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Abstract 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.

Tumor derived biomarkers including circulating tumor DNA (ctDNA) and/or circulating tumors cells (CTCs) may be detected and quantified through liquid biopsy (LB). ctDNA analysis through LB is a validated tool for monitoring response to systemic treatment and detecting molecular mechanisms of resistance at the time of progression of advanced stage malignancies. Several applications of ctDNA have been investigated in the diagnostic phase of cancer or in the post-curative treatment surveillance phase (e.g., minimal residual disease assessment after neoadjuvant or adjuvant therapy). Recently, the improvement of ctDNA technology and its implementation have affected early phase trials design, with significant changes in the inclusion and randomization phases. Implementation of LB has resulted in large-scale development of academic programs aimed at exploiting all the potential applications of ctDNA, such as patients extended molecular screening, molecular oriented treatment decision making, monitoring of anti-cancer treatments response. In this rapid evolving field, the challenge is no longer the technique, but the evaluation of the results and the interpretation of their impact on diagnosis, prognosis, or therapeutic decision. Leading research cancer centers may favor education for scientific community, by capturing data on this evolving technology and sharing knowledge.In this review we summarize the main applications and challenges of ctDNA genotyping in clinical trials, with special focus on ongoing studies. We finally describe the most important next generation academic and industry-sponsored programs addressing early cancer detection and prevention in high-risk populations through ctDNA genotyping.