The promises of a tumour-agnostic oncology are still challenged by conventional clinical trial design and regulatory processes
While the tissue-agnostic approach still holds promise as a step toward truly personalised cancer care, its impact has fallen short of early expectations a decade after the concept emerged in oncology. Today, patients are still largely treated according to the primary organ where their cancer origins. After all, from the perspective of an oncology professional, understanding the range of biological variation within one organ, such as the breast or prostate, is often more straightforward than mastering the complexities of a single oncogenic pathway across many tumour types. Also, the strongest demonstrations of precision medicine’s impact to date have come from organ-focused therapies, even when those breakthroughs were tied to a particular pathway within that tumour type.
In 2017, pembrolizumab became the first tissue-agnostic therapy receiving accelerated approval by the U.S. Food and Drug Administration (FDA) for all tumours exhibiting microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) in both adults and children, later gaining full approval in 2023 based on data from 504 patients across 30 cancer types from KEYNOTE-164 (NCT02460198), KEYNOTE-158 (NCT02628067) and KEYNOTE-051 (NCT02332668). Since then, additional nine tumour-agnostic therapies were approved in the U.S., while two agents have received approval by the European Medicines Agency (EMA) as of September 2025 (Nat Commun. 2025 May 29;16(1):4972).
Although the approval of tumour-agnostic agents from regulatory agencies often appears as a bottleneck for the progress of the field, this is only part of the story. In fact, because these approvals were largely based on single-arm, non-randomised studies with limited patient numbers, the comparative clinical benefit of tissue-agnostic therapies across different cancer types remains poorly understood.
Lessons learnt from research in cancer of unknown primary origin (CUP) well describe the complexity of targeting cancer beyond its origin or location. Historically, patients with CUP were treated with empiric chemotherapy regimens. Over the last two decades, advances in molecular profiling, first with microarrays and later with next-generation sequencing (NGS), showed that the biology of these tumours could be dissected. The challenge, however, was proving whether this approach translated into meaningful benefit for patients. Early phase III trials were largely negative, and while the second generation of studies using NGS has yielded slightly better results, the gains remain modest in terms of patient outcomes. Still, survival at one year after diagnosis has held steady at around 20%, with little progress over time (Ann Oncol. 2023. PMID: 36563965).
The current landscape of tumour-agnostic research shows strong willingness from both physicians and patients to embrace precision medicine, tempered by the limitations of the evidence generated so far, which ultimately affect regulatory decisions. The evolution of cancer care toward a tumour-agnostic approach is a collective effort, requiring all stakeholders in oncology to play their part. On one hand, oncologists need targeted education to view research opportunities differently; on the other hand, regulatory agencies must adapt their review and approval processes to accommodate a shift toward tumour-agnostic strategies. Innovating clinical trial design is key to generating convincing demonstrations of efficacy, that today is lacking, particularly with alterations that are more common, and especially in adult population rather than in paediatrics.
Lately, I am encouraged to see discussions around using non-randomised trials with prospective data alongside a ‘phantom’ or historical control arm. The idea is to use a contemporaneous control cohort which is large enough to minimise variability, so that new treatments can be compared meaningfully. If the results are positive, this approach could support regulatory approval.
ESMO is working actively in this area, and the release of the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S) for assessing the tumour-agnostic potential of molecularly guided therapies in 2024 has been warmly welcomed by the oncology community (Ann Oncol. 2024 Nov;35(11):936-953). It is a first step toward a common understanding among regulators and the clinical research community of the conditions in which tissue-agnostic development should be preferred to conventional trials. Going forward, more research will also be necessary to develop standard criteria for defining when a biomarker can be considered as tumour-agnostic in the first place.
