Phase II study of disitamab vedotin (RC48) in combination with tislelizumab and bevacizumab in patients (Pts) with HER2 alterations locally advanced or metastatic NSCLC: Primary analysis results of RESOLUTION.

Abstract

e20515 Background: Antibody-drug conjugates (ADC) have recently revolutionized the treatment of advanced NSCLC. RC48 is a novel ADC that carries a tubulin inhibitor targeting the HER2 protein, thereby specifically recognizing and killing these cells. It has demonstrated considerable anti-tumor effects in solid tumors. Combining ADCs with immunotherapeutic or anti-angiogenic agents may further improve outcomes for HER2-altered NSCLC. Therefore, additional investigation into combination therapies for NSCLC with HER2 alterations is warranted. Methods: RESOLUTION is a single-arm, phase II clinical trial designed to evaluate the efficacy and safety of a treatment in Pts with locally advanced or metastatic NSCLC harboring HER2 alterations. Eligible Pts who have not received prior systemic therapy will be enrolled. RC48 (2.0 mg/kg, intravenously, Q3W) combined with Tislelizumab (200mg, intravenously, Q3W) and Bevacizumab (7.5 mg/kg, intravenously, Q3W) is administered until unacceptable toxicities or disease progression. The primary endpoint is the ORR, while secondary endpoints include PFS, OS, DCR, and DOR. Disease response will be assessed by the investigator using RECIST 1.1 criteria. An interim analysis will be conducted after the first 9 Pts are evaluable to determine whether to proceed; the trial will be discontinued at this stage if fewer than 2 Pts demonstrate a response. Blood samples are collected at baseline (C1D1), and on days C3D1, C5D1, and at progression (PD) for next-generation sequencing (NGS)–based, longitudinal circulating tumor DNA (ctDNA) mutation and methylation analyses. Results: From April 2024 to January 2025, 9 Pts were evaluable for efficacy. Among these Pts, 3 Pts achieved a partial response and 6 had stable disease. The confirmed ORR was 33.3%, and the median duration of response was 5.1 months. Grade 1 and 2 treatment-related adverse events (TRAEs) occurred in 100% of Pts, and grade 3 TRAEs occurred in 22%. The most common TRAEs included proteinuria (55.5%). By January 2025, a total of 29 blood samples were collected at baseline, C3D1, C5D1, and PD timepoints. The study used PredicineCARE—a 152-gene, NGS–based ctDNA assay—and PredicineEPIC, a genome-wide ctDNA methylation assay, to longitudinally monitor genetic and epigenetic dynamics throughout treatment. The NGS analyses are ongoing. Conclusions: Our result suggested the combination therapy is a promising treatment strategy for NSCLC with HER2 alteration. The first-stage interim analysis revealed acceptable efficacy and manageable toxicity to support proceeding to the further stage. Clinical trial information: NCT06749860 .