Tumour-agnostic drug development is revolutionising precision oncology

Over the last decade, a paradigm shift has seen oncology move away, at least partially, from organ- or histology-based treatment to molecularly guided treatment across tumour types. In 2017, the US Food and Drug Administration (FDA) approved the first ever tumour-agnostic molecularly guided therapy: pembrolizumab for patients with unresectable or metastatic mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) solid tumours that have progressed following prior treatment (Ann Oncol. 2024;35:936–953). Since then, the FDA has approved two additional immunotherapy indications: one for dMMR/MSI-H tumours and another for tumour mutational burden-high tumours (Ann Oncol. 2024;35:936–953). In addition, small-molecule inhibitors have been approved to treat NTRK fusions and RET fusions and the complexity of tumour-agnostic therapies has increased with the approval of combination treatment for BRAF^V600E-mutated solid tumours. More recently, the first antibody–drug conjugate gained accelerated FDA approval for patients with certain HER2-positive (immunohistochemistry 3+) solid tumours.

However, further expansion of pan-cancer approaches is currently limited in some countries/regions outside the US, largely due to regulatory hurdles. For example, only a few tumour-agnostic molecularly-guided treatment options are approved by the European Medicines Agency – namely, larotrectinib, entrectinib and recently, repotrectinib for NTRK fusions and selpercatinib for RET fusions – compared with approximately 10 in the US. While a large proportion of the FDA approvals were based on single-arm trials, other global regulatory authorities require evidence from randomised trials, which are technically challenging or would take decades to conduct given the rarity of most tumour-agnostic therapeutic targets.

To provide a framework to assist and optimise drug development in this area, the ESMO Precision Medicine Working Group together with a multidisciplinary team of international experts recently developed the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S), a tool for assessing the tumour-agnostic potential of molecularly guided therapies (Ann Oncol. 2024;35:936–953). The minimum requirements that comprise the screener include providing robust preclinical, mechanistic evidence associated with prospective evidence from phase I–II trials. Clinical data involves demonstrating an objective response in at least one out of five patients in two-thirds of the investigated tumour types (and in a minimum of four tumour types), with at least five evaluable patients per tumour type in the setting of refractory disease. Furthermore, a conceptual taxonomy is proposed to categorise precision therapeutics as ‘tumour-agnostic,’ ‘tumour-modulated’ or ‘tumour-restricted.’ While some therapies are truly tumour-agnostic, the activity of others can be substantially modulated by tumour-specific biology (e.g. PARP inhibitors in tumours harbouring BRCA1/2 mutation/homologous recombination deficiency) or may only be seen in a restricted tumour-specific biology context (e.g. PI3K inhibitors in PIK3CA-mutated breast cancer).

Growing acknowledgement of the value of the tumour-agnostic approach and initiatives such as ETAC-S are encouraging the development of many more such treatments. However, key to their clinical success and wider accessibility is getting these agents to the right patients. Comprehensive tumour profiling – including DNA sequencing, RNA sequencing to identify fusions and immunohistochemistry to detect HER2/neu positivity – will need to become a part of routine diagnosis to reveal treatable alterations. Overcoming tumour heterogeneity and addressing resistance mechanisms are also important challenges to be tackled for increased efficacy.

Looking to the future, I can envisage the tumour-agnostic transformation being further propagated by artificial intelligence-based technologies, which have considerable potential to unleash a broader range of targets, thereby expanding the applicability of the approach to even more patients.