Drug Development in Tissue-Agnostic Indications

Abstract

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.

How do cancer clinicians perceive real-world data and the evidence derived therefrom? Findings from an international survey of the European Organisation for Research and Treatment of Cancer

“…Tumor-agnostic agents for instance are standardly tested in non-randomized, biomarker-driven enrichment trials (e.g. basket studies) ( Flaherty et al, 2017 ; Offin et al, 2018 ; du Rusquec and Le Tourneau, 2021 ; Seligson et al, 2021 ), which usually feature relatively small sample sizes. Here, observational RWD can offer valuable insights into the performance of these products in larger groups of patients ( Agarwala et al, 2018 ; Miksad et al, 2019 ), as long as the quality of the data is sufficiently high.…”

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

“…In contrast, only the dabrafenib plus trametinib combination has been successfully evaluated for BRAF V600E mutated tumors in the agnostic setting, while similar combinations, i.e., vemurafenib plus cobimetinib, or encorafenib plus binimetinib, have only histologyspecific indications for the time being. The European Medicines Agency (EMA) has a more cautious attitude towards tissue-agnostic approvals than the FDA, so the list of agnostic drugs and targets is currently less extensive in Europe than in the USA [23][24][25] (Table 1).…”

TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs

“…With the introduction of targeted therapy, molecular segmentation of cancer resulted in a small patient population. And this became a challenge for conducting clinical trials [ 28 ]. In crizotinib phase 3 clinical trials in Europe, for example, there was a patient selection process from NSCLC patients.…”

“…Due to the small number of patients, it is not easy to conduct clinical trials for cancers with low incidence. Tissue-agnostic drug development enables the participation of rare cancer patients in clinical trials; therefore, rare cancer patients can benefit from this new paradigm of drug approval process [ 28 ].…”