Analysis of circulating tumor DNA during checkpoint inhibition in metastatic melanoma using a tumor-agnostic panel.

Immunotherapy has revolutionized treatment of patients diagnosed with metastatic melanoma, where nearly half of patients receive clinical benefit. However, immunotherapy is also associated with immune-related adverse events, which may be severe and persistent. It is therefore important to identify patients that do not benefit from therapy early. Currently, regularly scheduled CT scans are used to investigate size changes in target lesions to evaluate progression and therapy response. This study aims to explore if panel-based analysis of circulating tumor DNA (ctDNA) taken at 3-week intervals may provide a window into the growing cancer, can be used to identify nonresponding patients early, and determine genomic alterations associated with acquired resistance to checkpoint immunotherapy without analysis of tumor tissue biopsies. We designed a gene panel for ctDNA analysis and sequenced 4-6 serial plasma samples from 24 patients with unresectable stage III or IV melanoma and treated with first-line checkpoint inhibitors enrolled at the Department of Oncology at Aarhus University Hospital, Denmark. TERT was the most mutated gene found in ctDNA and associated with a poor prognosis. We detected more ctDNA in patients with high metastatic load, which indicates that more aggressive tumors release more ctDNA into the bloodstream. Although we did not find evidence of specific mutations associated with acquired resistance, we did demonstrate in this limited cohort of 24 patients that untargeted, panel-based ctDNA analysis has the potential to be used as a minimally invasive tool in clinical practice to identify patients where the benefits of immunotherapy outweigh the drawbacks.

ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling - a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial.

BACKGROUND: An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30-80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation. STUDY DESIGN/METHODS: ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0-2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon's two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing. DISCUSSION: The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy. PROTOCOL VERSION: 16, 09-MAY-2022. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019-004771-40.