FDA Lifts Clinical Hold on Phase 1 Trial Evaluating XMT-2056 in HER2-Expressing Solid Tumors

The FDA has lifted the clinical hold placed on a phase 1 trial (NCT05514717) evaluating the HER2-directed, Immunosynthen STING agonist antibody-drug conjugate XMT-2056 as monotherapy in patients with HER2-high or -low advanced or recurrent solid tumors.^1,2

On March 13, 2023, the FDA placed a clinical hold on the phase 1 trial following the voluntary suspension by Mersana Therapeutics after a fatal, grade 5 serious adverse effect (AE) deemed related to XMT-2056 was reported.³ This serious AE occurred in a patient enrolled at the initial dose level in the dose-escalation portion of the trial.

The clinical hold was lifted after the trial investigators lowered the phase 1 dose-escalation starting dose of XMT-2056.¹

“An in-depth analysis of cytokine, pharmacokinetic, and other clinical data from patients enrolled in our phase 1 trial indicated that XMT-2056 is a highly potent innate immune agonist,” Martin Huber, MD, president and chief executive officer of Mersana Therapeutics, stated in a press release. “We are pleased to have aligned with FDA on the path forward and are excited to have the opportunity to continue to investigate the potential of XMT-2056 and our Immunosynthen ADC platform in the clinic."

The multicenter, open-label, first-in-human, phase 1 trial is investigating the safety and preliminary antitumor activity of intravenous XMT-2056 monotherapy in patients with previously treated, HER2-expressing, advanced or recurrent solid tumors, including gastric cancer, breast cancer, non–small cell lung cancer, and colorectal cancer.² The trial plans to enroll approximately 171 patients who have disease progression after treatment, are intolerant to treatment, or have disease that is contraindicated with available anticancer therapies known to confer benefit.

Key inclusion criteria include disease progression after treatment, intolerance to treatment, or 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. HER2 status was determined by institutional practice using immunohistochemistry, in situ hybridization, or next-generation sequencing.

Patients are excluded if they require immunosuppressive doses of systemic medications that could not be discontinued at least 2 weeks prior to the first dose of XMT-2056, received prior treatment targeting the STING pathway, and have untreated central nervous system metastases.

The primary end points of the trial are the frequency of dose-limiting toxicities associated with XMT-2056 during the first cycle of treatment, which will determine the maximum tolerated dose of the agent; the incidence of AEs during the dose-escalation and -expansion portions of the trial; and the overall response rate (ORR) per RECIST v1.1 criteria in the dose-expansion portion of the trial.

Secondary end points include ORR per RECIST v1.1 criteria in the dose-escalation portion; as well as the duration of response, disease control rate, and pharmacokinetics of XMT-1056 and the development of antidrug and neutralizing antibodies to XMT-2056 in the dose-escalation and dose-expansion portions of the trial.

In May 2022, the FDA granted orphan drug designation to XMT-2056 for use as a potential therapeutic option for patients with gastric cancer.⁴

References

1. Mersana Therapeutics announces FDA has lifted clinical hold on phase 1 clinical trial of XMT-2056. News Release. Mersana Therapeutics, Inc. October 31, 2023. Accessed October 31, 2023. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-fda-has-lifted-clinical-hold
2. A study of XMT-2056 in advanced/recurrent solid tumors that express HER2. ClinicalTrials.gov. Updated March 15, 2023. Accessed October 31, 2023. https://clinicaltrials.gov/ct2/show/NCT05514717
3. Mersana Therapeutics announces clinical hold on XMT-2056 phase 1 clinical trial. News release. Mersana Therapeutics. March 13, 2023. Accessed October 31, 2023. https://ir.mersana.com/news-releases/
4. Mersana Therapeutics announces FDA grant of orphan drug designation to XMT-2056 for the treatment of gastric cancer. News Release. Mersana Therapeutics, Inc. May 19, 2022. Accessed October 31, 2023. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-fda-grant-orphan-drug-designation