AMT-253 Demonstrates Early Efficacy and Manageable Safety in Melanoma

The MUC18-targeted antibody-drug conjugate (ADC), AMT-253, elicited responses that proved to be durable with an acceptable toxicity profile in patients with melanoma enrolled in two phase 1 studies (NCT06209580; NCT05906862) conducted in Australia and China.¹

Data, which were shared during the 2025 ESMO Congress, showed that in evaluable patients with melanoma (n = 56), the agent induced an objective response rate (ORR) of 28.6%, which comprised 15 confirmed partial responses (PRs) and 1 unconfirmed PR. The disease control rate (DCR) in this group was 73.2%. When broken down by dose level, those who received the ADC at 1.6 mpk (n = 1), 3.2 mpk (n = 4), 4.0 mpk by adjusted ideal body weight (AIBW; n = 1), 4.8 mpk (n = 35), 4.8 mpk AIBW (n = 8), and 5.6 mpk (n = 7), experienced ORRs of 0%, 25%, 100%, 28.6%, 37.5%, and 14.3%; the DCRs at these respective dose levels were 100%, 75%, 100%, 74.3%, 62.5%, and 71.4%.

Across subtypes of this disease, the ORR with the drug was reported to be higher in those who did not have prior exposure to chemotherapy in the adjuvant/neoadjuvant or advanced settings vs those who did. The data indicated that:

• In those with acral melanoma (n = 10), the ORR with AMT-253 was 50%, the DCR was 100%, the median duration of response (DOR) was 6.9 months, and the median progression-free survival (PFS) was 8.3 months.
• Those with mucosal melanoma (n = 3) experienced an ORR of 33.3%, a DCR of 66.7%, a median DOR that was not reached (NR), and a median PFS of 11.0 months.
• In those with unknown primary melanoma (n = 3), the ORR was 66.7%, the DCR was 100%, and the DOR and PFS were both NR.
• Lastly, in those with cutaneous melanoma (n = 20), the ORR, DCR, median DOR, and median PFS were 35%, 70%, NR, and 8.6 months.

“AMT-253, a first-in-class anti-MUC18 ADC, demonstrated promising antitumor efficacy with durable responses, particularly in melanoma,” Jun Guo, MD, of Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, in Beijing, China, and colleagues, wrote in a poster. “Overall safety and efficacy data support further clinical development of AMT-253 in melanoma and selected gynecological cancers.”

What Is the Mechanism of Action of AMT-253?

The ADC is comprised of a humanized IgG1 antibody, a proprietary self-immolative T moiety linker, and a topoisomerase I inhibitor exatecan. The drug-to-antibody ratio is 8. Preclinical data have previously showcased that AMT-253 had robust efficacy across a variety of solid tumors, such as melanoma, ovarian cancer, breast cancer, and head and neck cancer.

How Were the Two Trials Designed?

The studies^2,3 used accelerated titration with a single patient given the initial dose followed by a BOIN design of 3 to 6 patients per cohort. Notably, patients were enrolled irrespective of MUC18 expression.

For the dose-escalation portion of the study done in Australia, investigators evaluated AMT-253 at 1.6 mpk (n = 1), 3.2 mpk (n = 6), 4.8 mpk (n = 6), followed by 5.6 mpk (n = 6) and 4.0 mpk (n = 5), followed by 4.8 mpk AIBW (n = 6) and 4.0 mpk AIBW (n = 5).¹ Cohort 1 receives 4.8 mpk (n = 30) and cohort 2 receives 4.8 mpk AIBW (n = 26). They received the ADC every 3 weeks, with the maximum tolerated dose set at 4.8 mg/kg for both trials.

For the dose-escalation portion of the trial conducted in China, the ADC was evaluated at 1.6 mpk (n = 1), 3.2 mpk (n = 6), 4.8 mpk (n = 6), and 5.6 mpk (n = 6), with 4.8 mpk selected as the recommended dose for expansion. The dose-expansion phase comprises 6 cohorts: melanoma (cohort 1; n = 32), cervical cancer (cohort 2; n = 9), uterine leiomyosarcoma (cohort 3; n = 8), ovarian cancer (cohort 4; n = 0), endometrial cancer (cohort 5; n = 11), and other solid tumors (cohort 6; n = 2).

What Should Be Known About the Patient Population?

In the total population (n = 170), the median patient age was 57.0 years (range, 18-80). More than half of patients were female (64.1%) and had an ECOG performance status of 1 (65.3%). Regarding race, 52.9% of patients were Asian, 42.9% were Caucasian, 2.9% were other, and this information was unknown for 1.2% of patients. Patients had previously received 2.0 lines of therapy (range, 1-9).

Of the 170 patients, 43.5% had melanoma, with 37.8% having cutaneous disease, 37.8% having acral disease, 17.6% having mucosal disease, and 1.4% having uveal disease; for 5.4% of patients, their primary tumor site was unknown. Moreover, 26.5% of patients had gynecological cancers; 40.0% of patients had endometrial carcinoma, 35.6% had uterine leiomyosarcoma, and 24.4% had cervical squamous carcinoma. Thirty percent of patients had other solid tumors.

When looking at prior therapy in those with melanoma (n = 74), the majority had previous exposure to PD-(L)1 therapy (86.5%) and about one-third (29.7%) previously received CTLA-4 inhibition. Moreover, 32.4% of patients had previously received chemotherapy, the majority of which (95.8%) were enrolled in the Chinese study. Lastly, 13.5% of patients previously received a BRAF inhibitor with or without a MEK inhibitor.

As of the data cutoff date of September 8, 2025, a total of 170 patients received AMT-253; 53% were enrolled in the Australian study and 47% were enrolled in the Chinese study.

What Additional Efficacy Data Were Reported With AMT-253?

When looking specifically at the subset of patients with cutaneous melanoma who received the ADC at 4.8 mpk and 4.8 mpk AIBW (n = 18), at a median follow-up of 5.5 months, the ORR was 38.9%, the DCR was 66.7%, the median DOR was NR, and the median PFS was 8.6 months.

In those with endometrial carcinoma, AMT-253 elicited an ORR of 38.5%. The DCR was 100%, the median DOR was NR, and the median PFS was 8.2 months. In those with cervical squamous cancer, the ORR with the ADC was 30%, the DCR was 90%, the median DOR was NR, and the median PFS was 5.5 months. Lastly, AMT-253 elicited an ORR of 30.8% in uterine leiomyosarcoma; the DCR was 100%, the median DOR was 1.4 months, and the median PFS was 4.0 months. “A preliminary trend suggested a potential correlation between MUC18 expression level and efficacy,” the study authors wrote.

What Was Learned About the Safety Profile of AMT-253?

In the total population, 95.3% of patients experienced treatment-emergent adverse effects (TEAEs) with AMT-253; 62.4% of these effects were grade 3 or higher in severity. Treatment-related adverse effects (TRAEs) occurred in 92.9% of patients, with 53.5% of cases being grade 3 or higher. Serious toxicities were observed in 35.3% of patients; they were related to treatment in 24.1% of cases.

TRAEs led to dose reduction, delayed treatment cycle, or discontinuation for 23.5%, 35.3%, and 1.8% of patients, respectively. “The most frequent reasons for dose modifications were neutropenia, followed by thrombocytopenia and anemia,” the authors wrote. Notably, 1 grade 5 event was observed in a patient with gallbladder cancer who received the agent at 4.8 mg/kg AIBW; this patient had an underlying infection at baseline as well as declining hematological parameters and liver function before receipt of the drug.

The most common TRAEs experienced by at least 15% of patients included anemia (any grade, 39.4%; grade ≥3, 25.3%), neutropenia (20.6%; 38.2%), nausea (52.9%; 2.4%), thrombocytopenia (17.6%; 20%), leukopenia (20%; 16.5%), fatigue (29.4%; 1.8%), vomiting (24.1%; 1.2%), diarrhea (21.8%; 0.6%), lymphopenia (11.8%; 10%), increased alanine aminotransferase level (17.6%; 0.6%), and decreased appetite (15.9%; 1.2%).

“No cases of neuropathy or pneumonitis were observed,” the study authors concluded.

What Are the Next Steps for AMT-253?

"These initial data, together with our previously published preclinical findings*, highlight the potential of AMT-253 to offer meaningful outcome improvement to patients who have exhausted standard-of-care options,” Shu-Hui Liu, PhD, cofounder and chief scientific officer of Multitude Therapeutics, stated in a news release.⁴ “We look forward to further clinical confirmation of these results and to fully exploring the potential of this novel ADC for greater patient benefit."

Disclosures: Guo did not declare any conflicts of interest.

References

1. Guo J, Cui C, Kelly R, et al. Ongoing phase I trial results of AMT-253, a first-in-class MUC18-targeting antibody-drug conjugate in patients with melanoma and other advanced solid tumors. Ann Oncol. 2025;36(suppl 2):S651-S652. doi:10.1016/j.annonc.2025.08.1566
2. AMT-253 in patients with advanced solid tumors. ClinicalTrials.gov. Updated September 5, 2025. Accessed November 15, 2025. https://clinicaltrials.gov/study/NCT06209580
3. AMT-253 in patients with selected advanced solid tumours. ClinicalTrials.gov. Updated August 14, 2025. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05906862
4. Multitude Therapeutics announces encouraging interim phase I/II results from ongoing first-in-human study evaluating its MUC18-directed antibody-drug conjugate. AMT-253, in melanoma and other advanced solid tumors at the 2025 ESMO Annual Meeting. News release. October 19, 2025. Accessed November 14, 2025. https://www.prnewswire.com/news-releases/multitude-therapeutics-announces-encouraging-interim-phase-iii-results-from-ongoing-first-in-human-study-evaluating-its-muc18-directed-antibody-drug-conjugate-amt-253-in-melanoma-and-other-advanced-solid-tumors-at-the-2025-esmo-302588336.html