title: Combine and conquer: challenges for targeted therapy combinations in early phase trials.
abstract: Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit. We explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments necessitates creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials can contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, in order to realize the full potential of combination therapies.
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, London SM2 5PT, UK.
authors.forename: Juanita S
authors.initials: JS
authors.lastname: Lopez
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, London SM2 5PT, UK.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007107:Immune System / Q000502:physiology; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000628:therapy*; D018579:Patient Selection; D049490:Systems Biology; D059016:Tumor Microenvironment