Emiltatug ledadotin (Emi-Le)

Molecular subtype and histology are the principal modifiers described. ACC-I, enriched for NOTCH1-activating mutations and MYC, has a median overall survival of approximately 3 years versus 23 years for ACC-II. NOTCH1-mutant tumors are associated with solid histology, liver and bone metastases, and shorter overall survival (median 30 versus 122 months). ACC-I tumors overexpress B7-H4, and B7-H4 expression is an independent predictor of poor survival; in patient-derived xenografts, the B7-H4-directed ADC AZD8205 produced complete responses only in ACC-I/B7-H4-high models.

With axitinib plus avelumab, objective response rates were similar in ACC-I and ACC-II (15% and 20%), but median PFS was 1.8 versus 11.4 months and progression as best response occurred in 62% versus 0%. In real-world data, ACC-I was associated with worse outcomes across systemic treatments (HR 3.06). High-grade transformation (solid pattern in 69.6%) was associated with distant metastasis in 78.3%. Solid histology was the strongest predictor of shorter survival after pulmonary metastasis. Among emiltatug ledadotin-treated participants, the objective response rate was 35.6% in all evaluable ACC (45 participants) and 46.9% in the post hoc aggressive ACC subgroup (32 participants), a comparison that is not randomized. With rivoceranib, investigator-assessed response rates differed by prior VEGFR inhibitor exposure (18.6% versus 0%), and bone metastasis was an independent poor prognostic factor with VEGFR-TKIs.

Most comparator studies did not analyze effect by subtype, and the modifiers they did examine were mainly clinical. The randomized axitinib trial found that mutation burden and MYB fusion did not correlate with response, progression-free survival, or overall survival, that FANCM and PCTH2 mutations were respectively positive and negative predictors of progression-free survival, and that it had not captured detailed information on pathologic subtype. In the real-world lenvatinib cohort of 51 participants, site of metastatic disease, including bone and liver, was not associated with activity, younger age was associated with a higher probability of disease control, and the higher response rate seen with a 24 mg starting dose was not statistically significant. In the sorafenib trial, 19 of 23 participants had documented progression at entry, and of the 4 with stable disease at entry none responded, which indicates that apparent benefit depends on whether progression is required for enrollment. In the axitinib trial in salivary gland carcinomas, the only responder with four mutated genes was a non-ACC tumor and best response was stable or progressive disease in all 6 tumors without recurrent mutations. The claims-based ACC-I and ACC-II comparison found similar survival with chemotherapy and with VEGFR tyrosine kinase inhibitors across subtypes, but had limited sample sizes per treatment cohort and no clinical response data. In high-grade transformation, therapeutic targets such as HER2 overexpression may be confined to the high-grade component, so biopsy of metastatic disease may be needed to confirm which clone the metastasis derives from.