Lessons From Adaptive Randomization: Spying the I-SPY2 Trial in Breast Cancer
Authors: Bishal Gyawali, Saroj Niraula
Journal: Journal of the National Comprehensive Cancer Network (2020)

C ancer drug development is tedious and costly, occurring conventionally in 3 sequential phases of clinical trials.Such rigor of evaluation maximizes the chances that the new drug is adequately safe and effective before being used in clinical practice.It is common therefore for a new drug to cost .$600million and take more than a decade to progress from preclinical stage to phase III clinical trial and subsequent registration for public use. 1,2The vast majority of drugs fail during the process, often at a later phase of development at the expense of considerable financial, temporal, and human resource. 3Therefore, it is prudent that drugs be rigorously scrutinized before being tested in a phase III trial so that only those with high chances of benefit are chosen to move forward.Adaptive randomization is one of those innovative clinical trial designs intended for that purpose: to improve efficiency and save valuable resources. 4This trial design was recently in the spotlight after the results from another arm of the I-SPY2 trial, a phase II multiarm trial using adaptive randomization, was presented at the Plenary Session of the American Association for Cancer Research Annual Meeting 2020.The hallmark of adaptive randomization is the use of Bayesian theorem to estimate future probabilities based on previously known and evolving new information. 5This design offers several practical advantages over the conventional frequentist approach: it can test multiple drugs simultaneously, requires a smaller sample size, focuses resources on drugs that are most likely to succeed, and preferentially randomizes patients to treatments that are most likely to benefit.However, before widespread incorporation of this design into clinical trials, we need to ascertain that it does not compromise on the safety nets offered by conventional drug development.Drawing examples from the phase II I-SPY 2 trial, 6,7 this commentary highlights some issues and challenges in the adaptive randomization approach to consider in interpretations of such trials.I-SPY 2 is a 20-arm mega randomized controlled trial (RCT) in the neoadjuvant treatment of early breast cancer with the primary endpoint of pathologic complete response (pCR; ClinicalTrials.govidentifier: NCT01042379).The arms consist of one common control arm of standard neoadjuvant chemotherapy with paclitaxel (with an alternate control arm of paclitaxel 1 trastuzumab or pertuzumab 1 trastuzumab if HER2positive) against which other experimental arms are tested.The other 18 experimental arms consist of a single agent or a combination therapy in addition to paclitaxel.Assignment of patients to one of the experimental arms depends on the results of 10 different biomarker signatures based on hormone receptor and HER2 status and a 70-gene genomic assay so that patients are randomized to the arm with highest likelihood of response.So far, 6 experimental arms have been considered successful ("graduated"), [6][7][8][9][10][11] 4 have failed, and the rest 9,10 are either in progress or are halted.1442