FDA Grants Fast Track Status to MYTX-011 for NSCLC With cMET Overexpression

The FDA has granted fast track designation to MYTX-011 for use as a potential therapeutic option in patients with non–small cell lung cancer (NSCLC) and cMET overexpression.¹

The pH-dependent anti-cMET IgG1 antibody boosts tumor internalization and antibody-drug conjugate (ADC) cytotoxicity.² The agent has a clinically validated vcMMAE linker-payload and is conjugated at engineered cysteine residues.

MYTX-011 binds with high affinity at neutral or slightly acidic pH representative of the tumor microenvironment but is designed to rapidly release from cMET antigen in the acidic endolysosomes. As the cMET antigen recycles to the surface for additional binding, liberated MYTX-011 process the lysosomes and the linker is cleaved. pH engineering leads to more internalization, in vitro cytotoxicity, and better pharmacokinetics vs non-engineered controls.

The safety and preliminary effectiveness of MTYX-011 is under evaluation in patients with locally advanced, recurrent or metastatic NSCLC as part of the ongoing phase 1 KisMET-01 trial (NCT05652868).^1,3

“Receiving fast track designation from the FDA reinforces our focus on addressing the unmet needs of patients living with cMET-positive NSCLC, who currently have few effective treatments,” Brian Fiske, PhD, chief scientific officer and co-founder of Mythic Therapeutics, stated in a press release.¹ “We are proud of this significant milestone as it highlights the potential of MYTX-011, which is enabled by our FateControl platform, to expand ADC therapy to more NSCLC patients.”

The open-label, multicenter phase 1 trial is comprised of 2 parts: the dose-escalation and dose-expansion phase.² Those enrolled to the dose-escalation phase had to have previously treated, locally advanced or metastatic NSCLC who had measurable disease by RECIST v1.1 criteria. Patients were not limited by previous therapy, and they were unselected for cMET expression.

This portion of the research utilizes a BOIN design, which has a 3-subject minimum with a dose-limiting toxicity (DLT) rate of 0.3%. Per that algorithm, doses could be escalated or de-escalated and intermediate doses could be evaluated. Moreover, investigators are looking at DLTs experienced during cycle 1 to shed light on dosing algorithms and decisions. At dose levels that are determined to be safe, additional patients can be backfilled. MYTX-011 will be administered intravenously every 21 days for up to 2 years.³

The key objectives for part 1 include assessing the safety and tolerability of the ADC and identifying the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose.²

The dose-expansion portion of the research is comprised of 5 cohorts: those in cohort A will have nonsquamous NSCLC and high cMET expression and will be randomly assigned 1:1 to dose level A or dose level B; those in cohort B will have nonsquamous NSCLC with intermediate cMET expression; those in cohort C will have squamous NSCLC and cMET overexpression. Exploratory cohorts D and E will include patients with NSCLC and MET amplification or exon 14 skipping mutations and those with prior exposure to a cMET ADC or monoclonal antibody, respectively.

The primary objectives for part 2 of the trial include safety and tolerability, as well as overall response rate (ORR).

Secondary objectives of interest for both portions of the research include assessing pharmacokinetics, anti-drug antibodies, and preliminary antitumor activity in the form of ORR, duration of response, time to response, disease control rate, progression-free survival, and overall survival.

“While a small fraction of NSCLC tumors highly express cMET, a much broader patient population have tumors which overexpress cMET, but at lower levels,” Rebecca Heist, MD, MPH, of Massachusetts General Hospital and study investigator, added in the press release.1 “It’s important we continue investigating the potential of MYTX-011 for patients with NSCLC who need new approaches to treating their cancer as many either do not respond to, or develop resistance to, existing treatment options.”

KisMET-01 is currently enrolling patients, and estimates to enroll 150 participants.1,3 The estimated primary completion date for the trial is projected to be December 2025.³

Preclinical data on MYTX-011 will be presented at the upcoming AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.⁴

References

1. Mythic Therapeutics receives FDA fast track designation for MYTX-011 for patients with non-small cell lung cancer (NSCLC) with cMET overexpression. News release. Mythic Therapeutics. September 26, 2023. Accessed September 26, 2023. https://mythictx.com/2023/09/26/mythic-therapeutics-receives-fda-fast-track-designation-for-mytx-011-for-patients-with-non-small-cell-lung-cancer-nsclc-with-cmet-overexpression/
2. Spira AI, Johnson ML, Blumenschein GR, et al. Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):TPS9147. doi:10.1200/JCO.2023.41.16_suppl.TPS9147
3. Clinical study of antibody-drug conjugate MYTX-011 in subjects with non-small cell lung cancer. ClinicalTrials.gov. Updated September 26, 2023. Accessed September 26, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05652868
4. Mythic Therapeutics to present new preclinical data on MYTX-011, investigational cMET-targeting antibody-drug conjugate (ADC), at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. News release. Mythic Therapeutics. September 19, 2023. Accessed September 26, 2023.