Patient-Centric Approaches for Phase I Combination Trials Come on Stage

The heterogeneity of cancer molecular profiles and the widespread variability of anticancer responses has prompted the need to tailor therapies to individual genomic profiles. Although different molecularly guided therapeutics target-ing oncogene addiction have become the standard-of-care treatment of different cancers, single-agent activity is ham-pered by the development of resistance and patients receiving targeted agents will inevitably end up progressing. In this setting, novel rational combinations are poised to become key in overcoming intrinsic and acquired resistance mechanisms while prolonging the duration of clinical benefi t achieved for these agents when used as monotherapies. The June 2012 FDA approval of the combination of per-tuzumab and trastuzumab with docetaxel for HER2-positive breast cancer marked the first approval of a combination therapy involving multiple targeted therapies. More than a decade has passed, and the number of preclinical publica-tions exploring different combinations of targeted therapies is rapidly expanding. However, only very few have reached routine clinical care. As described in Fig. 1 , multiple rea-sons underlie the scarcity of targeted therapy combinations into the clinic. Challenges associated with the development of novel treatment combinations include biomarker discov-ery for patient selection, development of clear scientifically rational combinations, the potential for additive toxicities, and the constraints of established clinical trial development paradigms and regulatory requirements ( 1 ). Over the past few years, and more importantly since the beginning of the COVID-19 pandemic, the drug development field has evolved toward more patient-centered approaches. Examples of this include, but are not limited to, the imple-mentation of virtual appointments as part of phase I clini-cal trial protocols; defi nition of patient-reported outcomes