Initial dose escalation results from its ongoing Phase 1 KisMET-01 study evaluating the investigational ‘next generation’ cMET-targeting Antibody-drug Conjugates (ADC), MYTX-011, in patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held May 31st – June 4th, 2024. MYTX-011 is being developed by clinical-state biotech Mythic Therapeutics.

“The initial dose escalation results from our ongoing Phase 1 KisMET-01 study, coupled with the previously presented preclinical data are encouraging and underscore MYTX-011’s potential to serve patients with a broad range of cMET expression,” noted Gilles Gallant, BPharm, Ph.D., FOPQ, Chief Development Officer at Mythic Therapeutics.

“ADCs have been a transformative class of treatment for patients impacted by cancer, but we know that there is a large population of patients with low-to-moderate target expression who are unlikely to benefit from them. These initial data potentially represent significant promise for patients who have historically been ineligible for treatment due to their level of target expression or tumor type, and we look forward to continuing our dose escalation and expansion study.”

A novel approach
MYTX-011 is a novel cMET-targeted Drug-to-antibody ratio (DAR) of 2 vcMMAE* ADC with an antibody that has been engineered to have pH-dependent binding, which results in higher internalization and payload delivery to tumor cells with a range of cMET expression.

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The investigational agent leverages Mythic’s innovative FateControl™ technology which is designed to allow ADCs to actively navigate inside of cells, potentially increasing delivery of anti-cancer agents to tumor cells with less impact on healthy cells. This breakthrough approach takes the next step beyond linker-payload technologies and is designed to improve ADC efficacy against a broad set of molecular targets and patient profiles.[1]

Ongoing study
MYTX-011 is currently being evaluated in the Phase 1 KisMET-01 clinical trial, a first-in-human, open-label, multi-center, dose escalation and dose expansion study enrolling patients with locally advanced, recurrent or metastatic NSCLC (NCT05652868). The study is comprised of a Part 1 dose escalation in patients with NSCLC of any histology and regardless of cMET expression level, followed by Part 2 dose expansion in cohorts specified by cMET expression and histology. The primary objectives of Part 1 are to assess safety and tolerability and determine the recommended phase 2 dose. Secondary objectives include assessment of pharmacokinetics (PK) and preliminary anti-tumor activity.

As of April 30, 2024, 42 patients had been enrolled and received at least one dose of MYTX-011. Data from 41 patients was available by data cutoff and median follow-up was 15 weeks. Patients were dosed between 1.0 to 6.7 mg/kg on a once every three weeks schedule (Q3W). Treated patients had a median of three prior lines of therapy. As of data cutoff, PK data were available in patients who received doses 1.0 to 5.0 mg/kg. PK of MYTX-011 showed nearly dose proportional exposure up to 5.0 mg/kg. Little separation of ADC and total mAb concentration was noted, suggesting good stability of MYTX-011, supporting dosing every 3 weeks. MYTX-011 has been well tolerated with low incidence of common AEs associated with MMAE or cMET targeted therapeutics. No dose-limiting toxicity was reported, and dose escalation is ongoing. Given that dose escalation is ongoing and the overall median follow-up as of the data cutoff was 15 weeks, efficacy data will be presented in a future conference or publication.

“Patients with locally advanced or metastatic NSCLC who have not responded or become resistant to previous therapies represent an urgent unmet need,” said Melissa Johnson, M.D., Director of Lung Cancer Research at Sarah Cannon Research Institute. “Observing the favorable safety, tolerability and PK of MYTX-011 across a diverse range of cMET-expressing patients is encouraging. We look forward to seeing additional safety and efficacy data from the Phase 1 study.”

Note: * Val-Cit (Valine–citrulline/vc) linker + Monomethyl auristatin E (MMAE)

Clinical trials
Clinical Study of Antibody-Drug Conjugate MYTX-011 in Subjects With Non-Small Cell Lung Cancer – ClinicalTrials.gov ID NCT05652868

Reference
[1] Gera N, Fitzgerald KM, Ramesh V, Patel P, Kanojia D, Colombo F, Kien L, Aoyama S, Xu L, Jean J, Deshpande AM, Comb WC, Chittenden T, Fiske BP. MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells. Mol Cancer Ther. 2024 Apr 30. doi: 10.1158/1535-7163.MCT-23-0784. Epub ahead of print. PMID: 38684230.

Featured image: Attendees during the Plenary Session at the American Society for Clinical Oncology (ASCO) Annual Meeting 2015. Photo Courtesy: © 2015 – 2024 ASCO/Scott Morgan.

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