Summary: benchmarks for outcomes in aggressive R/M ACC

The goals of systemic therapy in R/M ACC are tumor control, symptom palliation, and prolongation of progression-free survival, because no systemic treatment has been shown to improve overall survival. Survival benchmarks differ by subgroup: after pulmonary metastasis, median overall survival was 7.2 years in a cohort of 219 participants, whereas ACC-I has a median overall survival of approximately 3 years, and high-grade transformation was associated with an average survival of 35.9 months. After surgery and radiotherapy for high-grade transformation, median progression-free survival was 18.0 months compared with 37.0 months in matched non-transformed ACC. Treatment benchmarks include a pooled VEGFR inhibitor objective response rate of 6% and 6-month disease control rate of 54%; a 6-month PFS rate of 73.0% with axitinib versus 23.0% with observation and a median PFS of 10.8 versus 2.8 months in the randomized trial, with a median PFS of 14.5 months in participants who crossed over to axitinib after progression; a 6-month PFS rate of 69.3% and a 12-month rate of 46.2% with sorafenib, with median PFS of 11.3 months and median overall survival of 19.6 months; a median PFS of 14.8 months, a 6-month PFS rate of 75.7%, and a median overall survival of 16.1 months in a real-world lenvatinib cohort of 51 participants; and a median PFS of 1.8 months and median overall survival of 11.3 months in ACC-I treated with axitinib plus avelumab.

Against these benchmarks, the interim phase 1 analysis of emiltatug ledadotin reported, in 32 evaluable participants with aggressive ACC (solid histology or high-grade transformation), an objective response rate of 46.9%, a disease control rate of 81.3%, and a median PFS of 7.8 months. In the same post hoc subset, median duration of response was 6.4 months. At the earlier October 1, 2025 data cut-off, median overall survival had not been reached in participants with ACC. These are single-arm, post hoc, interim data, and quality of life outcomes have not been reported in the cited sources.

Survival in R/M ACC overall

“Despite these characteristics, survival of patients with R/M AdCC is generally prolonged, with an OS rate of 40% at 10 years” (opens the source at this quote in a new tab)

“Recurrent/metastatic (R/M) ACC is generally indolent with median survival exceeding 5 years; however, survival is shortened in those with distant metastases outside of the lungs and in those who require treatment within 3 years of R/M diagnosis” (opens the source at this quote in a new tab)

“For all 219 patients, the median OS from ACC diagnosis was 13.5 years (95% confidence interval [CI], 11–15.7), with a median follow‐up time of 14.8 years. The median OS from metastasis was 7.2 years (95% CI, 5.9–8.3), with a median follow‐up time of 9.3 years.” (opens the source at this quote in a new tab)

Survival in aggressive ACC under current therapy

“Additionally, we also found a statistically significant difference in the median OS between ACC-I (11.3 months; 95% CI, 6–NR) and ACC-II (36 months; 95% CI, 17.5–NR; HR, 0.25; 95% CI, 0.09–0.66; P = 0.01; Fig. 1D).” (opens the source at this quote in a new tab)

“HGT was associated with increased recurrence (55.0%) and distant metastasis (78.3%), leading to an average survival of 35.9 months and a 3-years mortality rate of 35.0%.” (opens the source at this quote in a new tab)

Emiltatug ledadotin: reported efficacy in aggressive ACC

“This analysis (n=32 evaluable participants) reported promising signals:” (opens the source at this quote in a new tab)
“Consistent tumor shrinkage, with an ORR of 46.9%, DCR of 81.3% and median PFS of 7.8 months.” (opens the source at this quote in a new tab)
“Disease control rate was 82.2%.” (opens the source at this quote in a new tab)

Choice of endpoint: PFS versus objective response

“Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.” (opens the source at this quote in a new tab)

“Further investigation of rivoceranib in a placebo-controlled trial evaluating a time-to-event endpoint is warranted.” (opens the source at this quote in a new tab)

Overall and progression-free survival with lenvatinib in a real-world cohort

“The median OS was 16.1 months (95% CI 12.2-NR) (Figure 1) and the median PFS was 14.8 months (95% CI 9.4–16.9) (Figure 2), with a six-month PFS of 75.7%.” (opens the source at this quote in a new tab)
“This is the largest cohort of ACC patients treated with lenvatinib to date in a real-life setting. Our study confirms the activity of lenvatinib observed in phase II studies.” (opens the source at this quote in a new tab)

Landmark progression-free and overall survival rates with sorafenib

“PFS and OS at 6 months were 69.3% (CI, 46.1–84.1) and 82.6% (CI, 60.1–93.1), and at 12 months were 46.2% (CI, 25.1–65.0) and 73.9% (CI, 50.8–87.4), respectively” (opens the source at this quote in a new tab)
“The primary endpoint of this trial was to determine PFS at 12 months, which was seen in 46.2% of patients (CI, 25.1–65.0).” (opens the source at this quote in a new tab)

Tumor shrinkage without objective response, and overall survival after crossover

“The majority of patients on axitinib experienced tumor shrinkage (17 of 27 patients, 63.0%), and there was no partial response (PR) or progressive disease (PD) in this group (Fig. 2C).” (opens the source at this quote in a new tab)
“The median PFS of axitinib after crossover was 14.5 months (95% CI, 10.7–20.3 months; Table 2, per-protocol population; evaluable patients).” (opens the source at this quote in a new tab)
“No difference in OS was observed between the two groups, which might be attributed to the extensive crossover to axitinib in the placebo arm due to disease progression. It is difficult to conclude whether early use of axitinib is better than delayed use after progression; however, axitinib has been shown to induce a definite delay in progression and may thus be effective against symptomatic deterioration due to progression.” (opens the source at this quote in a new tab)

Outcomes achievable with cytotoxic and targeted systemic therapy

“One may conclude that to date, systemic treatment employing cytotoxic chemotherapy or targeted molecular therapies does not yet result in patient cure with advanced (locally recurrent or metastatic) AdCC. At best, temporary partial disease response or stabilization may be achieved. Chemotherapy therefore should be reserved as a palliative treatment for patients with poorly controlled disease or affected with symptomatic metastases” (opens the source at this quote in a new tab)
“Moreover, the majority of AdCCs have a slow growth pattern, making it difficult to assess the efficacy of the particular systemic therapy, as objective tumor responses are uncommon” (opens the source at this quote in a new tab)
“Advances in therapeutic modalities have not had a significant impact on the natural history of AdCC of the head and neck.” (opens the source at this quote in a new tab)

Progression-free survival after surgery and radiotherapy in high-grade transformation

“The majority (73.9%; 17/23) of patients underwent surgery followed by radiotherapy.” (opens the source at this quote in a new tab)
“After a median follow-up of 29.0 months (range 6–108 months), the mortality rate was 47.8% (11/23), with an average survival of 35.9 months. The 3-year mortality rate was 34.8% (8/23), and the median PFS was 18.0 months (mean 25.1 months).” (opens the source at this quote in a new tab)
“In the non-HGT control group consisting of 23 patients, 73.9% (17/23) underwent surgery and radiotherapy.” (opens the source at this quote in a new tab)
“The 3-year mortality rate was 4.3% (1/23), and the median PFS was 37.0 months (mean 36.1 months).” (opens the source at this quote in a new tab)

Emiltatug ledadotin (Emi-Le)

Expected outcomes of therapy