A single-arm study design with non-inferiority and superiority time-to-event endpoints: a tool for proof-of-concept and de-intensification strategies in breast cancer.
Miguel Sampayo-Cordero, Bernat Miguel-Huguet, Andrea Malfettone, Elena López-Miranda, María Gion, Elena Abad, Daniel Alcalá-López, Jhudit Pérez-Escuredo, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés
Author Information
Miguel Sampayo-Cordero: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Bernat Miguel-Huguet: Gerència Territorial Metropolitana Sud, Institut Català De La Salud, Hospital Universitari De Bellvitge, Barcelona, Spain.
Andrea Malfettone: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Elena López-Miranda: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
María Gion: Hospital Universitario Ramón y Cajal, Madrid, Spain.
Elena Abad: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Daniel Alcalá-López: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Jhudit Pérez-Escuredo: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
José Manuel Pérez-García: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Antonio Llombart-Cussac: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
Javier Cortés: Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
De-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative. Single-arm studies are also commonly used to evaluate novel treatment strategies (ESMO evidence tier B). A single-arm design that includes both non-inferiority and superiority primary objectives will enable the ranking of clinical activity and other parameters such as safety, pharmacokinetics, and pharmacodynamics data. Here, we describe the statistical principles and procedures to support such a strategy. The non-inferiority margin is calculated using the fixed margin method. Sample size and statistical analyses are based on the maximum likelihood method for exponential distributions. We present example analyses in metastatic and adjuvant settings to illustrate the usefulness of our methodology. We also explain its implementation with nonparametric methods. Single-arm designs with non-inferiority and superiority analyses are optimal for proof-of-concept and de-escalation studies in oncology.
