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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

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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 (R 2). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2 = 0.81, 95% confidence interval [CI] 0.51–0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2 = 0.89, 95% CI 0.62–0.96) in FL and was moderately correlated with 2-year OS (R 2 = 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 R 2 = 0.66 (95% CI 0.52–0.98) and R 2 = 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.

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Abbreviations

ABC:

Activated B-cell-like

ASCO:

American Society of Clinical Oncology

CI:

Confidence interval

CR:

Complete response

CRu:

Unconfirmed complete response

CT:

Computed tomography

DLBCL:

Diffuse large B-cell lymphoma

FDG-PET:

Positron emission tomography with 2-[18F]fluoro-2-deoxy-d-glucose

FL:

Follicular lymphoma

GCB:

Germinal center B-like

MCL:

Mantle cell lymphoma

MRD:

Minimal residual disease

NHL:

Non-Hodgkin lymphoma

OS:

Overall survival

PFS:

Progression-free survival

PI:

Prediction interval

RCT:

Randomized controlled trial

R 2 :

Pearson’s coefficient of determination

SE:

Standard error

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Acknowledgments

The authors would also like to thank Dr. Kelong Han and Dr. Bryan Hains for valuable advice during the manuscript preparation.

Authors’ Contributions

Zhu, Lu, Chu, Chai, and Jin were responsible for the conception and design of the study; Zhang and Green for the collection and assembly of data; and Zhu, Green, Lu, Chu, and Chai for data analysis and interpretation. All authors participated in manuscript writing and approved the final version of the manuscript.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Rui Zhu, Dan Lu & Jin Yan Jin

  2. Department of Clinical Science Oncology, Genentech, South San Francisco, California, USA

    Yu-Waye Chu

  3. Department of Biostatistics, Genentech, South San Francisco, California, USA

    Akiko Chai

  4. Quantitative Solutions, Menlo Park, California, USA

    Michelle Green & Nancy Zhang

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  1. Rui Zhu
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  2. Dan Lu
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Correspondence to Rui Zhu.

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This work was supported by Genentech.

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Zhu, Lu, Chu, Chai, and Jin are Genentech employees and Roche shareholders, and Green and Zhang are Quantitative Solutions employees.

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Zhu, R., Lu, D., Chu, YW. et al. 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. AAPS J 19, 669–681 (2017). https://doi.org/10.1208/s12248-017-0056-x

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