Circulating tumor DNA concentrations and blood tumor mutation burden as biomarkers of outcomes in a phase 1 study of select advanced solid tumors.

Abstract

e14550 Background: Circulating tumor DNA (ctDNA) and tumor mutation burden (TMB) have demonstrated value as biomarkers of response in oncology clinical trials. INCB099280, a small-molecule programmed cell death ligand–1 inhibitor, has shown efficacy and acceptable safety in a phase 1, open-label, multicenter study in patients with advanced solid tumors (Prenen H, et al J Clin Oncol. 2024;42(suppl 16):2608). As part of the exploratory objectives of this phase 1 trial, both ctDNA and blood TMB (bTMB) were evaluated, and results are presented herein. Methods: Eligible patients were aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤1 and had disease progression following prior treatment or were ineligible for/without access to standard treatment. The study consisted of an INCB099280 dose escalation phase (100 mg once daily to 800 mg twice daily), then a dose expansion phase in 3 patient cohorts (immunotherapy [IO]-naive; IO-naive with microsatellite instability-high [MSI-H]/deficient DNA mismatch repair [dMMR] tumors; prior anti– PD-1 treatment). Biomarkers of pharmacologic activity and response, including cell-free DNA (cfDNA) and bTMB, were analyzed as part of the exploratory objectives. cfDNA was prepared from whole blood collected at baseline and during treatment. cfDNA from 116 patients was analyzed using the PredicineATLAS™ platform, which is a 600-gene panel that identifies 4 types of gene alterations (single nucleotide variants, insertions, and deletions, copy number variations, and DNA rearrangements), and reports bTMB and estimated ctDNA tumor fraction. Correlation of ctDNA tumor fraction and bTMB with response and correlation of ctDNA tumor fraction with tumor volume was performed. Additional evaluations included prediction of response based on tumor type and variant allele frequency (VAF) of hallmark genes in tumor types of patients with a response. Results: Two of two patients with a complete response (CR) and 8 of 9 patients with a partial response (PR) had decreased ctDNA tumor fraction during treatment, which predicted a decrease in tumor volume. The median baseline bTMB score was higher in patients with CR or PR (20.3 mutations/megabase [mut/Mb]) compared with patients with stable or progressive disease (8.0 mut/Mb), p = 0.026. ctDNA tumor fraction reduction predicted response very well in cervical and endometrial cancer, as well as other tumor types. Decreases in VAF of hallmark genes were observed in the study. A reduction in VAF of the BRAF and APC genes was observed in the ctDNA from the CR patient with colorectal cancer, and a reduction in VAF of the AR gene was observed in the CR patient with prostate cancer. Conclusions: Baseline bTMB scores and changes in ctDNA tumor fraction during treatment were associated with response to INCB099280 in a phase 1, open-label, multicenter study in patients with advanced solid tumors. Clinical trial information: NCT04242199 .