RC108 in combination with furmonertinib in patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) with MET overexpression: Results from a phase Ib/II trial.

8592 Background: Patients (pts) who have progressed on EGFR-TKI treatment have limited treatment choices when accompanied by MET overexpression. RC108 is a MET-directed ADC with the microtubule inhibitor monomethyl auristatin E (MMAE) as the cytotoxin and it may overcome primary/secondary MET-driven resistance to EGFR-TKI. We report the preliminary safety and efficacy results of RC108+furmonertinib (F, a third-generation EGFR-TKI) in pts with MET-overexpressing and EGFR-mutated locally advanced or metastatic (la/m) NSCLC who failed prior EGFR-TKI from a phase 1b/2 trial (NCT05821933). Methods: The key eligibility criteria were histologically or cytologically confirmed la/m NSCLC with at least one documented EGFR sensitizing mutation, MET-overexpression (defined as IHC 1+/2+/3+ in ≥10% of tumor cells), and disease progression on prior 1st/2nd/3rd-generation EGFR-TKI treatment. Pts received RC108 (at doses of 1.5 or 2.0 mg/kg, Q3W) + F (80 mg, QD) until disease progression or intolerable toxicity. Radiological tumor assessment was performed every 6 weeks by investigators per RECIST v 1.1. The primary endpoints were safety and objective response rate (ORR). Data cutoff date for this analysis was Sep 12, 2024. Results: A total of 31 pts were enrolled and received at least one dose of treatment, including 2 and 29 pts in the 1.5 and 2.0 mg/kg cohorts, respectively. The most frequent treatment-related adverse events (TRAEs) were nausea (51.6%), asthenia (48.4%), decreased appetite (45.2%), vomiting (45.2%), white blood cell count decreased (35.5%), alopecia (35.5%), and hypoesthesia (32.3%). Grade ≥3 TRAEs occurred in 7 (22.6%) pts. TRAEs led to treatment discontinuation in 1 (3.2%) pt. One pt died due to abnormal hepatic function, possibly related to the study treatment per the investigator’s assessment. Among the 24 pts with at least one post-baseline tumor assessment in the 2.0 mg/kg cohort (79.2% with ECOG PS 1, 58.3% with exon 19 deletion, 33.3% with exon 21 L858R, and 62.5% with ≥2 prior lines of treatment), the ORR was 37.5% (95% CI: 18.8-59.4) and disease control rate (DCR) was 75.0% (95% CI: 53.3-90.2). In the 18 pts with ≥10% of tumor cells with 1+/2+/3+ membrane staining and ≤20% tumor cells with strong (3+) cytoplasmic staining, ORR was 50.0% (95% CI: 26.0-74.0) and DCR was 83.3% (95% CI: 58.6-96.4). The progression-free survival data were immature and under follow-up. Conclusions: RC108+F showed encouraging antitumor activity with manageable safety profile in pts with MET-overexpression. At the same time, this study demonstrated better efficacy in the population with lower MET expression in the cytoplasm. We will continue to explore more beneficial populations in future studies. Clinical trial information: NCT05821933 .