Lessons learned from deescalation trials in favorable risk HPV-associated squamous cell head and neck cancer–a perspective on future trial designs

In recent years several clinical studies have investigated deintensified treatments in human papillomavirus (HPV)associated head and neck squamous cell carcinoma. Two large phase III trials, RTOG 1016 and De-ESCALaTE, which attempted to reduce toxicity by replacing radiotherapy in combination with cisplatin with the use of cetuximab in combination with radiotherapy, recently suggested that radiotherapy þ cetuximab leads to inferior survival compared with standard therapy (observed HRs of 1.45 and 5 in RTOG 1016 and De-ESCALaTE), as well as increased rates of locoregional failure. These unexpected results should prompt a careful examination of deintensification trials, both in HPV-associated oropharyngeal cancer and in other contexts. Statistical designs for deintensification studies should be consistent with the study aims of reducing toxicities while maintaining survival nearly identical to the standard of care. We suggest criteria to design future deintensification trials and discuss important operating characteristics, including tradeoffs between power and stringent early stopping rules to reduce the number of patients exposed to inferior treatments. Using retrospective analyses of previous clinical studies, we compared designs with different operating characteristics. As an example, using outcomes data from RTOG 1016 and De-ESCALaTE, we conducted analyses to determine advantages of (i) stringent futility early-stopping rules and of (ii) study designs that leverage both toxicity and efficacy endpoints for interim analyses. We show that increasing the frequency of interim-futility analyses has little impact on power, but the average study duration and number of subjects enrolled before the trial is closed for inferiority can decrease substantially (from 57.8 to 18 months, and from 764 to 645 subjects). Moreover, the number of observed deaths during the study can be reduced by up to 68%.