There has been a recognition that a significant percentage of patients with NSCLC have a mutation. Patients with METex14 skipping alterations typically have a more advanced form of lung cancer that is often associated with a poor prognosis and limited response to standard therapy, including immunotherapy. Studies have demonstrated that incorporation of pH-dependent binding in the antibody component of a c-MET–targeting ADC MYTX-011 can overcome the requirement for high c-MET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower c-MET levels. 

In ASCO 2025, Mythic Therapeutics presented updated data from its Phase I KisMET-01 study evaluating its investigational c-MET-targeting ADC candidate, MYTX-011, in patients with previously treated, locally advanced or metastatic NSCLC. In Part 1 of the MYTX-011 dose escalation study, 66 heavily pretreated patients showed promising anti-tumor activity regardless of c-MET expression, EGFR mutation status, or prior taxane use. In non-squamous, c-MET+ tumors, Overall Response Rate (ORR) was 39% in c-MET high/intermediate and 36% in c-MET low groups; notably, a 50% ORR was seen in EGFR-mutant, c-MET-high/intermediate tumors. DCR was 80% at 12 weeks and 52% at 24 weeks, with responses durable up to 8.9 months. Four patients with squamous, c-MET-low tumors also experienced clinical benefit. 

MYTX-011 demonstrated a favorable PK and a manageable safety profile, with common TRAEs including blurred vision and keratopathy. Grade ≥3 TRAEs occurred mainly at ≥5.8 mg/kg doses. Based on safety and efficacy, 5.0 mg/kg Q3W was selected as the recommended Phase II dose to be compared with 4 mg/kg Q3W in Part 2.

KOL insights

“The early data from the MYTX-011 study, showing compelling anti-tumor activity and durable responses in patients with lung cancer, together with a well-tolerated safety profile, are highly encouraging.” – Expert Opinion

Conclusion

TABRECTA (capmatinib) and TEPMETKO (tepotinib) are FDA-approved c-MET exon 14 inhibitors offering key treatment options for NSCLC patients with c-MET alterations. However, TABRECTA was withdrawn in Germany after G-BA deemed its added benefit unproven. In Japan, HAIYITAN’s PMDA approval strengthens its role in the expanding c-MET space. Meanwhile, no approved therapies exist for c-MET overexpressed NSCLC in the 7MM, though companies like AbbVie, Mythic, and Regeneron are actively developing candidates. 

The entry of MYTX-011 into the NSCLC treatment landscape represents a novel approach, as it is among the first ADCs specifically targeting c-MET in this setting. Unlike traditional small-molecule inhibitors, MYTX-011 leverages targeted drug delivery to c–MET–expressing tumor cells, offering a potentially more precise and durable response. It's encouraging early data, including efficacy across varying c-MET expression levels and in patients with prior therapies, positions it as a promising option in an area with limited treatment choices for c–MET–overexpressing NSCLC.