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

• Published in: International journal of molecular sciences Vol. 25; no. 7; p. 4094
• Main Authors: Aleksakhina, Svetlana N, Ivantsov, Alexander O, Imyanitov, Evgeny N
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-04-2024
• Subjects: agnostic markers; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B7-H1 Antigen; BRCA1 Protein; BRCA2 Protein; Breast cancer; Cancer therapies; Carcinogens; Clinical trials; DNA repair; Drug approval; Drug therapy; Drugs; FDA approval; Genetic testing; Genomes; HRD; Humans; Immunotherapy; kinase inhibitors; Kinases; Lung cancer; Melanoma; microsatellite instability; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Patients; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; targeted therapy; TMB; Tumors; TMB; microsatellite instability; targeted therapy; agnostic markers; kinase inhibitors; HRD
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25074094

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
V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying
and
translocations, biallelic
inactivation and/or homologous recombination deficiency (HRD), strong
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.