FDA Grants Orphan Drug Designation to XMT-2056 for Gastric Cancer

FDA

The FDA has granted an orphan drug designation to XMT-2056 for use as a potential therapeutic option for patients with gastric cancer, according to an announcement from Mersana Therapeutics.¹

XMT-2056, an Immunosynthen STING-agonist antibody-drug conjugate (ADC), 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.

“The FDA’s decision to grant orphan drug designation to XMT-2056 for the treatment of gastric cancer is an important recognition of its potential in this area of high unmet medical need,” Anna Protopapas, president and chief executive officer of Mersana Therapeutics, stated in a press release. “We are eager to bring XMT-2056 and its unique mechanism of action into the clinic mid-year to investigate its safety, tolerability and anti-tumor activity in gastric and other cancers.”

Gastric cancer accounts for approximately 1.5% of all new cancers diagnosed annually in the United States. Gastric cancer and gastroesophageal cancer overexpress HER2 at rates ranging from 4.4% to 53.4%.²

STING pathway agonism has been identified as a potential therapeutic mechanism to generate an antitumor immune response, although the systemic administration of a free STING agonist may be limited by toxicity. However, the administration of the drug via an ADC could be better suited for systemic administration with reduced toxicity.³

Preclinical studies of XMT-2056 demonstrated the agent produced in vitro STING activity with a more than 100-fold improvement in activity vs a free payload. Additionally, XMT-2056 achieved in vivo efficacy after a single intravenous dose with no major effect on systemic cytokines. Furthermore, XMT-2056 demonstrated good exposure in non-human primates and was well tolerated at a dose level 10-fold higher than required for sustained tumor regression in mouse models.

Additionally, in a ratHER2-engineered EMT-6 syngeneic mouse model, in vivo studies in gastric and breast cancer models with varying levels of HER2 expression showed that XMT-2056 generated potent antitumor activity in a dose- and target-dependent manner, including in models with very low HER2 expression.⁴

Since XMT-2056 does not compete for binding with trastuzumab (Herceptin) or pertuzumab (Perjeta), preclinical studies examined the use of XMT-2056 with these anti-HER2 therapies. Results showed that XMT-2056 plus trastuzumab or pertuzumab achieved increased antitumor activity vs either agent alone. It is also hypothesized that XMT-2056 can generate efficacy when combined with immune checkpoint inhibitors, due to the innate immune activation by XMT-2056.

The agent will be investigated in a phase 1 trial in a range of HER2-expressing solid tumors, including gastric cancer, breast cancer, and non–small cell lung cancer. The trial is still under development and has not been announced.

References

1. 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://bit.ly/3wutxbC
2. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol. 2016;22(19):4619-4625. doi:10.3748/wjg.v22.i19.4619
3. 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
4. Duvall JR, Bukhalid RA, Cetinbas NM, et al. XMT-2056, a HER2-targeted immunosynthen STING-agonist antibody-drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab. Presented at: American Association for Cancer Research 2022 Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 3503/5.