The RMST represents the area under the survival curve from time 0 to a specific follow-up time point; it is called restricted mean survival time because given X as the time until any event, the expectation of X (mean survival time) will be the area under the survival function (from 0 to infinity). Covariates used for regression analysis were immunotherapy versus nonimmunotherapy, occurrence of crossovers in the trials, time horizon of the trials, year of approval, trial phase, existence of companion diagnostics for the drug, approval type of the drug (regular/accelerated), and line of therapy (trials specific for first-line vs other). Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale measure the same construct of clinical benefit? Results: Twenty-five RCTs totaling 12 870 patients were included in this study. Pharm Stat 2018;17:202–213. Trastuzumab emtansine for HER2-positive advanced breast cancer. Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw. Available at: http://www.bbc.com/news/health-37588541. The magnitude and clinical meaningfulness of survival benefit in contemporary oncology trials have been under scrutiny, especially with the increases in variety and price of oncology drugs. By default, this assumes that the longest survival time is equal to the longest survival time in the data. Cherny NI, Dafni U, Bogaerts J, . p(#) specifies the percentile of survival time to be computed. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. J Clin Oncol 2016;34:2925–2934. Control Clin Trials 1986;7:177–188. the difference in RMST, the ratio of RMST and the ratio of … Manuscript writing: Rahmadian, Delos Santos, Cheung, Chan. Results: Ninety-four trials with a total of 51,639 patients were included. New York Times. Williams B. Immunotherapy: a game-changer for cancer treatment? Several regression‐based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model‐free method of taking the area under the survival function. We classified drugs as either immunotherapy or nonimmunotherapy based on recently published literature focusing on checkpoint inhibitors for purposes of consistency.21,27 RMST differences and ratios were meta-analyzed according to type of endpoint (PFS/OS) to estimate overall aggregate survival benefits, followed by subgroup analysis for immunotherapy and nonimmunotherapy and then comparison between immunotherapy and nonimmunotherapy. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. Verma S, Miles D, Gianni L, . Our meta-regression results showed that even after adjustment for potential covariates, the magnitude of benefit of FDA-approved drugs in 2011 through 2017 did not seem to improve over the years, which is consistent with current literature. Waterfall plots were created to visualize RMST values between immunotherapy and nonimmunotherapy trials (supplemental eFigures 11–14). Saluja R, Arciero VS, Cheng S, . Lancet 2016;387:1837–1846. Section ‘A strategy fordesignandanalysis of clinicaltrials’discusses our pro- … N Engl J Med 2016;375:754–766. N Engl J Med 2010;363:711–723. Available at: https://www.cnn.com/2017/06/02/health/immunotherapy-cancer-debate-explainer/index.html. This allows to link your profile to this item. Huang B, Kuan PF. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer—PROSELICA. Brahmer J, Reckamp KL, Baas P, . Note that because PFS events happen sooner than deaths, the true additivity of the relationship, mean PFS + mean SPP = mean OS, may be obscured. There is a considerable body of methodological research about the restricted mean survival time as alternatives to the hazard ratio approach. All extracted trials were published in English. Multiple studies have measured the magnitude of clinical benefit using the ASCO Value Framework (ASCO-VF) and the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS).31,32 However, both frameworks have been criticized for portions of unclear grading criteria, which could lead to misinterpretations, discrepancies in measurement of clinical benefit, and low absolute concordance.14 Studies analyzing clinical benefit of FDA-approved drugs using these frameworks have concluded that most drugs did not have meaningful clinical benefit.33–35 Although these frameworks can be used to quantify benefits, clinicians would require an in-depth and detailed understanding of the intricacies of the framework algorithms to understand the possibilities that lead to a specific score (ASCO-VF) or grade (ESMO-MCBS), which may make the output less accessible to clinicians or decision-makers with respect to the underlying magnitude of survival benefit of oncology drugs. Fehrenbacher L, Spira A, Ballinger M, . Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. Funding: The Canadian Centre for Applied Research in Cancer Control (ARCC) received core funding from the Canadian Cancer Society Research Institute through grant 2105-703549. strmst2 performs k-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. Measures of RMST fully capture absolute and relative survival benefits presented in KM curves. Restricted mean survival time, a robust measure that represents the mean event-free survival time in a prespecified period, may provide useful information on treatment effect that complements conventional measures of relative and absolute risk reductions. With various studies showing a steady increase in the cost and variety of novel oncology drugs, the benefits associated with these drugs are not necessarily following the same upward trend.14–16, Restricted mean survival time (RMST) is increasingly being recognized as a robust and clinically interpretable summary measure alternative to HR and median survival time because it directly quantifies information of the entire observed survival curve.7,17 RMST is defined as the area under the KM curve up to a specific time point (t), which is the follow-up time of the study.18,19 Because this measure takes the average (ie, mean, not median) to summarize the entire survival profile, it does not rely on the proportional hazards assumption and captures the benefit across the entire trial.6,19 RMST difference is the difference between the area under the KM curve of the treatment arm and the control arm, and has been proposed as a measure of absolute survival benefit as an alternative to median survival time.6 RMST ratio is the ratio of the RMSTs between the treatment arm and the control arm.7 An RMST ratio >1 shows an improvement in survival in the treatment arm. September 27, 2017. Hodi FS, O’Day SJ, McDermott DF, . http://fmwww.bc.edu/repec/bocode/s/strmst2.ado, http://fmwww.bc.edu/repec/bocode/s/strmst2.sthlp, http://fmwww.bc.edu/repec/bocode/s/strmst2pw.ado, http://fmwww.bc.edu/repec/bocode/s/strmst2pw.sthlp, http://fmwww.bc.edu/repec/bocode/s/strmst2_example.do, http://fmwww.bc.edu/repec/bocode/p/pbc.dta, STRMST2: Stata module to compare restricted mean survival time. The restricted mean survival time (RMST) is an alternative treatment outcome measure that can be estimated as the area under the survival curve up to a prespecified time horizon and hence can account for all survival information before that time horizon. The package calculates the study sample size and power in designing clinical trials using the difference in restricted mean survival time (RMST). We conducted this meta-analysis by identifying a list of immunotherapy and nonimmunotherapy oncology drugs approved by the FDA from January 2011 through November 2017 through a search of the Hematology/Oncology (Cancer) Approvals & Safety Notifications page on the FDA website (2016–2017 notifications) and archives (2011–2015 notifications).23 Notifications regarding marketing approvals, drug packaging changes, optical imaging agents, tests, treatments for adverse effects, biosimilars, nononcologic conditions, and announcements were excluded from our search. I encountered some issues when calculating restricted mean survival time (RMST) in R and I made some attempts. Summary statistics of included trials are shown in Table 1. You can help correct errors and omissions. Eisenberger M, Hardy-Bessard AC, Kim CS, . Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer. 1 n ∫ ˝ 0 {∫ ˝ t S(u)du}2 h(t)dt P (U t): Forest plots were generated to illustrate OS and PFS absolute and relative survival benefits (supplemental eFigures 7–10). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Marcus R, Davies A, Ando K, . Our study is not without limitations. Uno H, Tian L, Cronin A, . Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer. Conversely, the adjusted absolute survival benefit for PFS was 1.28 months less for immunotherapy than for nonimmunotherapy (1.99 vs 3.27 months, respectively; P=.02) (supplemental eTable 4). US Food & Drug Administration. Etzioni R, Gulati R, Lin DW. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. After the process of selection for clinical trials (Figure 1), 94 trials representing 66 drugs with a total of 51,639 patients were included. Immunotherapy trials sometimes exhibit nonproportional hazards, often because of late postprogression benefit (ie, after median survival times) or nonuniform divergence of the survival curves with potential plateau of the immunotherapy arm, with some trials even exhibiting crossing of survival curves.9–13 Median survival time also does not account for the “tail of the curve,” where the benefit of immunotherapy is more pronounced. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. October 9, 2016. The routine reporting and use of RMST may assist patients, physicians, and payers in making more informed and responsible decisions regarding the healthcare of patients with cancer. Motzer RJ, Escudier B, McDermott DF, . BBC. N Engl J Med 2017;376:1015–1026. Description Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. It is estimable even under heavy censoring in restricted mean survival time, is. Of RECIST to measure response to immunotherapy drugs provide a greater survival benefit in cancer drug development their. Model used for all analyses was random effects as well as unadjusted for... 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