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End points and statistical considerations in immuno-oncology trials: impact on multiple myeloma.

ABSTRACT: Unlike conventional cancer treatment, immuno-oncology therapies are commonly associated with delayed clinical benefit and durable responses, as seen with immuno-oncology therapies for multiple myeloma (MM). Therefore, a longer-term approach to immuno-oncology data assessment is required. Appropriate study designs, end points and statistical methods are essential for evaluating immuno-oncology therapies to assess treatment outcomes, and may better accommodate immuno-oncology clinical trial data. In addition to conventional end points including median progression-free survival (PFS) and overall survival (OS), end points such as hazard ratios for PFS and OS over time, PFS and OS landmark analyses beyond the median, and immune-response end points might provide better indications of the efficacy of immuno-oncology therapies. Long-term data with these agents will allow better prediction of outcomes in MM.

SUBMITTER: Hoering A

PROVIDER: S-EPMC5705823 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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End points and statistical considerations in immuno-oncology trials: impact on multiple myeloma.

Hoering Antje A Durie Brian B Wang Hongwei H Crowley John J

Future oncology (London, England) 20170411 13

Unlike conventional cancer treatment, immuno-oncology therapies are commonly associated with delayed clinical benefit and durable responses, as seen with immuno-oncology therapies for multiple myeloma (MM). Therefore, a longer-term approach to immuno-oncology data assessment is required. Appropriate study designs, end points and statistical methods are essential for evaluating immuno-oncology therapies to assess treatment outcomes, and may better accommodate immuno-oncology clinical trial data. ...[more]

PMID: 28395525

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Project description:ImportancePhase 2 trials and early efficacy end points play a crucial role in informing decisions about whether to continue to phase 3 trials. Conventional end points, such as objective response rate (ORR) and progression-free survival (PFS), have demonstrated inconsistent associations with overall survival (OS) benefits in immune checkpoint inhibitor (ICI) trials. Restricted mean duration of response (DOR) is a rigorous metric that combines both response status and duration information. However, its utility in clinical development has not been comprehensively explored.ObjectiveTo determine whether using restricted mean DOR in phase 2 trials can advance promising regimens to phase 3 trials sooner and eliminate unfavorable regimens earlier and with a higher degree of confidence compared with PFS and ORR.Design, setting, and participantsThis simulated modeling study randomized phase 2 screening trials by resampling 1376 patients from 2 completed randomized phase 3 trials of ICIs. Data were analyzed from August 2019 to July 2020.ExposuresUse of ICIs.Main outcomes and measuresRestricted mean DOR, PFS, ORR, and OS were estimated and compared between groups. Three scenarios were considered: (1) significant differences in OS, PFS, and ORR; (2) significant differences in OS and noticeable differences in ORR but not PFS; and (3) no differences in OS, PFS, or ORR. For each setting, 5000 randomized phase 2 trials with different sample sizes were simulated, with additional censoring applied to mimic staggered accruals and ensure fair comparisons between different analysis methods. Probabilities of concluding positive phase 2 trials using PFS, ORR, and DOR were summarized and compared.ResultsThe restricted mean DOR difference correctly estimated a positive OS benefit more frequently than did the ORR or PFS tests, across different sample sizes, significance levels, and censoring levels evaluated. When both OS and PFS differed, the ranges of true-positive or power rates were 79.2% to 98.7% for DOR, 56.3% to 93.2% for PFS, and 67.0% to 96.0% for ORR. When OS differed but PFS did not, the ranges of power rates were 24.0% to 76.0% for DOR, 3.0% to 19.0% for PFS, and 10.5% to 38.0% for ORR. When OS was similar, the false-positive rate of restricted mean DOR test was close to the chosen significance level.Conclusions and relevanceThese findings suggest that restricted mean DOR in randomized phase 2 trials is potentially more sensitive and useful than PFS and ORR in estimating the subsequent phase 3 conclusions and, thus, may be considered to complementarily facilitate decision-making in future clinical development.

Project description:Importance:Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. Objective:To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). Design, Setting, and Participants:This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. Main Outcomes and Measures:The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. Results:In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). Conclusions and Relevance:From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

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End points and statistical considerations in immuno-oncology trials: impact on multiple myeloma.

Publications

End points and statistical considerations in immuno-oncology trials: impact on multiple myeloma.

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