title: Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.
abstract: Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R2). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R2= 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R2= 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R2= 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R2= 0.66 (95% CI 0.52-0.98) and R2= 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.
authors.affiliation: Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. zhu.rui@gene.com.
authors.forename: Rui
authors.identifier: 0000-0002-8851-8562
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Clinical Science Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.affiliation: Department of Biostatistics, Genentech, South San Francisco, California, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Chai
authors.affiliation: Quantitative Solutions, Menlo Park, California, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Green
authors.affiliation: Quantitative Solutions, Menlo Park, California, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Jin Yan
authors.initials: JY
authors.lastname: Jin
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D017063:Outcome Assessment, Health Care
chemical_list: D000970:Antineoplastic Agents
keywords: meta-analysis; non-Hodgkin lymphoma; progression-free survival; surrogate endpoints