ESMO launches new system to assess agnostic potential of oncology drugs

Considering the need standardize the development of tumor-independent drugsThe ESMO Precision Medicine Working Group (PMWG), together with a multidisciplinary team of international experts, developed the ESMO Tumor Agnostic Classifier and Score (ETAK-S), an easily applicable set of minimum requirements for the assessment and approval of the tumor-specific potential of molecularly targeted treatment options (MGTOs).

“In recent years, we have seen a shift in the development of molecularly targeted treatment options from organ-based development to biomarker-guided therapies that are effective across a broad range of diseases,” he says. Benedikt WestphalenPresident of ESMO PMWG. “Until now, it has been unclear when a drug can be considered tumor-independent. ETAC-S aims to bridge this gap by providing a standardized set of minimum requirements and a classification system.“intended for integration into various stages of the drug development process,” he adds.

Thus, Westphalen notes that the use of ETAC-S will help researchers, pharmaceutical companies and regulators assess whether MGTO has tumor-independent potential, “thereby informing the next steps in the drug development process.”

ETAC-S, very useful tool

ETAC-S could be used at the end of early-phase trials, where patients with different types of cancer have received a new cancer therapy. “At this stage of drug development, we propose that trial results be assessed based on three minimum requirements that must be met to confirm that the MGTO in question has the potential to be tumour-independent,” he explains. Diogo Martins-Branco

co-author of the study.

Specifically, the therapy had to demonstrate an objective response in at least one in five patients (ORR ≥20 percent) in two-thirds of the tumor types studied (and in ≥4 tumor types), with at least five patients evaluable in each tumor type in the context of refractory disease. “The evaluation will determine whether MGTO has the potential to provide more confirmatory evidence of activity in a population of patients with different types of tumors that have the same changes which causes cancer if the minimum requirements are met, or whether it should be studied in a population of patients with organ-of-origin-defined cancer if it does not pass a tumor-specific assessment but shows a signal of tumor-limited activity,” explains Martins-Branko.

In a study published in the journal Annals of Oncology, Westphalen, Martins-Branco and a team of experts described the methodology used to derive these minimum requirements for receiving tumor-independent potentialThey reviewed publicly available data for seven oncology indications approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) as of December 2023.

After pooling the clinical data supporting each approval, the team tested various scenarios involving three key factors: objective response rate, number of tumor types studied, and number of patients per tumor type. Minimum requirements that make up the filter were then identified and tested positively with the available data for two new accelerated, tumor-agnostic FDA approvals in the first half of 2024: an antibody-drug conjugate trastuzumab deruxtecan

for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors and a kinase inhibitor reporectinib for patients with locally advanced or metastatic solid tumors with NTRK gene fusions, demonstrating high reliability.

Classification of cancer treatment methods

To provide a realistic categorization that goes beyond the distinction between agnostic and tumor-specific effects of MGTO, the group also proposed a conceptual taxonomy for classifying the therapeutic effect of the treatments under investigation, taking into account the full biological context of the tumor plus key molecular aberrations. These were proposed three categories:

• Tumor independent: by targeting a moving molecular aberration that predominantly determines the therapeutic effect, regardless of the specific biology of the tumor.
• Modulated by tumor: when the therapeutic effect on a tumor-specific molecular aberration is modulated by the specific biology of the tumor.
• Limited by tumor: when the therapeutic effect on a particular molecular aberration is present only in a particular biological context of the tumor.

«Classify cancer treatment methods “According to its molecular/tumor determinants of effect, based on a thorough taxonomy, it will profoundly change the way cancer is treated,” says Martins-Branco. “The next step will be a literature review to collect data from published anticancer drug development studies, which will be key to defining the boundaries between what is purely tumor-independent and what is tumor-modulated,” he points out, while outlining the group’s future methodological work aimed at improving the robustness of ETAC-S.

“ETAC-S will be useful to highlight a change in how we classify diseases into a broader group called cancer.“focusing on the molecular changes that drive tumor development rather than the organ of origin,” Westphalen adds. “By taking this approach, we may be able to address the drug development delays we currently face in the future,” he says.

For example, a drug initially developed for a specific indication may take several years to become effective in other tumors with the same molecular changes. “With cancer cases rapidly increasing and requiring urgent action, Streamline the drug development process by offering a useful standardized framework. “Regulatory assessment will speed up access to effective treatments, especially for diseases where treatment options are limited,” Westphalen concludes.