had incremental cost-effectiveness ratios above a willingness-to-pay threshold of $150,000 per QALY. Disease-level cost evidence is limited to combined oral cavity, oropharyngeal, and salivary gland cancers ($79,151 in total healthcare spending in the year after diagnosis in the commercially insured population) and to a German radiotherapy evaluation in ACC (26,863 euros per life-year gained). For diagnostic testing, a reference Medicare payment for comprehensive genomic profiling (FoundationOne CDx) was $3,500.00 during its initial advanced diagnostic laboratory test period. Budget impact cannot be estimated from public data as of September 2026.

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.