Analysis of tumor burden versus progression-free survival for Phase II decision making.

PURPOSE: There have been recent recommendations to use percentage change in tumor burden (dTB) as a primary endpoint in randomized Phase II trials. We assessed whether dTB is better for the decision to start a Phase III trial than is progression-free survival (PFS).

METHODS: We repeatedly sampled patients from six large randomized trials to obtain simulated Phase II trials. We derived PFS and dTB endpoints on the trial patients and determined the fraction of simulated trials with positive results for each endpoint. We supplemented these analyses with regression analyses to assess the ability of PFS and dTB to predict overall survival (OS).

RESULTS: The best PFS endpoint included tumor assessments through 6 months after the last patient enrolled. With 70 patients in each simulated Phase II trial, the estimated rate of a correct 'Phase III go' decision ranged from 0.74 to 0.91 across the six parent studies. The best dTB endpoint was the last dTB through 6 months after the last patient enrolled, with corresponding rates of 0.54 to 0.81. The PFS rate was better than the dTB rate in five studies. PFS and dTB are individually statistically significant predictors of OS (p < 0.05). In all six studies PFS added significantly to the regression models with dTB included, while in only two studies did dTB add significantly to the regression model with PFS included.

CONCLUSION: Analysis of PFS in randomized Phase II trials generally leads to better 'Phase III go' decisions than does analysis of dTB. Tumor burden analyses should be used in supportive analyses to a primary PFS analysis.