Dosing de novo combinations of two targeted drugs: Towards a customized precision medicine approach to advanced...

Area of Science:

• Oncology
• Pharmacology
• Genomics

Background:

• Metastatic cancers exhibit complex genomic alterations, often rendering single-agent therapies (monotherapies) ineffective.
• Developing individualized combination therapies is crucial for overcoming drug resistance in cancer treatment.

Purpose of the Study:

• To inform the selection of safe starting doses for novel, two-agent, targeted drug combinations in adult oncology.
• To analyze the relationship between drug class, target overlap, and safe additive doses in targeted drug combinations.

Main Methods:

• A systematic review of clinical trials involving targeted drug doublets in adult oncology patients (PubMed, 2010-2013).
• Calculation of dose percentage for each drug (combination dose / full single-agent dose) x 100.
• Analysis of additive dose percentages across 95 combinations from 144 studies (N=8568 patients).

Main Results:

• In 51% of trials, both drugs in a combination could be administered at 100% of their full single-agent dose.
• The lowest safe additive dose percentage was 60% when drug targets or classes overlapped, or when mTOR inhibitors were present.
• When drug classes/targets did not overlap and mTOR inhibitors were absent, the lowest safe additive dose percentage reached 143%.

Conclusions:

• This analysis provides a knowledge base for determining safe starting doses for new targeted drug combinations.
• Findings facilitate the development of customized combination therapies in clinical trials and practice.
• Understanding drug interactions is key to optimizing targeted cancer treatment strategies.