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. 2024 Dec 1;155(11):1939-1943.
doi: 10.1002/ijc.35129. Epub 2024 Aug 13.

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials

Alexander D Sherry  1 , Timothy A Lin  2 , Zachary R McCaw  3   4 , Esther J Beck  1 , Ramez Kouzy  1 , Joseph Abi Jaoude  5 , Adina H Passy  1 , Avital M Miller  1 , Gabrielle S Kupferman  1 , Clifton David Fuller  1 , Charles R Thomas Jr  6 , Eugene J Koay  7 , Chad Tang  8   9   10 , Pavlos Msaouel  9   11 , Ethan B Ludmir  7   12
Affiliations

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials

Alexander D Sherry et al. Int J Cancer. .

Abstract

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

Keywords: clinical progression; phase III: Randomized controlled trials; quality of life; surrogate endpoints.

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Conflict of interest statement

Dr. Sherry reports honoraria from Sermo, Inc. Dr. McCaw reports employment at Insitro. Dr. Fuller receives unrelated funding and salary support from the: NIH NIBIB Research Education Programs for Residents and Clinical Fellows Grant (R25EB025787-01); the NIDCR Academic Industrial Partnership Grant (R01DE028290); the NCI Parent Research Project Grant (R01CA258827); and an NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369). Dr. Fuller has received direct industry grant support, honoraria, and travel funding from Elekta AB, and receives direct infrastructure support from The University of Texas MD Anderson Cancer Center core grant (multidisciplinary Radiation Oncology/Cancer Imaging Program [P30CA016672-44]) and the MD Anderson Program in Image-guided Cancer Therapy. Dr. Koay reports grants from National Institutes of Health, Stand Up 2 Cancer, MD Anderson Cancer Center, Philips Healthcare, Elekta, and GE Healthcare; personal fees from RenovoRx and Taylor and Francis; and a consulting/advisory role with Augmenix. Dr. Tang reports grants from the Cancer Prevention & Research Institute of Texas, and the Department of Defense (DoD), and he receives royalties from Wolters Kluwer and consulting fees and honoraria from Siemen Healthineer, Lantheus, Telix, Molli Surgical, and Boston Scientific. Dr. Msaouel reports honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; non-branded educational programs supported by Exelixis, Pfizer, and DAVA Oncology; leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and as a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research (all unrelated to this manuscript’s content). No other authors report any conflicts of interest.

Figures

Figure 1.
Figure 1.
A forest plot is shown with univariable logistic regressions for trial-level covariates and the odds of using clinical criteria for progression. The 95% confidence interval is shown, and the red line represents an OR of 1. Abbreviation: OR, odds ratio.
See this image and copyright information in PMC

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