Validation of Biomarkers as Surrogates for Clinical Endpoints

Buyse, Marc; Vangeneugden, Tony; Bijnens, Luc; Renard, Didier; Burzykowski, Tomasz; Geys, Helena; Molenberghs, Geert

doi:10.1201/9780203911235.ch7

Cited by 11 publications

(17 citation statements)

References 39 publications

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“…14 PFS has been shown to be a valid surrogate endpoint for OS in advanced ovarian and advanced colorectal cancer. 10, 23–25 Other disease sites, including advanced breast cancer, 26–29 advanced prostate cancer 30–31 , advanced gastric cancer 32 , and advanced non–small-cell lung cancer (NSCLC) 33 have not supported PFS as a surrogate endpoint for OS. Within NSCLC, PFS has been assessed as a possible surrogate endpoint for OS with conflicting conclusions.…”

Section: Discussionmentioning

confidence: 99%

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

Foster

Renfro

Schild

et al. 2015

Journal of Thoracic Oncology

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Introduction We previously reported that PFS may be a candidate surrogate endpoint for OS in first-line ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient- and trial-level surrogacy of PFS using data from 7 new first-line phase II/III ES-SCLC trials and across all 10 trials as well (7 new, 3 previous). Methods Individual patient data were utilized across the 7 new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall’s τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression of Cox model effects (WLS R2) and correlation of the copula effects (Copula R2). The minimum effect on the surrogate (MES) needed to detect a non-zero treatment effect on OS was also calculated. Results The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (Copula R2 = 0.90 (SE=0.27); WLS R2 = 0.83 (95% CI: 0.43, 0.95); MES=0.67; Kendall’s τ = 0.58) and across all 10 trials (Copula R2 =0.81 (SE=0.25); WLS R2=0.77 (95% CI: 0.47–0.91); MES=0.70; Kendall’s τ =0.57). Conclusions PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative endpoint to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting.

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Section: Discussionmentioning

confidence: 99%

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

Foster

Renfro

Schild

et al. 2015

Journal of Thoracic Oncology

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“…Whereas a meta-analysis of several trials might have yielded more convincing evidence than a single trial, other surrogate end points have been validated using centers or countries as the units of analysis when the number of trials was limited. [32][33][34] The cross-validation performed using a "leave-one-out" approach provides some reassurance that the results were robust. 15 Even so, our results should be confirmed in an independent trial or set of trials.…”

Section: Discussionmentioning

confidence: 99%

“…Other criteria have been proposed in the literature for the validation of surrogate end points, but those adopted here have been used extensively in solid tumors both in the adjuvant treatment and advanced disease settings. [3][4][5]7,13,15,16,23,[31][32][33][34] The trial on which this analysis was based did not achieve significance in its secondary overall survival end point; however, it is noteworthy that the presence or lack of a significant overall survival benefit appears to have little bearing on the success or failure of surrogate validations in solid tumor trials. 3,7 With the available follow-up data in the HDC/IL-2 trial at the time of the database lock, 236 patients had experienced an event contributing to the leukemia-free survival end point (110 in the treatment group and 126 in the control group).…”

Section: Discussionmentioning

confidence: 99%

Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission

Buyse¹,

Michiels²,

Squifflet³

et al. 2011

Haematologica

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BackgroundIn trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia. Design and MethodsData were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis. ResultsKaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R 2 ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R 2 =0.88-0.93). ConclusionsThe significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model.

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“…This problem is fraught with difficulties, but will undoubtedly require large numbers of observations from randomized trials [23]. Likewise, the identification of biomarkers that can be used in lieu of clinical endpoints will require large-scale collaboration and use of metaanalytic techniques [24].…”

Section: Endpointsmentioning

confidence: 99%

Challenges in breast cancer clinical trial design in the postgenomic era

Loi

Buyse

Sotiriou

et al. 2004

Current Opinion in Oncology

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There is an urgent need to break from traditional clinical development and to incorporate new molecular knowledge and translational research in the design of clinical trials. The success of new approaches in BC research critically depends on well-conducted translational research linked to prospective clinical trials, and international collaboration, bringing together human and technological resources.

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Validation of Biomarkers as Surrogates for Clinical Endpoints

Cited by 11 publications

References 39 publications

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission

Challenges in breast cancer clinical trial design in the postgenomic era

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