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In Proof-of-Concept NSCLC Trial, Mythic Hoping to Show Broad Utility of Antibody-Drug Conjugate

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NEW YORK – Mythic Therapeutics is advancing an antibody-drug conjugate for MET-driven cancers designed to be more tolerable than other targeted therapies and to go after tumor cells with a wide range of MET expression.

The Waltham, Massachusetts-based firm began a Phase I trial this year of its lead program studying MYTX-011 in patients with locally advanced, recurrent, or metastatic non-small cell lung cancer with cMET overexpression, MET amplification, or MET exon 14 skipping mutations.

This study is the first-in-human trial for a drug developed using Mythic's antibody-drug conjugate (ADC) drug discovery platform, called FateControl. The firm is hoping its approach to ADCs, which is focused on how the therapeutic agent is delivered to tumor cells, will increase the proportion of patients who can receive a cMET-targeted ADC.

Researchers presented data from a preclinical study involving cancer cell lines at the American Association for Cancer Research's annual meeting this year and showed that MYTX-011 could deliver three times more of the drug payload to tumor cells with moderate and high cMET expression. At the same time, MYTX-011's payload affected about 50 percent fewer normal cells compared to two other ADCs in the study, said Mythic CSO Brian Fiske.

If these findings can be replicated in humans, it would mean that MYTX-011 is effective for patients with low to high cMET expression and that they can take the drug for a longer period because it is more tolerable.

"Where ADCs tend to be restricted, especially in solid tumors, is for targets that are very highly expressed," Fiske said. "We want to be able to go after targets like MET where traditional ADCs have shown some responses, but only in the highest-expressing patient populations. We want to be able to take much larger sets of patients who express intermediate and low levels of that [target] and have them respond, too."

Fiske added that many other companies developing ADCs focus on the drug payload or the linker that connects the antibody and the payload and releases it at the target cell. But Mythic's focus on the antibody and the targeting approach to the tumor cell, he explained, is what drives the firm's focus on developing ADCs for patients with high and low target expression.

There are more than a dozen ADCs for cancer approved in the US. The most widely used ADCs for solid tumors target HER2 expression, such as Daiichi Sankyo's and AstraZeneca's Enhertu (trastuzumab deruxtecan) and Genentech's Kadcyla (trastuzumab emtansine) for HER2-positive breast cancer. Other ADCs approved for solid tumors include Gilead's TROP2-directed breast cancer therapy Trodelvy (sacituzumab govitecan-hziy), Seagen's Tivdak (tisotumab vedotin-tftv) for cervical cancer, and Immunogen's Elahere (mirvetuximab soravtansine-gynx) for folate receptor alpha-positive ovarian cancer.

In recent years, researchers began exploring HER2-directed ADCs in tumors with different HER2 expression levels, finding that these drugs could also benefit a subset of patients with lower expression. That research eventually led to the US approval of Enhertu for HER2-low metastatic breast cancer.

Similarly, in exploring its ADC in patients with a range of MET expression, Mythic designed the KisMET-01 trial to include separate cohorts of NSCLC patients characterized by high or intermediate MET expression. Patients are screened for MET expression by centrally performed immunohistochemistry testing. The trial also includes a cohort for NSCLC patients with MET amplification or exon 14 skipping mutations.

The company expects to complete the dose-escalation portion of the study in 2025 and the dose-expansion portion in 2027, said Gilles Gallant, Mythic's chief development officer. Fiske added that the firm hopes to have some early data next year. Gallant also noted that the firm expects to open the trial at sites outside the US soon.

"We would love to have patients on this drug out until 2027 because that would mean it's tolerable, and if they're receiving it, they're still having good outcomes from an efficacy standpoint," Fiske said.

In NSCLC, MET is overexpressed on the surface of tumor cells in as many as 70 percent of patients, while MET mutations, such as the exon 14 skipping mutation, occur in less than 5 percent of NSCLC patients, Gallant said. For cMET-overexpressing patients, there are no approved targeted therapies available, he added.

"MET overexpression or mutation is associated normally with shorter survival and poor prognosis," Gallant said. "This [alteration] is often seen at the time when the patient progresses after treatment."

Patients in the US with metastatic NSCLC harboring MET exon 14 skipping mutations do have a couple of targeted treatment options: Novartis' Tabrecta (capmatinib) and Merck KGaA's Tepmetko (tepotinib). Both FDA-approved drugs are tyrosine kinase inhibitors targeting MET.

Gallant said the firm aims to show proof-of-concept for MYTX-011 in high to low cMET-expressing NSCLC in the KisMET-01 trial, and if successful, there may be opportunities to expand its use into other tumor types that express cMET, such as gastric and head and neck cancer.

"If we see positive data as the single agent in this proof-of-concept study, there is also the possibility of combining the drug with other active drugs that can treat lung cancer to advance the combination in earlier disease in lung cancer," Gallant said.

While Mythic has not disclosed any other ADC programs in development, Fiske noted that the firm hopes to develop drugs for other targets like MET that have a range of expression in solid tumors using its platform.

"We're building a technology specifically to go after lower-expressing patients, lower-expressing targets," Fiske said. "We hope to pioneer this new way of going after bigger sets of patients and broadening the impact of ADCs for patients."