Liquid biopsy and the future of tumour-agnostic treatments

The emergence of tumour-agnostic therapies targeting genomic alterations, rather than tissue of origin, has reshaped oncology drug development. Approvals of agents directed against biomarkers such as NTRK fusions, MSI-high status, and high tumour mutational burden (TMB) demonstrate the viability of this paradigm. However, identifying eligible patients, understanding resistance, and efficiently running clinical trials across rare molecular subsets remain major challenges.¹

It wasn’t until 2017, when the US Food and Drug Administration granted the first tumour-agnostic approval to pembrolizumab for the treatment of MSI or mismatch repair-deficient solid tumours.² For the last decade, progress has been steady, but relatively slow, yielding nine approved tumour-agnostic therapies in the United States as of 2025.³ Liquid biopsy-based tools, particularly the use of circulating tumour DNA (ctDNA) for sensitive detection and precise characterisation of cancer, are positioned as a critical enabler of tumour-agnostic therapeutic development.

Tumour-agnostic trial designs benefit from emerging tools

The slow pace of tumour-agnostic approvals can be attributed, in part, to a lack of validated tools and regulatory pathways available to support highly complex and nuanced trials. Tumour-agnostic programmes that leverage master protocols support simultaneous evaluation of multiple therapies or hypotheses across indications under a unified infrastructure. The landmark NCI-MATCH trial leveraged a master protocol for a basket trial to match over 1,200 patients to targeted therapies based entirely on genomic profiles, rather than histology, demonstrating that genomic sequencing can efficiently funnel rare, underserved cancer populations into viable clinical development programmes.²

Master protocols can also be used in umbrella trials to stratify a single cancer type into distinct molecular subgroups to evaluate multiple targeted therapies simultaneously, while platform trials, such as ComboMATCH, extend this framework through perpetual, adaptive designs to evaluate multiple therapies, including novel combinations, against a common control group.²

While tumour-agnostic master protocols offer operational consolidation, each trial is resource-intensive and can be risky. Development risk is compounded by the difficulty of predicting whether molecularly guided treatments are modulated by tumour-specific biology. For instance, clinical trials of the BRAF inhibitor, vemurafenib, demonstrated lineage-specific effects, achieving an 81% response rate in melanoma, but yielding only a 5% response rate in colorectal cancer. The difference in response was attributed to epidermal growth factor receptor (EGFR)-mediated reactivation specific to colorectal cancer. This was confirmed when a later trial showed colorectal cancer patients responded well to a BRAF inhibitor combination therapy that blocked EGFR reactivation.³

In the last few years, tools such as the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S), have been developed to help the research community and regulators evaluate whether a molecularly targeted therapy is appropriate for tumour-agnostic development by predicting the degree to which molecularly guided treatments are likely to be modulated by tumour-specific effects.⁴ However, developers still must exercise extreme caution when interpreting trial data. Exploratory analyses, especially non-prespecified or post-hoc subgroup evaluations, carry a risk of generating false-positive conclusions if not rigorously controlled and prespecified.⁵

Given the nuances of a tumour-agnostic approach, success of a programme heavily depends on the choice of biomarkers for patent enrolment and outcomes assessment. During patient enrolment, biomarker-based screening must reliably identify likely responders and be broadly accessible to patients with solid tumours. Meanwhile, tumour-agnostic approaches to outcomes assessment should facilitate real-time adaptability of trial design if tumour-specific effects emerge. Highly-sensitive, non-invasive, and tumour-agnostic biomarker-based tools, such as liquid biopsy, are key to achieving these requirements by pairing precision and sensitivity with accessibility.

Liquid biopsy scales up tumour-agnostic screening

Liquid biopsies utilising next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) represent a paradigm shift in the scalability and affordability of screening for tumour-agnostic clinical trials, because they offer a cost-effective, rapid, and tumour-agnostic way to screen for molecular targets that characterise otherwise heterogeneous tumour types.² By relying on a minimally invasive blood draw, rather than invasive tissue biopsies, liquid biopsies can identify patients eligible for targeted therapies within days, bypassing the costs and weeks-long turnaround time of tissue sampling.⁶

However, developers must also recognise scenarios in which relying solely on a tumour’s genomic profile is suboptimal for predicting therapeutic benefit. Future agnostic classifiers may therefore benefit from incorporating inflammatory markers that account for host-response factors and the tumour microenvironment.⁷ Interleukin-8 (IL-8), for example, has emerged as a crucial tumour-agnostic biomarker for predicting immune checkpoint inhibitor response. Clinical studies consistently demonstrate that high levels of IL-8 in plasma correlates with reduced therapeutic benefit from immune checkpoint inhibitors across multiple solid tumours.⁷

Real-time outcomes assessment boosts trial efficiency

Beyond their diagnostic utility, ctDNA biomarkers are reshaping how developers predict clinical outcomes and manage trial timelines. Traditional assessments of solid tumour responses rely on standard imaging technologies to detect changes in tumour volume, which may not appear for months.⁸ In contrast, measuring dynamic changes in ctDNA levels allows developers to assess a tumour's response to targeted therapies long before macroscopic changes become evident.

For developers, tracking tumour evolution in real-time facilitates highly adaptive trial designs needed for successful early-phase development. By providing earlier efficacy readouts, ctDNA biomarkers empower developers to quickly halt continuation of ineffective treatments, improving the economic efficiency of tumour-agnostic drug development programmes.⁹

Perhaps the most transformative benefit of using ctDNA for outcomes assessment arises from its sensitivity to early signs of residual disease. This enables developers to test a therapeutic intervention at pre-metastatic stages, when molecularly targeted therapies may be best able to improve long-term patient outcomes.¹⁰

While regulators have not formalised the use of ctDNA as a validated surrogate biomarker for clinical outcomes, efforts at tumour-agnostic validation are underway.⁹ Standardised frameworks, such as the Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST), aim to formalise the use of ctDNA as a pan-cancer surrogate endpoint.⁸

Tumour-agnostic development invests in the future

Experts are increasingly optimistic that development of tumour agnostic therapies will accelerate in the coming years, broadening access to molecularly targeted therapies.¹¹ This optimism is fuelled by recent concrete successes and developers' propensity to consider tumour-agnostic potential of novel targets and therapeutic candidates early on.

In 2025, the DESTINY-PanTumor02 trial demonstrated the tumour-agnostic potential of an antibody-drug conjugate across diverse HER2-positive solid tumours.³ A first-in-human GUARDIAN-101 trial is currently evaluating a novel T-cell engager targeting the previously elusive p53 R175H mutation across various solid tumours.¹¹

Beyond oncology, advances in tumour-agnostic biomarker tools, clinical trial frameworks, and regulatory infrastructure pave the way for the development of molecularly targeted therapies across the broader healthcare ecosystem. The radiating benefits of pioneering tumour-agnostic trials within and beyond oncology may help make current development hurdles more worthwhile.

References

About the author

Dr Bea Mann, PhD, is senior director and oncology therapeutic expert at ICON. As the head of the Oncology Drug Development Services group, Dr Mann is responsible for overseeing the scientific and medical oncology clinical development strategies globally. She brings to ICON more than 16 years of pharmaceutical industry experience (Medical Affairs) having worked as a medical & scientific advisor in the field of oncology and haematology at Roche and GSK. She has extensive experience across all phases of development from pre-clinical to commercialisation. Dr Mann joined ICON in 2016 and in her current role has an expert understanding of the oncology research environment and a thorough understanding of the rapidly changing guidelines for the development of anticancer drugs from study design to protocol development. She has a PhD in Medicinal Chemistry & Drug Development from Nottingham University, UK and was a major contributor to the identification, development, and commercialisation of two linker molecules as part of her oncology research.