Circulating tumor DNA as a biomarker for neratinib and trastuzumab efficacy in HER2-mutated advanced solid tumors: Insights from KCSG AL20-17/KM23 phase II trial

BackgroundThe KCSG AL20-17/KM23 trial assessed the efficacy of neratinib combined with trastuzumab in heavily pretreated patients with HER2-mutated solid tumors. This study aimed to investigate the potential of circulating tumor DNA (ctDNA) as a biomarker for predicting treatment outcomes with this dual anti-HER2 combination.MethodsctDNA samples were collected during the screening visit before treatment initiation and either at the end of treatment or upon disease progression. This report primarily focuses on analyzing the screening samples using Guardant360® to identify pathogenic mutations based on the ClinVar or OncoKB databases.ResultsAmong the 40 enrolled patients, ctDNA from 32 individuals was successfully analyzed. Most patients exhibited HER2 mutations in their ctDNA consistent with those found in their tumor tissues. However, three patients showed no detectable HER2 mutations in their ctDNA, of whom two had stable disease, and one had progressive disease as their best response. Other prevalent mutations included TP53 mutations (n=20), EGFR amplification (n=6), PIK3CA amplification (n=3), HER2 amplification (n=3), and KRAS mutation (n=3). EGFR amplification tended to be associated with shorter survival, although not statistically significant (median PFS 2.02 vs 3.42 months, p = 0.055; median OS 5.98 vs 13.71 months, p = 0.153). The median ctDNA fraction was 5.705% (range: 0.11-71.97). Higher ctDNA fractions were associated with poorer survival outcomes, with a selected cutoff point of 11.47% (median PFS 4.87 vs 2.01 months, p = 0.02; median OS 13.71 vs 4.64 months, p = 0.036).ConclusionsThis study underscores the potential of ctDNA as a predictive and prognostic biomarker for patients with HER2-mutated advanced-stage solid tumors treated with neratinib and trastuzumab. The presence of HER2 mutations in ctDNA generally matched those in tumor tissues, and elevated ctDNA fractions were linked to poorer outcomes. Further research is necessary to validate the role of ctDNA in optimizing anti-HER2 therapy for HER2-mutated tumors.Clinical trial identificationNCT06083662.Legal entity responsible for the studyKorean Cancer Study Group (KCSG).FundingKorean Cancer Study Group (KCSG); Ministry of Health & Welfare, Republic of Korea (grant number: HI17C2206).DisclosureAll authors have declared no conflicts of interest.