Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer

Abstract

BackgroundThe duration of, resources required for and cost of clinical trials could be reduced if a surrogate end point was to be used in place of survival. We assessed the extent to which the objective response rate (ORR) is predictive of mortality, how much difference in the ORR is needed to predict an obvious survival difference and what factors could affect the association between the two parameters during the first-line treatment of extensive disease (ED)-small-cell lung cancer (SCLC). MethodsWe used the ORRs and median survival times (MSTs) from 48 phase III trials of first-line chemotherapy involving 8779 randomised patients with ED-SCLC in a linear regression analysis. The MST difference was calculated as the difference in MST between the investigational and reference arms; the ORR difference was similarly defined. ResultsORR difference between the treatment arms was modestly associated with the MST difference in the overall trials (R2=0.3314). In contrast, the relationship was stronger among only trials in which prophylactic cranial irradiation was given to those having an objective response to the initial chemotherapy (R2=0.6279). In this trial setting, large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR). ConclusionsIn the first-line treatment of ED-SCLC, a favourable relationship was detected between the two parameters in the selected trial setting. Large ORR differences were needed to predict a survival benefit, clearly suggesting the need for new chemotherapeutic agents.