PET-CR as a potential surrogate endpoint in untreated DLBCL: meta-analysis and implications for clinical trial design

Abstract

This study’s focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.

Keywords:

• Bayesian hierarchical model
• clinical trial simulation
• diffuse large B-cell lymphoma
• end-of-treatment PET-complete response
• meta-analysis
• progression-free and overall survival

Disclosure statement

Thomas Witzig has received grants/contracts from Kura Oncology, Acerta, Karyopharm, and Incyte; provided educational consulting for Curio Science; and served on an advisory board for Seattle Genetics and ADC.

Marek Trnĕnỷ has provided consulting services for Takeda, Bristol-Myers Squibb, Incyte, Abbvie, Amgen, Roche, GIlead Sciences, Janssen, MorphoSys, and Novartis; and received honoraria from Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, Abbvie, Roche, Novartis, and MorphoSys.

Donald A. Berry is co-owner of Berry Consultants, a company that designs and analyzes clinical trials for pharmaceutical and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia.

Kristine Broglio was an employee of Berry Consultants at the time the analyses described herein were conducted and the initial draft of the manuscript was written. She now has employment and stock ownership with Astrazeneca.

Anna McGlothlin is an employee of Berry Consultants.

Barbara Wendelberger is an employee of Berry Consultants.

Corrine F. Elliott is an employee of Berry Consultants.

Margaret Foster is a contract employee of Berry Consultants, a company that designs and analyzes clinical trials for pharmaceutical and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia.

Lale Kostakoglu has served as a consultant to Hoffman-La Roche.

Maurizio Martelli has served on an advisory board for Gliead, Novartis, Roche, Janssen, Takeda, Sandoz, and Incyte; received lecture fees from Novartis, Gilead, Roche Takeda, Eusapharma, Servier, and Incyte.

Tina Nielsen has employment and stock ownership with Hoffmann-La Roche, Ltd.

Grzegorz S. Nowakowski has participated as a consultant on a data safety monitoring board or advisory board for Blueprint Medicines, Bantam Pharmaceutical, Karyopharm Therapeutics, Kite Pharma, Kymera Therapeutics, TG Therapeutics, Zai Lab Limited, Selvita Inc., Debiopharm, Ryvu Therapuetics, Celgene Corporation, MorphoSys AG, Genentech Inc., Fate Therapeutics, MEI Pharma Inc., Curis, Incyte Corp., Abbvie, ADC Therapeutics, Seagen, Bristol-Myers Squibb, F Hoffman-La Roche Limited

Umberto Vitolo is a member of an advisory board for Bayer, Incyte, Gilead, and Genmab; and has received lecture fees from Janssen, Abbvie, Incyte, Celgene, and Gilead.

Denis Sehin has employment and stock ownership with F. Hoffman-La Roche, Ltd.

Carol Ward has employment and stock ownership with Hoffman-LaRoche, Ltd.

Federico Mattiello has employment and stock ownership with Hoffman-LaRoche, Ltd.

Laurie Sehn has received research funding from Roche/Genentech and Teva; consulting fees and honoraria from Abbvie, Acerta, Amgen, Apobiologix, Astra Zeneca, Celgene, Chugai, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Roche/Genentech, Sandoz, Seattle Genetics, Servier, Teva, Takeda, TG Therapeutics, and Verastem.

No other potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was funded by Genentech/Roche through a contract with Berry Consultants, LLC.