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J Cancer 2017; 8(9):1562-1567. doi:10.7150/jca.18686 This issue Cite

Research Paper

Response Rates as Predictors of Overall Survival: A Meta-Analysis of Acute Myeloid Leukemia Trials

Suresh K. Agarwal¹, Naveen Mangal^{1, 2}, Rajeev M. Menon¹, Kevin J. Freise¹, Ahmed Hamed Salem^{1, 3✉}

1. Abbvie, Inc., North Chicago, IL, USA;
2. Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA;
3. Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

✉ Corresponding author: Ahmed Hamed Salem, PhD, AbbVie Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL 60064 Telephone: +1 847- 938-0776 Facsimile: +1 847-938-5193 Email: ahmed.salemcom

Abstract

Background: Response rates such as overall response rate (ORR), complete response (CR) and complete response with incomplete blood recovery (CRi) can be evaluated in a much shorter period of time than overall survival (OS), potentially accelerating decision making during drug development. The objective of this work was to evaluate the relationship between ORR, CR, CRi or better (CRi+CR) rates and median OS to determine whether response rates could be used as predictors of median OS in acute myeloid leukemia (AML).

Methods: A review of published literature was conducted to identify relevant AML clinical trials. Weighted linear regression was performed with various linearizing transformations of response rates and median OS. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively.

Results: Twenty trials involving 26 cohorts were included in the meta-analysis. Azactidine treatment was a significant predictor with longer OS compared to decitabine or low dose cytarabine for a given response rate (P < 0.005). Linear regression analysis indicated that the correlation of both CRi or better rates and CR rates with median OS was higher than that of ORR with median OS. The final model showed a strong correlation between CRi or better rates and median OS (R²=0.66).

Conclusion: Significant correlation between CRi or better rates and median OS in AML highlights the potential for CRi or better rate, in addition to CR rate, to serve as surrogate markers for median OS.

Keywords: Acute myeloid leukemia, surrogate endpoints, overall survival, response rates, azacitidine, meta-analysis.

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