We consider the design of such trials according to a wide range of possible survival distributions in the control and research arm (s). Background: Restricted mean survival time is a measure of average survival time up to a specified time point. Previous presentation: An abstract of this study was presented at the 2018 ASCO Annual Meeting, June 1–8, 2018, in Chicago, Illinois (Abstract 6617), and the Canadian Centre for Applied Research in Cancer Control 7th Annual Conference, May 27–28, 2018, in Montreal, Quebec (Abstract 131). Nevertheless, our findings represent the totality of the evidence from the directly observed survival data that were available for decision-making at the time of FDA approval. Recent studies have questioned whether the magnitude of benefit of FDA-approved contemporary oncology drugs has been increasing over time, just as their costs have been. Overall, absolute survival benefits of recent oncology drugs are modest. Urol Oncol 2015;33:122–127. BBC. Fundamental aspects of this approach are captured here; detailed overviews of the RMST methodology are provided by Uno and colleagues.16., 17. Lenalidomide after stem-cell transplantation for multiple myeloma. the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Waterfall plots were created to visualize RMST values between immunotherapy and nonimmunotherapy trials (supplemental eFigures 11–14). Results were considered statistically significant if the P value was. J Clin Oncol 2016;34:2925–2934. You can help adding them by using this form . 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. An algorithm developed by Guyot et al25 to solve the inverted KM equations was applied to reconstruct pseudo-individual patient data files based on the KM curves6,8,19,22 and to calculate the RMST of experimental and control arms, RMST difference, RSMT ratio, and their 95% confidence intervals.26 RMST estimates were truncated at the time point (t) of the KM curves, which is defined as the minimum of the largest observed survival time between the treatment and control arms.18,19 Extraction of curve coordinates and RMST calculations were independently performed by 2 reviewers. Biometrika 1994;81:515–526. September 27, 2017. Available at: https://CRAN.R-project.org/package=survRM2. Results: Ninety-four trials with a total of 51,639 patients were included. Williams B. Immunotherapy: a game-changer for cancer treatment? Lugowska I, Teterycz P, Rutkowski P. Immunotherapy of melanoma. Restricted mean survival time is a measure of average survival time up to a specified time point. Conventional measures of survival benefit have clinical limitations that were previously overlooked in immunotherapy trials.7, An interpretable and robust measure of clinical efficacy in survival analyses is critical to capture the full context of the benefits of oncology drugs and to make more informed decisions about the cost versus benefit of treatment options. Note that because PFS events happen sooner than deaths, the true additivity of the relationship, mean PFS + mean SPP = mean OS, may be obscured. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. Eisenberger M, Hardy-Bessard AC, Kim CS, . Immunotherapy cancer drug hailed as ‘game changer’. For example, p(25) will compute the 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? Mean overall absolute survival benefits in contemporary oncology drugs seem to be only modest for OS (1.6 months), with a slightly higher benefit in PFS (3 months). Pak K, Uno H, Kim DH, . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer. 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. The package calculates the study sample size and power in designing clinical trials using the difference in restricted mean survival time (RMST). The difference in restricted mean survival times (RMSTs) up to a pre‐specified time point is an alternative measure that offers a clinically meaningful interpretation. Hematology/Oncology (cancer) approvals & safety notifications. 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). Regression analysis of restricted mean survival time based on pseudo-observations. Unlike median survival time, it is estimable even under heavy censoring. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. The adjusted relative survival benefit for OS was higher for immunotherapy than for nonimmunotherapy by a factor of 1.08 (P=.01) (supplemental eTable 5). Data review and statistical analyses: Rahmadian, Delos Santos. Our study is not without limitations. Improved survival with ipilimumab in patients with metastatic melanoma. J Oncol Pract 2018;14:e280–e294. Clinical trials used by the FDA for drug approval were recorded and retrieved from a PubMed search. Accessed April 27, 2018. Sensitivity analyses for melanoma, NSCLC, and nonmelanoma and non-NSCLC subgroups (supplemental eFigures 15–20) produced results similar to those of the primary analyses, which showed that immunotherapy had greater absolute survival benefit in OS and less absolute survival benefit in PFS. JAMA Oncol 2017;3:1692–1696. Background: Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Lancet 2016;387:1540–1550. Brahmer J, Reckamp KL, Baas P, . Data interpretation: Chan. Available at: https://www.cnn.com/2017/06/02/health/immunotherapy-cancer-debate-explainer/index.html. Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? For PFS, immunotherapy showed less absolute PFS benefit than nonimmunotherapy by 1.67 months (1.56 months [95% CI, 1.02–2.09] vs 3.23 months [95% CI, 2.85–3.61], respectively; PFigures 2 and 3). After adjusting for potential confounders, mean absolute survival benefit of immunotherapy is only approximately 1 month greater than nonimmunotherapy in OS and approximately 1 month less than nonimmunotherapy in PFS. survival data are often quite skewed with long right tails, the restricted mean survival or the median survival time are generally preferred as summary statistics. Hodi FS, Hwu WJ, Kefford R, . Sutradhar R, Austin PC. Meta-analyses demonstrated that overall aggregate absolute survival benefits, measured using RMST difference, showed additional benefit in the experimental arms over the control arms by 1.55 months (95% CI, 1.32–1.77) for OS and 2.99 months (95% CI, 2.65–3.33) for PFS (Figure 2). 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. Methods: Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. Grambsch PM, Therneau TM. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. If the inline PDF is not rendering correctly, you can download the PDF file here. J Clin Oncol 2016;34:1510–1517. With this method, the treatment effect is defined as the difference in restricted mean between the trial arms. Contrary to popular belief that immunotherapy provides much more benefit than nonimmunotherapy, our findings suggest that observed survival benefits of immunotherapy were not dramatically superior to those of nonimmunotherapy. J Clin Oncol 2016;34:1813–1819. If discrepancies greater than the margin of error were found, the 2 reviewers repeated the extraction and calculation process to determine the reason for the discrepancy. See general information about how to correct material in RePEc. Three kinds of between-group constrast metrics (i.e. Marcus R, Davies A, Ando K, . JAMA Oncol 2015;1:539–540. Accessed March 12, 2018. Abbreviations: KM, Kaplan-Meier; PFS, progression-free survival; OS, overall survival. Meta-analysis results of RMST difference (absolute survival benefit). Author contributions: Study design: Everest, Chan. Tibau A, Molto C, Ocana A, . Ann Epidemiol 2018;28:54–57. Association of immunotherapy with durable survival as defined by value frameworks for cancer care. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for those measures. Available at: Williams B. Immunotherapy: a game-changer for cancer treatment? Uno H, Claggett B, Tian L, . strmst2pw is a postestimation command that can be used after strmst2 with the covariates option specified, and summarizes pairwise comparisons for the previous analysis. Summary statistics of included trials are shown in Table 1. 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. Nat Rev Clin Oncol 2018;15:268–270. Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09–1.13) and 1.42 for PFS (95% CI, 1.36–1.48). 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. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. Available at: Association of immunotherapy with durable survival as defined by value frameworks for cancer care, New modalities of cancer treatment for NSCLC: focus on immunotherapy, Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received, ESMO–Magnitude of Clinical Benefit Scale version 1.1, Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000-2015. Of the 94 included trials, proportional hazards assumption was found to be violated in 45 trials; 9 (69%) of the immunotherapy trials and 36 (44%) of the nonimmunotherapy trials were found to have nonproportional hazards. ODS Graphics must be enabled for graphs to be produced. 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. 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). All extracted trials were published in English. Nivolumab versus everolimus in advanced renal-cell carcinoma. Hope and hype around cancer immunotherapy. After the process of selection for clinical trials (Figure 1), 94 trials representing 66 drugs with a total of 51,639 patients were included. In addition, because of the crossing of survival curves in some immunotherapy trials,9–13 a subgroup of patients (eg, those with rapidly progressive disease) could seem to benefit more from cytotoxic therapy than immunotherapy, which shows its benefits later. Ann Oncol 2017;28:1111–1116. Lifetime Data Anal 2004;10:335–350. Available at: https://www.forbes.com/sites/oppenheimerfunds/2016/09/26/immunotherapy-game-changer-for-cancer-treatment/#4c93b67f19d7. Trinquart L, Jacot J, Conner SC, . The limitations of RECIST to measure response to immunotherapy drugs is also a potential limitation. N Engl J Med 2017;376:1015–1026. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation. Forest plots were generated to illustrate OS and PFS absolute and relative survival benefits (supplemental eFigures 7–10). the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. For relative survival benefit measures, HRs rely on the proportional hazards assumption, which depends on the number of observed events and not directly on exposure times or sample size of the study.6 HRs also may vary with time and thus violate the proportional hazards assumption.7,8 When the proportional hazards assumption is violated, the HR estimate may not be a statistically valid measurement of the treatment effect and becomes difficult to interpret clinically. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. 1,2 In this article, we discuss the advantages of an alternative analytical procedure based on the restricted mean survival time (RMST) 1,2 via 3 examples. Magnitude of clinical benefit of cancer drugs approved by the US Food and Drug Administration. Here, we propose the use of the restricted mean survival time at a prespecified, fixed time point as a useful general measure to report the difference between two survival curves. Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. However, reporting survival benefits of immunotherapy using these measures is potentially challenging. Literature search and data extraction: Parshad, Everest. 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. Motzer RJ, Escudier B, McDermott DF, . Proportional hazards tests and diagnostics based on weighted residuals. Ann Oncol 2017;28:2340–2366. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. In recent years, immunotherapy has emerged as an alternative to chemotherapy and has been commonly viewed as a “game changer” for its potential to improve survival in a small proportion of patients.1–4 Randomized controlled trials often report measures of absolute survival benefit as differences in median survival times or differences in survival rates at specific times on Kaplan-Meier (KM) curves, whereas measures of relative survival benefit are reported as hazard ratios (HRs). Fehrenbacher L, Spira A, Ballinger M, . JAMA Oncol 2018;4:326–332. Results: Twenty-five RCTs totaling 12 870 patients were included in this study. Hope and hype around cancer immunotherapy. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. Accessed March 12, 2018. Available at: http://www.bbc.com/news/health-37588541. Meta-analysis results of RMST ratio (relative survival benefit). J Clin Oncol 2016;34:786–793. 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. We further aimed to compare whether immunotherapy drugs provide a greater survival benefit than nonimmunotherapy drugs. Restricted mean survival time (RMST) is a useful summary measurement of the time-to-event data, and it has attracted great attention for its straight We use cookies to enhance your experience on our website.By continuing to use our website, you are agreeing to our use of cookies. Uno H, Wittes J, Fu H, . It provides a more easily understood measure of the treatment effect of an intervention in a controlled clinical trial with a time to event endpoint. 1 n ∫ ˝ 0 {∫ ˝ t S(u)du}2 h(t)dt P (U t): Comparison of the restricted mean survival time with the hazard ratio in superiority trials with a time-to-event end point. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Alternatives to hazard ratios for comparing the efficacy or safety of therapies in noninferiority studies. Hodi FS, O’Day SJ, McDermott DF, . Del Paggio JC, Azariah B, Sullivan R, . Forbes. J Clin Oncol 2012;30:3499–3506. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2015;373:123–135. DerSimonian R, Laird N. Meta-analysis in clinical trials. Only phase II/III randomized controlled trials with a primary endpoint of overall survival (OS) and/or progression-free survival (PFS) with published KM curves were included in this study. For example, if survival associated with a control arm were high, a “good” HR (such as 0.5) would still represent little relative survival gained (RMST ratio may be only 1.2 rather than 2.0 as one may incorrectly expect) (supplemental eFigure 1, available with this article at JNCCN.org). In addition, the varying patient populations among the immunotherapy and nonimmunotherapy trials is an inherent limitation in the comparison between the 2 types of treatment. 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. curve: the Restricted Mean Survival Time (RMST), the average survival time up to a given time point. Evidence of nonproportional hazards was examined for each curve using the Grambsch-Therneau test, with a P value 24. Our study quantified that contemporary oncology drugs give modest mean survival benefits of 1.6 months for OS and 3 months for PFS. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. You can help correct errors and omissions. BBC. Subgroup meta-analyses of immunotherapy versus nonimmunotherapy were conducted for melanoma and non–small cell lung cancer (NSCLC) because immunotherapy has been viewed as highly beneficial in these populations.29,30 Sensitivity analyses excluding those tumor sites were also conducted. survRM2: comparing restricted mean survival time. July 30, 2016. DigitizeIt software (version 2.3.3) was used to digitize published KM curves (OS and PFS). J Natl Cancer Inst 2018;110:486–492. Abbreviations: IV, inverse variance; OS, overall survival; PFS, progression-free survival; RMST, restricted mean survival time. 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.

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