Mohammed Kashif Siddiqui1, Jerzy Tyczynski2, Ankit Pahwa1, Ancilla W Fernandes3. 1. PAREXEL International, Chandigarh, Chandigarh, India. 2. Global Medical Evidence and Outcomes Research, AstraZeneca, Gaithersburg, MD, USA. 3. Health Economics and Outcomes Research, AstraZeneca, Gaithersburg, MD, USA. Electronic address: Ancilla.Fernandes@astrazeneca.com.
Abstract
OBJECTIVE: Evaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC). METHODS: Systematic review consistent with PRISMA criteria, identified randomized, controlled trials reporting overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in recurrent OC. MEDLINE® and Embase® searches (year 2000-March 23, 2015) were augmented by bibliographic screening. Proposed surrogate measures (independent variables) were ORR and disease control rate. True clinical outcomes (dependent variables) were median OS and PFS. Analyses were performed on unweighted and weighted data using correlation analysis, linear regression, and surrogate threshold effect (STE). Smaller STE indicates greater predictive precision with magnitude of STE dependent on variance of prediction. RESULTS: Thirty-nine studies were included for review, representing 9223 platinum-sensitive and resistant patients. Objective response rate (r=0.82; P<0.001) was a better predictor than disease control rate (r=0.58; P<0.001) and strongly correlated with PFS (r=0.85; P<0.0001). Weighted-regression analysis demonstrated that for each 10% increase in ORR, PFS increased by 1.20months and OS by 2.83months. Regression analysis of treatment effects (odds ratio of response, hazard ratio of survival) suggests that a 10% increase in odds ratio of ORR would result in 2.5% reduction in the hazard ratio of OS. Based on weighted data, STE indicated that an ORR of ≥1% is needed to achieve nonzero OS benefit. CONCLUSION: This systematic review supports ORR as a possible surrogate clinical trial endpoint for OS in recurrent OC with at least second-line therapy.
OBJECTIVE: Evaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC). METHODS: Systematic review consistent with PRISMA criteria, identified randomized, controlled trials reporting overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in recurrent OC. MEDLINE® and Embase® searches (year 2000-March 23, 2015) were augmented by bibliographic screening. Proposed surrogate measures (independent variables) were ORR and disease control rate. True clinical outcomes (dependent variables) were median OS and PFS. Analyses were performed on unweighted and weighted data using correlation analysis, linear regression, and surrogate threshold effect (STE). Smaller STE indicates greater predictive precision with magnitude of STE dependent on variance of prediction. RESULTS: Thirty-nine studies were included for review, representing 9223 platinum-sensitive and resistant patients. Objective response rate (r=0.82; P<0.001) was a better predictor than disease control rate (r=0.58; P<0.001) and strongly correlated with PFS (r=0.85; P<0.0001). Weighted-regression analysis demonstrated that for each 10% increase in ORR, PFS increased by 1.20months and OS by 2.83months. Regression analysis of treatment effects (odds ratio of response, hazard ratio of survival) suggests that a 10% increase in odds ratio of ORR would result in 2.5% reduction in the hazard ratio of OS. Based on weighted data, STE indicated that an ORR of ≥1% is needed to achieve nonzero OS benefit. CONCLUSION: This systematic review supports ORR as a possible surrogate clinical trial endpoint for OS in recurrent OC with at least second-line therapy.
Authors: Ingrid A Mayer; Aleix Prat; Daniel Egle; Sibel Blau; J Alejandro Pérez Fidalgo; Michael Gnant; Peter A Fasching; Marco Colleoni; Antonio C Wolff; Eric P Winer; Christian F Singer; Sara Hurvitz; Laura García Estévez; Peter A van Dam; Sherko Kümmel; Christoph Mundhenke; Frankie Holmes; Naveen Babbar; Laure Charbonnier; Ivan Diaz-Padilla; Florian D Vogl; Dalila Sellami; Carlos L Arteaga Journal: Clin Cancer Res Date: 2019-02-05 Impact factor: 12.531