Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Abstract

Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS.Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data.Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009).Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32).Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS.Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion.Table 1Results of E1900 based on an EFS endpoint versus an OS endpoint.SubgroupNOS HR (DNR 90/DNR 45) & 95% CIWald PEFS HR (DNR 90/DNR 45) & 95% CIWald PDNR 45DNR 90Age< 50 yrs ³ 50 yrs188 142172 1550.66 (0.50, 0.85) 0.81 (0.62, 1.06)0.002 0.1180.64 (0.50, 0.82) 0.86 (0.67, 1.10)0.0004 0.23CytogeneticFavorable Intermediate Unfavorable38 141 5951 127 630.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16)0.027 0.012 0.2250.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05)0.32 0.001 0.09SubgroupNOS HR (MUT/WT) & 95% CIWald PEFS HR (MUT/WT) & 95% CIWald PFLT3-ITDWT MUT456 1471.62 (1.31, 2.01) <.00011.48 (1.21, 1.82) 0.0002DNMT3AWT MUT371 1191.30 (1.03, 1.65) 0.031.23 (0.98, 1.54) 0.07IDH1WT MUT465 360.88 (0.59, 1.33)0.550.91 (0.62, 1.34)0.64IDH2WT MUT451 500.63 (0.43, 0.93)0.020.68 (0.48, 0.97)0.03NPM1DNR 45 DNR 90245 2570.84 (0.61, 1.16) 0.60 (0.41, 0.89)0.30 0.010.90 (0.66, 1.22) 0.59 (0.41, 0.84)0.49 0.004 DisclosuresNo relevant conflicts of interest to declare.