Skip to main content

Table 4 Key components of individualized dynamic studies

From: Approaches to modernize the combination drug development paradigm

Key components Comments
Molecular and immune profiling at baseline • Whole-exome or whole-genome sequencing, ideally using fresh tumor biopsies
• Transcriptomic profiling
• Proteomic validation
• Immuno-phenotyping
• Parallel ctDNA/cfDNA
• PDX or PDO
Dynamic monitoring of molecular and immune landscapes • Serial tumor biopsies may trigger concerns of safety and may not capture spatial heterogeneity
• Novel strategies include serial monitoring of ctDNA/cfDNA, molecular imaging, and radiomics evaluation
• ctDNA/cfDNA may assist with monitoring of treatment efficacy and early detection of resistant clones, although whether circulatory biomarkers reflect spatial tumor heterogeneity remains to be addressed
• Assays need to have fast turnaround to allow “real-time” decision-making
Correlation of molecular monitoring with radiological response • Requires exploration in future studies
• Radiological response may not always provide the full picture, as in the case of mixed responses, and may lag behind treatment resistance
• Also, pseudoprogression may occur in some cases with immuno-oncology agents
Multidimensional treatment algorithms at key decision points in response to molecular results • If multiple mutations are present, treatment prioritization is required. Considerations may include relevance and level of evidence for the actionability of the mutation(s): that is, “driver” versus “passenger” mutations; allele frequency of mutation(s), and copy number change in the case of amplifications; downstream and parallel pathway aberrations that may confer treatment resistance; and availability of drugs and drug combinations. Sequential or alternating approaches may also be considered
• Evaluation of immunotherapeutic approaches in cases of high mutational burden or other immune biomarkers to assess their predictive role
• With the detection of emerging clones, consider changing therapeutic strategy ahead of radiological progression
Access to approved and investigational agents • Requires collaboration with industry and academic partners
  1. ctDNA circulating tumor DNA, cfDNA cell-free DNA, PDO patient-derived organoid, PDX patient-derived xenograft