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 |