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

Abstract

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

Keywords: HRD; TMB; agnostic markers; kinase inhibitors; microsatellite instability; targeted therapy.

Figure 1

The concept of agnostic therapy. Some tumor vulnerabilities are shared across various cancer types; therefore, their targeting is potentially effective irrespective of the histological origin of a given malignancy. Activating mutations in kinases involved in the MAPK signaling pathway are the best established agnostic targets. High tumor mutation burden, which may be caused by external carcinogens, errors in DNA repair pathways, or alterations in DNA polymerases, is associated with increased tumor antigenicity and, therefore, its sensitivity to immune therapy. Homologous recombination deficiency may be attributed to the inactivation of BRCA1/2 or some other genes; it renders tumor responsiveness to DNA double-strand-break-inducing drugs.