FDA Halts Phase 1 Trial of XMT-2056 for HER2+ Recurrent/Metastatic Solid Tumors

As a result of the FDA’s clinical hold on the phase 1 trial, no patients with HER2-positive recurrent or metastatic solid tumors will be enrolled or dosed with XMT-2056.

The FDA has placed a clinical hold on the phase 1 trial (NCT05514717) of XMT-2056 following a report of a patient who experienced a recent grade 5 serious adverse event (SAE) that was deemed to be related to XMT-2056. The SAE and its cause remain under investigation.1

The SAE was reported in the second patient who had been enrolled at the initial dose level in the dose-escalation portion of the phase 1 trial. In the trial, patients enrolled were those previously treated with HER2-positive recurrent or metastatic solid tumors.

During the time of the clinical hold, no patients will be enrolled or dosed in the trial.

“In line with our steadfast commitment to patient safety, we have been proactive in our response to this event. With the clinical hold in place, our efforts for XMT-2056 are now focused on undertaking the work required to fully analyze this SAE and consider potential next steps for development,” said Anna Protopapas, president ,and chief executive officer of Mersana Therapeutics, in the press release. “At the same time, we continue to make progress with our UpRi and XMT-1660 clinical trials, which remain unaffected.”

XMT-2056 is the first immunosynthen-based STING-agonist antibody drug conjugate (ADC) product candidate made by Mersana to enter the clinic. Previously in May 2022, the FDA granted an orphan drug designation to the ADC for the treatment of patients with gastric cancers as the treatment revealed more than 100-fold increased potency vs the free STING-agonist payload.

In vitro and in vivo studies have shown XMT-2056 to activate the STING pathway in tumor-resident immune cells and tumor cells. This allows for a potential advantage compared with other innate immune activating pathways. In these studies, XMT-2056 was also well-tolerated in non-human primates at significantly higher exposure levels than those required for anti-tumor activity and generated favorable pharmacokinetics after repeat doses.2

This first-in-human, open-label, phase 1 study of XMT-2056 is evaluating XMT-2056 in previously treated patients with advanced/recurrent solid tumors which are expressing HER2.3

Within the XMT-2056 monotherapy trial will be dose-escalation and dose-expansion portions. In the dose-escalation portion, investigators will assess the safety and tolerability of XMT-2056 and work to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D). The RP2D will be determined based on the totality of the clinical data, including safety and preliminary anti-tumor effect, pharmacokinetics, and relevant biomarker data.

Approximately 171 patients with recurrent or metastatic solid tumors with HER2 expression, disease progression after treatment, and those who are intolerant to treatment or are contraindicated with available anti-cancer therapies will be enrolled in the trial. Patients must have an ECOG performance status 0 or 1, have measurable disease as defined by RECIST version 1.1, and have a fresh tumor biopsy tissue available to submit to a central laboratory.

Patients will be excluded if they have received immunosuppressive doses of systemic medications that cannot be discontinued for at least 2 weeks before the first dose and during study drug treatment administration, have received previous treatment that targets the STING pathway, have a diagnosis of another malignancy that required active treatment within the last 2 years, and if they have untreated central nervous system metastases, history of leptomeningeal metastasis, or carcinomatous meningitis.

However, patients will be eligible for enrollment if their CNS metastases are adequately treated and if participants are neurologically stable for at least 2 weeks before the time of enrollment. Those enrolled must also be off corticosteroids, or on a stable/decreasing dose of ≤ 10 mg prednisone daily.

The primary end points of the trial include frequency of dose-limiting toxicities, incidence of adverse events, and objective response rate (ORR) as assessed by the investigator per RECIST version 1.1. Secondary end points include ORR, duration of response, disease control rate, and pharmacokinetics.

1. Mersana Therapeutics announces clinical hold on XMT-2056 phase 1 clinical trial. News release. Mersana Therapeutics, Inc. March 13, 2023. Accessed March 14. 2023. https://bit.ly/3JdMioW
2. Duvall JR, Bukhalid RA, Cetinbas NM, et al. XMT-2056, a well-tolerated, immunosynthen-based STING-agonist antibody-drug conjugate which induces anti-tumor immune activity. Cancer Res. 2021;81(suppl 13):1738. doi:10.1158/1538-7445.AM2021-1738
3. A study of XMT-2056 in advanced/recurrent solid tumors that express HER2. ClinicalTrials.gov. Updated February 27, 2023. Accessed March 13, 2023. https://clinicaltrials.gov/ct2/show/NCT05514717?term=XMT-2056&draw=2&rank=1

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