Pembrolizumab as second-line therapy for advanced urothelial carcinoma. Demetri GD, von Mehren M, Jones RL, . Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. Everest L, Shah M, Chan KKW. Note that because PFS events happen sooner than deaths, the true additivity of the relationship, mean PFS + mean SPP = mean OS, may be obscured. See general information about how to correct material in RePEc. 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. DerSimonian R, Laird N. Meta-analysis in clinical trials. 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. September 27, 2017. Because existent measures of survival benefits often have limitations, particularly in immunotherapy trials, we recommend that RMST values be reported alongside the conventional measures to provide a more complete and realistic picture of the survival benefits of oncology drugs. Del Paggio JC. Tibau A, Molto C, Ocana A, . JAMA Oncol 2015;1:539–540. 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. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. October 9, 2016. Available at: https://www.nytimes.com/2016/07/31/health/harnessing-the-immune-system-to-fight-cancer.html. ODS Graphics must be enabled for graphs to be produced. US Food & Drug Administration. 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. 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. The margin of error agreed on was RMST values ±1 week a priori. The difference between two arms in the restricted mean survival time is an alternative to the hazard ratio. Because RMST methods seem to be a reasonable alternative approach to measure survival benefits to overcome limitations of conventional measures, our study aimed to quantify the magnitude of survival benefit in oncology drugs recently approved by the FDA, using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit) in a meta-analysis. Four separate meta-regression analyses for the following endpoints were conducted: OS RMST differences, OS RMST ratios, PFS RMST differences, and PFS RMST ratios. 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. In this paper, we discuss the calculation of RMST at any given time point (up to the largest observation) using PROC LIFETEST. However, reporting survival benefits of immunotherapy using these measures is potentially challenging. This suggests the need for future research of immunotherapy biomarkers and clinicopathologic predictors to allow better selection of patients for immunotherapy. Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? 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. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. All material on this site has been provided by the respective publishers and authors. We further aimed to compare whether immunotherapy drugs provide a greater survival benefit than nonimmunotherapy drugs. Magnitude of clinical benefit of cancer drugs approved by the US Food and Drug Administration. Theoretical aspects of RMST (or Kaplan–Meier integrals) are well studied [5–7] and currently RMST is experiencing a renaissance [8–10] being hailed as a model-free, easy to interpret statistic with implications in causal inference [11]. Also, RSMT difference and ratio may or may not increase with longer follow-up, depending on whether there are substantial separations of the survival curves at the end of the follow-up. Waterfall plots were created to visualize RMST values between immunotherapy and nonimmunotherapy trials (supplemental eFigures 11–14). 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. Williams B. Immunotherapy: a game-changer for cancer treatment? Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. Eisenberger M, Hardy-Bessard AC, Kim CS, . Our study quantified that contemporary oncology drugs give modest mean survival benefits of 1.6 months for OS and 3 months for PFS. the various RePEc services. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received. New York Times. Hematology/Oncology (cancer) approvals & safety notifications. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. Etzioni R, Gulati R, Lin DW. 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. However, the percentage of patients estimated to respond to checkpoint inhibitor drugs was 0.14% in 2011 and increased to 12.46% in 2018.38 Although the benefit of immunotherapies has been shown to be more significant in subgroups of patients with certain cancer types (ie, melanoma and NSCLC29,30), there is a paucity of data comparing the magnitude of immunotherapy versus nonimmunotherapy options. BMC Med Res Methodol 2013;13:152. Van Cutsem E, Tabernero J, Lakomy R, . 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. Furthermore, the benefit, on average, of all combined nonimmunotherapies using RMST was marginal. When requesting a correction, please mention this item's handle: RePEc:boc:bocode:s458154. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for those measures. Mailankody S, Prasad V. Five years of cancer drug approvals: innovation, efficacy, and costs. If the inline PDF is not rendering correctly, you can download the PDF file here. Hematology/Oncology (cancer) approvals & safety notifications. N Engl J Med 2012;367:1783–1791. Marcus R, Davies A, Ando K, . 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. BBC. Available at: Proportional hazards tests and diagnostics based on weighted residuals, Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. Huang B, Kuan PF. Unlike median survival time, it is estimable even under heavy censoring. Available at: https://CRAN.R-project.org/package=survRM2. Our meta-regression results show that immunotherapies had only 0.91 months greater absolute survival benefit than nonimmunotherapies for OS and 1.28 months less absolute survival benefit than nonimmunotherapies for PFS, suggesting that, overall, the benefits are not as outstanding as presumed. US Food & Drug Administration. Cicènas S, Geater SL, Petrov P, . Forbes. Pharm Stat 2018;17:202–213. strmst2pw is a postestimation command that can be used after strmst2 with the covariates option specified, and summarizes pairwise comparisons for the previous analysis. You can help adding them by using this form . Cheng S, McDonald EJ, Cheung MC, . Bellmunt J, de Wit R, Vaughn DJ, . Subgroup analyses for immunotherapy versus nonimmunotherapy were performed to compare survival benefits. Accessed December 2017. Verma S, Miles D, Gianni L, . Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies. July 30, 2016. Restricted mean survival time (RMST) can provide additional insight to the survival distribution and is not subject to underestimation by definition. 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. Schnipper LE, Davidson NE, Wollins DS, . Of these trials, 13 were used for immunotherapy approval representing 4 immunotherapy drugs, and 81 were used for nonimmunotherapy approval representing 62 nonimmunotherapy drugs (supplemental eTable 1). ESMO–Magnitude of Clinical Benefit Scale version 1.1. Biometrika 1994;81:515–526. Examining trends in cost and clinical benefit of novel anticancer drugs over time. Restricted mean survival time ^ and ^ IPW are equivalent! Contemp Oncol (Pozn) 2018;22:61–67. Results: Ninety-four trials with a total of 51,639 patients were included. Meta-analyses of RMST differences and ratios were conducted using Review Manager software (version 5.3) to estimate overall absolute and relative survival benefits of the drugs and to compare those of immunotherapy versus nonimmunotherapy. The computational model used for all analyses was random effects. The objectives in a survival analysis may include estimation of one or more of these statistics at specified Changbin Guo discuss some new and dedicated features available in SAS/STAT 15.1 that let you analyze the restricted mean survival time (RMST). Ann Epidemiol 2018;28:54–57. The occurrence of crossovers was included as a covariate only for OS RMST difference and ratio analyses. 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). BBC. 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). Cherny NI, Dafni U, Bogaerts J, . Daratumumab, bortezomib, and dexamethasone for multiple myeloma. Accessed March 12, 2018. J Clin Oncol 2016;34:2925–2934. Ann Oncol 2017;28:2340–2366. JAMA Netw Open 2019;2:e192535. Three kinds of between-group constrast metrics (i.e. Obinutuzumab for the first-line treatment of follicular lymphoma. September 26, 2016. Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 3; 10.6004/jnccn.2019.7362. In contrast, for OS, immunotherapy showed a larger absolute survival benefit than nonimmunotherapy by 0.59 months (2.02 months [95% CI, 1.60–2.44] vs 1.43 months [95% CI, 1.18–1.68], respectively; P=.02) and marginally larger relative survival benefit than nonimmunotherapy (1.18 [95% CI, 1.14–1.23] vs 1.09 [95% CI, 1.07–1.11], respectively; P=.0006) (see Figures 2 and 3). 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). Ben-Aharon O, Magnezi R, Leshno M, . © 2019-2020 National Comprehensive Cancer Network. Public profiles for Economics researchers, Various rankings of research in Economics & related fields, Curated articles & papers on various economics topics, Upload your paper to be listed on RePEc and IDEAS, RePEc working paper series dedicated to the job market, Pretend you are at the helm of an economics department, Data, research, apps & more from the St. Louis Fed, Initiative for open bibliographies in Economics, Have your institution's/publisher's output listed on RePEc. July 30, 2016. Literature search and data extraction: Parshad, Everest. Association of immunotherapy with durable survival as defined by value frameworks for cancer care. Submitted May 1, 2019; accepted for publication September 18, 2019. Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer. Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw. Restricted mean survival time analysis. Decisions on finalized calculation results were made after discussion between reviewers. 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. 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). RMST summary statistics and their distributions are shown in supplemental eTable 2 and eFigures 2A and 2B, respectively. Guyot P, Ades AE, Ouwens MJ, . Measures of RMST fully capture absolute and relative survival benefits presented in KM curves. Pharm Stat 2018;17:202–213. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. Section ‘A strategy fordesignandanalysis of clinicaltrials’discusses our pro- … We describe different methods of estimating it and we illustrate its application to three RCTs in cancer. Lenalidomide after stem-cell transplantation for multiple myeloma. September 27, 2017. The package calculates the study sample size and power in designing clinical trials using the difference in restricted mean survival time (RMST). We have no references for this item. Comparison of long-term survival benefits in trials of immune checkpoint inhibitor vs non-immune checkpoint inhibitor anticancer agents using ASCO Value Framework and ESMO Magnitude of Clinical Benefit Scale. Pak K, Uno H, Kim DH, . N Engl J Med 2017;376:1015–1026. You can help correct errors and omissions. Meta-regression was conducted to adjust for potential confounders. Meta-regression was conducted using Comprehensive Meta-Analysis software (version 31; Biostat, Inc.) to assess and adjust for the confounding effects of covariates. the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. It has been shown that HR is a relative measure of the rate of death and tends to overestimate the relative survival benefit.4,8,21 Comparability of treatment effects of immunotherapy drugs between RMST ratios and HR estimates has also been shown to be in general agreement.21 It has been suggested that it may be useful to report RMST in immunotherapy trials, in which the benefit typically is at the tail of the curve.3,21,22. 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). Ferris RL, Blumenschein G Jr, Fayette J, . The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … Results were considered statistically significant if the P value was. Inverse variance was used as the statistical method, with random effects as the model of analysis.28 Forest plots were generated for meta-analyses of RMST differences and ratios for OS and PFS separately, including analytical results of overall benefits and subgroup benefits for immunotherapy and nonimmunotherapy. 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. Immunotherapy cancer drug hailed as ‘game changer’. First, if the KM curves extracted from published trials were of low quality, the accuracy of the RMST estimation may be affected. Background: Restricted mean survival time is a measure of average survival time up to a specified time point. curve: the Restricted Mean Survival Time (RMST), the average survival time up to a given time point. You can get the restricted mean survival time with print (km, print.rmean=TRUE). The variable Cell is specified in the STRATA statement to compute the RMST for each type of cancer cell. J Clin Oncol 2014;32:2380–2385. N Engl J Med 2016;375:1856–1867. 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. JAMA Netw Open 2019;2:e196803. It also allows you to accept potential citations to this item that we are uncertain about. and rmean (restricted mean) computes the mean survival time restricted to the longest follow-up time. Conclusions: Absolute survival benefits of recent oncology drugs are modest. New York Times. In the section ‘Restricted mean survival time (RMST)’, we describe the RMST and the corresponding standard deviation (RSDST) in general terms and specifically for a piecewise exponential distribution. 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. Brahmer J, Reckamp KL, Baas P, . N Engl J Med 2010;363:711–723. Howard J. Available at: Grady D. Harnessing the immune system to fight cancer. 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. Our study is not without limitations. N Engl J Med 2016;375:754–766. 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. J Natl Cancer Inst 2018;110:486–492. N Engl J Med 2015;372:142–152. This analytical approach utilizes the restricted mean survival time (RMST) or tau (τ)-year mean survival time as a summary measure. These studies have found that even though costs are consistently and rapidly increasing, the benefits do not necessarily follow the same trends.14–16 Although the variety of oncology drugs has increased over the years, these drugs do not necessarily provide increasing survival benefit. Body of methodological research about the restricted mean survival time is a measure of the and!, Jacot J, de Wit R, Arciero VS, cheng S, SL... Average, of all combined nonimmunotherapies using RMST was marginal Kaplan-Meier ; PFS, progression-free survival RMST... 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