MYTX-011, a cMET-targeting antibody-drug conjugate (ADC), in patients with previously treated, advanced NSCLC: Updated dose escalation results in the phase 1 KisMET-01 study.

Abstract

8613 Background: MYTX-011 is a novel cMET-targeting vcMMAE ADC engineered for pH-dependent binding. This results in more efficient payload delivery, which drives efficacy in tumors over a wide range of cMET expression, including potentially >50% of NSCLC patients (pts). Here we report safety and preliminary efficacy from dose escalation pts who received ≥4.0 mg/kg (mpk), the clinically active dose range, in the Phase 1 KisMET-01 study. Methods: KisMET-01 (NCT05652868) is a multicenter, first-in-human study of MYTX-011 in pts with previously treated, locally advanced or metastatic NSCLC. The study comprises dose escalation in pts with NSCLC of any histology or cMET expression, followed by dose expansion in cMET-positive (cMET+) pts selected by immunohistochemistry (Ventana SP44). In dose escalation, cMET expression is analyzed whenever tumor tissue is available. Results: As of 7 Jan 2025, 85 pts received ≥1 dose of MYTX-011 (1.0–8.3 mpk Q3W), and 59 pts received doses ≥4.0 mpk. PK showed near dose proportional exposure and low unconjugated MMAE across dose levels. In pts who received ≥4.0 mpk, median age was 67 yr (43–83) and median prior lines of therapy was 3 (1–10); median follow-up was 4.2 mo (0.1–10.4). TRAEs of any grade (Gr)/Gr ≥3 occurred in 90%/48% of pts; the most common (any Gr TRAE ≥20% of pts) were blurred vision (49%), keratopathy (44%), nausea (29%), fatigue (20%), AST increased (20%), and keratitis (20%). Gr 3 or higher TRAEs that occurred in ≥5% of pts were keratopathy (15%), blurred vision (12%), and neutropenia (10%). Ocular events led to treatment discontinuation in 5 (8%) pts, with 3 of 5 treated at doses higher than 5.0 mpk. Unadjudicated pneumonitis/ILD was reported in 2 (3%) pts, both Gr 1 or 2 with 1 leading to treatment discontinuation. Peripheral neuropathy was reported in 15%; all were Gr 1 or 2 and did not lead to dose reduction or discontinuation. No treatment-related death was reported. 35 of 59 pts who received ≥4.0 mpk were cMET+ (2+ at ≥25% tumor cells) with a median follow-up of 3.7 mo (0.7–10.3). ORR was 38% in cMET+ pts with ≥1 post-baseline disease assessment (n=29). DCR at 6 wk/12 wk/24 wk was 97%/83%/53%. ORR was 44% in cMET+ Non-squamous (NSQ) EGFR wild-type (n=16), 38% in NSQ EGFR-mutant (n=8), and 25% in squamous cell carcinoma (n=4). Antitumor activity was similar in cMET+ pts across expression levels and known cutoffs, and no clear dose-response relationship was observed in doses ≥4.0mpk. Doses of 5.0 mpk Q3W with dose-break (2-on 1-off) and 4.0 mpk Q3W were selected for further evaluation in dose expansion. Conclusions: MYTX-011 is well tolerated with low rates and severity of AEs commonly associated with cytotoxic and cMET-targeting agents. Preliminary anti-tumor activity suggests MYTX-011 can potentially benefit a wide range of cMET-expressing NSCLC pts. Dose expansion is currently ongoing as of January 2025. Clinical trial information: NCT05652868 .