In response to the emerging need to standardise tumour-agnostic drug development, the ESMO Precision Medicine Working Group (PMWG) together with a multidisciplinary team of international experts, have developed the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S), an easily applicable set of minimum requirements to screen and claim the tumour-agnostic potential of molecularly guided treatment options (MGTOs).
“Over the last couple of years, we have seen a shift in the development of molecularly guided treatment options, away from organ-based development and towards biomarker-driven therapies that have activity across a broad spectrum of diseases,” said Dr Benedikt Westphalen, Chair of the ESMO PMWG. “Until now, it was unclear when a drug could be considered tumour-agnostic. ETAC-S aims to bridge this gap by providing a standardised set of minimum requirements and a classification system, designed to be integrated into the various steps of the drug development process,” he continued. “Using ETAC-S will support investigators, pharmaceutical companies and regulators to assess whether a MGTO has tumour-agnostic potential thus informing the next steps of the drug development process” he stressed.
The ETAC-S can be used at the end of early phase trials, when patients with different cancers have received a new cancer therapy. “At this stage of drug development, we propose that the trial results are screened based on three minimum requirements that need to be met to claim tumour-agnostic potential of the MGTO under examination,” explained Dr Diogo Martins-Branco, co-first author of the manuscript. Specifically, the therapy must have shown an objective response in at least one out of five patients (ORR≥20%) in two-thirds of the investigated tumour types (and in ≥4 tumour types), with at least five evaluable patients in each tumour type, in the setting of refractory disease. “The screening will inform whether the MGTO has potential to generate further confirmatory evidence of activity across a population of patients with different tumour types sharing the same alteration that drives cancer if the minimum requirements are met, or if it should be investigated in a population of patients with cancer defined by the organ of origin if it fails the tumour-agnostic screening but showed a signal for tumour-restricted activity,” Martins-Branco continued.
Figure 1 (1). Abbreviation: ORR, objective response rate
In a manuscript published today in Annals of Oncology (2), Westphalen, Martins-Branco and the group of experts have described the methodology used to derive these minimum requirements to claim tumour-agnostic potential. They reviewed publicly available data for seven tumour-agnostic indications approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) as of December 2023. After these clinical data supporting each approval were summarised, the group tested different scenarios involving three key factors: objective response rate (ORR), number of tumour types studied, number of patients per tumour type. The minimum requirements that compose the screener were then defined and tested positively on data available for two new tumour-agnostic accelerated FDA approvals in the first half of 2024, the antibody-drug conjugate trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours, and kinase inhibitor repotrectinib for patients with locally advanced or metastatic solid tumours with NTRK gene fusion, demonstrating high reliability.
To provide a realistic categorisation that goes beyond drawing a line between tumour-agnostic and tumour-specific effects of an MGTO, the group also proposed a conceptual taxonomy to classify the therapeutic effect of investigational therapies by considering the complete biological context of the tumour beyond a key targeted driver molecular aberration. Three categories have been proposed:
- Tumour-agnostic, when targeting a driver molecular aberration predominantly defines the therapeutic effect, irrespective of tumour-specific biology;
- Tumour-modulated, when the therapeutic effect on a targeted driver molecular aberration is modulated by the tumour-specific biology;
- Tumour-restricted, when the therapeutic effect on a targeted driver molecular aberration is only present in a tumour-specific biology context.
Figure 2 (3). Abbreviations: DMA, targeted driver molecular aberration; TB, tumour-specific biology
“Categorising cancer therapies according to their molecular/tumour determinants of effect based on a robust taxonomy would profoundly change the way we treat cancer,” said Martins-Branco. “The next step will be to review the literature for collecting data from publications of tentative tumour-agnostic drug development trials that will be key in defining cutoffs between what is purely tumour-agnostic and what is tumour-modulated," he explained, while outlining the future methodological work of the group, aimed at refining the solidity of ETAC-S.
“ETAC-S will be useful in highlighting the shift in how we classify diseases within the wider group called ‘cancer’, focusing on the molecular alterations driving tumour development rather than the organ of origin,” Westphalen added. “By adopting this approach, in the future we can address the delays in drug development that we are currently struggling with.” For instance, a drug initially developed for a specific indication may be demonstrated effective in other tumours sharing the same molecular alteration only after several years. “Against a backdrop of dramatically increasing cancer cases which require urgent measures, optimising the drug development process by proposing a standardised framework useful for regulatory assessment will expedite access to effective therapies, particularly in those conditions with limited treatment options,” Westphalen concluded.
References
- Figure 1. From The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development, by Westphalen CB, Martins-Branco D, Beal JR, et al, 2024, 35(11), Annals of Oncology, p. 10
- Westphalen CB, Martins-Branco D, Beal JR, et al. The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development. Ann Oncol. 2024;35(11) DOI: 10.1016/j.annonc.2024.07.730
- Figure 2. From The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development, by Westphalen CB, Martins-Branco D, Beal JR, et al, 2024, 35(11), Annals of Oncology, p. 10