FDA Places Clinical Hold on Phase 1 Trial of XMT-2056 in HER2-expressing Solid Tumors

The FDA has placed a clinical hold on a phase 1 trial (NCT05514717) investigating the antibody-drug conjugate (ADC) XMT-2056 for the treatment of patients with advanced/recurrent solid tumors that express HER2, according to an announcement from Mersana Therapeutics.^1,2 No patients will be enrolled or dosed during the clinical hold.

The company previously informed the regulatory agency that it was voluntarily suspending the trial due to a grade 5 serious adverse effect (SAE) that was deemed to be related to XMT-2056. The SAE and its cause remain under investigation. The SAE occurred in the second patient treated at the initial dose level in the dose-escalation portion of 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,” Anna Protopapas, president and chief executive officer of Mersana Therapeutics, stated in a news release. “At the same time, we continue to make progress with our UpRi and XMT-1660 clinical trials, which remain unaffected.”

XMT-2056 is an Immunosynthen STING-agonist ADC that was created by leveraging a differentiated antibody that binds to a novel HER2 epitope, making it a treatment option as a single agent or in combination with other HER2-directed therapies.³ In May 2022, the FDA granted an orphan drug designation to XMT-2056 for use as a potential therapeutic option for patients with gastric cancer.

The open-label, first-in-human phase 1 trial was evaluating XMT-2056 in previously treated patients with advanced/recurrent solid tumors expressing HER2.² Patients were required to have disease progression after treatment, be intolerant to treatment, or have contraindications with available anti-cancer therapies known to confer benefit, based on investigator's judgement. Measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1 were also required. HER2 status was determined by institutional practice using immunohistochemistry, in situ hybridization, or next-generation sequencing.

Key exclusion criteria included immunosuppressive doses of systemic medications that could not be discontinued at least 2 weeks prior to the first dose of XMT-2056, prior treatment targeting the STING pathway, and untreated central nervous system metastases.

The multicenter study included dose-escalation and -expansion phases, where patients were being treated with intravenous XMT-2056 monotherapy.

Frequency of dose-limiting toxicities, rate of AEs, and objective response rate (ORR) in the expansion phase were serving as the trial’s primary end points. Secondary end points included ORR in the escalation phase, duration of response, disease control rate, and pharmacokinetics.

References

1. Mersana Therapeutics announces clinical hold on XMT-2056 phase 1 clinical trial. News release. Mersana Therapeutics. March 13, 2023. Accessed March 13, 2023. https://ir.mersana.com/news-releases/
2. 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
3. Mersana Therapeutics announces FDA grant of orphan drug designation to XMT-2056 for the treatment of gastric cancer. News release. Mersana Therapeutics. May 19, 2022. Accessed May 19, 2022. https://ir.mersana.com/news-releases/