Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer

Liang, Fei; Zhang, S.; Wang, Q.; Li, W.

doi:10.1093/annonc/mdy075

Cited by 45 publications

(38 citation statements)

References 38 publications

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“…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.…”

Section: Introductionmentioning

confidence: 81%

“…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 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 metaanalysis.…”

Section: Introductionmentioning

confidence: 81%

“…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. Inverse variance was used as the statistical method, with random effects as the model of analysis.…”

Section: Meta-analysismentioning

confidence: 99%

“…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 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 metaanalysis. We further aimed to compare whether immunotherapy drugs provide a greater survival benefit than nonimmunotherapy drugs.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Rahmadian

Santos

Parshad

et al. 2020

Journal of the National Comprehensive Cancer Network

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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. 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. 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. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders. Results: Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32–1.77) and 2.99 months for PFS (95% CI, 2.65–3.33). 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 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). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders. Conclusions: Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. 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.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 81%

Section: Meta-analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Rahmadian

Santos

Parshad

et al. 2020

Journal of the National Comprehensive Cancer Network

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“…However, non-proportional hazards have been frequently reported in ICI trials due to the long-term survival and delayed clinical effect [57,58]. Complementary methods to evaluate treatment effects such as the ratio of restricted mean survival time should be anticipated in pre-planned statistical analyses [59,60].…”

Section: Choosing the Most Accurate Statistical Methodsmentioning

confidence: 99%

Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future

Cohen

André

2020

Cancers

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Immune checkpoint inhibitors (ICI) have reshaped therapeutic strategies for cancer patients. The development of ICI for early stage colorectal cancer is accompanied by specific challenges: (i) the selection of patients who are likely to benefit from these treatments, i.e., patients with tumors harboring predictive factors of efficacy of ICI, such as microsatellite instability and/or mismatch repair deficiency (MSI/dMMR), or other potential parameters (increased T cell infiltration using Immunoscore® or others, high tumor mutational burden, POLE mutation), (ii) the selection of patients at risk of disease recurrence (poor prognostic features), and (iii) the choice of an accurate clinical trial methodological framework. In this review, we will discuss the ins and outs of clinical research of ICI for early stage MSI/dMMR CC patients in adjuvant and neoadjuvant settings. We will then summarize data that might support the development of ICI in localized colorectal cancer beyond MSI/dMMR.

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Correcting the Conclusion in a Study of Frameworks for Measurement of Absolute or Clinical Benefit—In Reply

2019

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To the Editor Saluja et al 1 evaluated the correlation of the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the American Society of Clinical Oncology's Value Framework (ASCO-VF) with absolute and relative survival measures, including the algorithmically calculated restricted mean survival time (RMST) derived from published Kaplan-Meier curves. Their conclusion regarding the shared inadequacy of ASCO-VF and ESMO-MCBS is based heavily on an unsubstantiated premise regarding RMST as a gold standard for evaluating survival benefit, and it is inconsistent with the results.Comparison of an established scale to an efficacy measure that is not a gold standard cannot confirm or annul the scale's value. 2 Despite its merits, RMST is not a gold standard measure; it is not incorporated into the CONSORT statement, not routinely measured and reported, and its value as an efficacy measure tested in place of the hazard ratio (HR) remains under investigation. 3 Furthermore, the calculation of RMST derived from Kaplan-Meier curves is prone to error, especially in view of the low-resolution images and the internal variability of the extraction software used. Indeed, the mean absolute relative difference between our RMST calculations (R UD ) and the authors' (R S ) is not trivial (mean[|R UD -R S |/ R S ] = 14%).In contrast, ESMO-MCBS version 1.1 scores are calculated without ambiguity in a transparent and reproducible manner based on published and readily available data and the CONSORT requirements. 4,5 Scores reflect both absolute and relative benefit, prognostic weighting and adjustments accounting for nonproportionate gains (particularly at the tail of the curve). The moderate correlation between a composite measure to one of its components (eg, ESMO-MCBS to median survival) reflects that the composite includes additional independent information, providing further credence to the ESMO-MCBS.In addition, we note 3 further issues: ESMO-MCBS scoring was incorrect for 15 of the 79 studies, despite online availability of correct scores for 10 of 15 studies (https://www.esmo. org/Guidelines/ESMO-MCBS). Second, because HR is the only survival benefit component of ASCO-VF, the correlation of a measure with itself (HR to HR), with the reported correlation of 1, is a futile comparison. Finally, the conflation between the ESMO-MCBS and the ASCO-VF in the conclusion is not consistent with the presented data that highlighted the substantially better correlation to RMST of the ESMO-MCBS version 1.1 plus tail of the curve (moderate ρ = 0.67) in contrast to that of the ASCO-VF (weak ρ = 0.40).

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Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer

Abstract: Ratio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.

Cited by 45 publications

References 38 publications

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time

Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future

Correcting the Conclusion in a Study of Frameworks for Measurement of Absolute or Clinical Benefit—In Reply

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