Correlation of Milestone Restricted Mean Survival Time Ratio With Overall Survival Hazard Ratio in Randomized Clinical Trials of Immune Checkpoint Inhibitors

Abstract A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.

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The use of restricted mean survival time to estimate the treatment effect in randomized clinical trials when the proportional hazards assumption is in doubt

Statistics in Medicine ◽

10.1002/sim.4274 ◽

2011 ◽

Vol 30 (19) ◽

pp. 2409-2421 ◽

Cited By ~ 204

Author(s):

Patrick Royston ◽

Mahesh K. B. Parmar

Keyword(s):

Clinical Trials ◽

Survival Time ◽

Treatment Effect ◽

Randomized Clinical Trials ◽

Proportional Hazards ◽

Mean Survival Time ◽

Proportional Hazards Assumption ◽

Restricted Mean Survival Time

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41P Cardiotoxicity of immune checkpoint inhibitors: A meta-analysis of randomized clinical trials

Annals of Oncology ◽

10.1016/j.annonc.2020.10.528 ◽

2020 ◽

Vol 31 ◽

pp. S1432

Author(s):

E. Agostinetto ◽

D. Eiger ◽

M. Lambertini ◽

M. Ceppi ◽

M. Bruzzone ◽

...

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis

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Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

10.20944/preprints201808.0307.v3 ◽

2018 ◽

Author(s):

Antonino Grassadonia ◽

Isabella Sperduti ◽

Patrizia Vici ◽

Laura Iezzi ◽

Davide Brocco ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Phase Iii ◽

Cochrane Central Register

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

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Infections in cancer patients treated with immune checkpoint inhibitors: Data from randomized trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2637 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2637-2637

Author(s):

Cinzia Solinas ◽

Anna Maria Morelli ◽

Andrea Luciani ◽

Antonio Ghidini ◽

Fausto Petrelli

Keyword(s):

Clinical Trials ◽

Cancer Patients ◽

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Trials ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Cochrane Library ◽

And Control

2637 Background: Febrile neutropenia and infections are well studied complications of chemotherapy (CT) and some targeted agents employed in oncology. Less is known about the risk of infection associated with the use of immune checkpoint inhibitors (ICIs) in cancer patients. The present systematic review and meta-analysis was performed to address this question in patients diagnosed with solid tumors enrolled in randomized trials employing ICIs as experimental treatment. Methods: The Cochrane Library, EMBASE, and Pubmed databases were searched from inception through December 1st, 2020. Randomized clinical trials comparing any ICI alone, with CT, or with other agents vs CT, placebo, or other agents in patients with solid tumors were included. Two independent reviewers used a standardized data extraction and quality assessment form. Discordant cases were discussed with a third independent investigator. The following information was extracted: baseline study characteristics, including the primary tumor, author, year of publication, type of trial, type of disease, and the type of therapy (experimental and control arms); and the incidence of any-grade (grades [G] 1–5), low-grade (G1–2), and high-grade (G3–4), fatal event (G5) infections, and type of event. Random or fixed-effect models were used according to the statistical heterogeneity. Results: 36 randomized clinical trials were deemed eligible. The total population reached 21451 patients. In the pooled analysis, the use of ICIs was associated with a similar risk of all-grade infections (relative risk, RR = 1.02; 95% CI 0.84–1.24; P = 0.85) compared to non-ICI treatments (G1-5 events: 9.6 vs. 8.3%). When the ICIs alone arms were compared to CT, the experimental arms were associated with a 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85; P = 0.01; N = 18 studies). Compared to CT, the combination of ICIs and CT increased the risk of all-grade infections (RR = 1.37, 95% CI 1.23–1.53; P < 0.01; N = 13 studies) and severe infections (RR = 1.52, 95% CI 1.17–1.96; P < 0.01; N = 12 studies). Fatal infections were similar in the experimental and control arms (0.5%). Conclusions: In patients with advanced solid tumors, when ICIs were administered with CT, the risk of all-grade and G3-5 infections was significantly increased. Compared to CT alone, ICIs were safer and their use should be recommended for frail patients. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors use.

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Cardiovascular toxicity incidence following immune checkpoint inhibitors in randomized clinical trials: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2636 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2636-2636

Author(s):

Camila Bragança Xavier ◽

Carlos Diego Holanda Lopes ◽

Guilherme Harada ◽

Artur Katz ◽

Denis Leonardo Fontes Jardim

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Best Supportive Care ◽

Phase Iii ◽

Increased Risk ◽

Meta Analyses

2636 Background: Immune checkpoint inhibitors (ICIs) are widely used in oncology and may be associated with a variety of immune-related toxicities. Cardiovascular (CV) adverse effects (AEs) are underreported in randomized clinical trials (RCTs), and the real risk associated with ICIs use has yet to be defined. Therefore, we aimed to investigate the incidence and risk of cardiovascular toxicities in patients receiving ICIs, using an up-to-date meta-analysis of prospective RCTs. Methods: We conducted a systematic search of the literature from January 1st, 2010 until July 1st, 2020 to identify RCTs testing ICIs for solid tumors, either in monotherapy or in combination between them. Our initial search yielded a total of 21,249 relevant publications. For CV AEs incidence estimation, we included phase III RCTs testing PD-1, PD-L1, CTLA-4 inhibitors or any combination of these agents. For relative risk (RR) assessment, we included phase II or phase III RCTs testing the same agents and with placebo or best supportive care (BSC) as the comparator. Data were extracted by independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. CV AEs were categorized based on the Common Toxicity Criteria (CTCAE) and stratified by ICIs type. Analyses were conducted using random effects model. Results: After screening and eligibility assessment, a total of 21,118 patients (67 cohorts from 57 trials) were available for this meta-analysis. We categorized the cohorts by ICIs regimen as monotherapy with a PD-1 inhibitor (35 cohorts; 10,241 patients), PD-L1 inhibitor (12 cohorts; 3,755 patients), CTLA-4 inhibitor (11 cohorts; 4,135 patients), and combination therapy (9 cohorts; 2,987 patients). Incidence measures are described in the table. Deaths from any CV cause occurred in 0.20% of the patients (95%CI 0.10%; 0.20%). For RR analysis, we included 12 cohorts from 11 RCTs. Risk of experiencing all grade AEs was numerically higher among patients who received ICIs than placebo or BSC (RR 1.16; 95%CI 0.98; 1.37; p=0.09). When only grade 3-5 CV AEs were considered, ICIs were associated with increased risk (RR 1.36; 95%CI 1.06; 1.73; p= 0.01). Additional analyses were conducted to estimate the RR of individual CV AEs including arrhythmia, cardiac arrest, heart failure, stroke, hypertension, myocardial infarction, myocarditis, pericardial events, and thromboembolic events. None of the analysis identified a significant additional risk. Conclusions: This meta-analysis corroborates the preclinical rationale of worsen CV risk related to ICIs use.[Table: see text]

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Restricted mean survival time: Does covariate adjustment improve precision in randomized clinical trials?

Clinical Trials ◽

10.1177/1740774518759281 ◽

2018 ◽

Vol 15 (2) ◽

pp. 178-188 ◽

Cited By ~ 4

Author(s):

Theodore Karrison ◽

Masha Kocherginsky

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Survival Time ◽

Treatment Effect ◽

Randomized Clinical Trials ◽

Linear Models ◽

Covariate Adjustment ◽

Survival Times ◽

Mean Survival Time ◽

Restricted Mean Survival Time

Background: Restricted mean survival time is a measure of average survival time up to a specified time point. There has been an increased interest in using restricted mean survival time to compare treatment arms in randomized clinical trials because such comparisons do not rely on proportional hazards or other assumptions about the nature of the relationship between survival curves. Methods: This article addresses the question of whether covariate adjustment in randomized clinical trials that compare restricted mean survival times improves precision of the estimated treatment effect (difference in restricted mean survival times between treatment arms). Although precision generally increases in linear models when prognostic covariates are added, this is not necessarily the case in non-linear models. For example, in logistic and Cox regression, the standard error of the estimated treatment effect does not decrease when prognostic covariates are added, although the situation is complicated in those settings because the estimand changes as well. Because estimation of restricted mean survival time in the manner described in this article is also based on a model that is non-linear in the covariates, we investigate whether the comparison of restricted mean survival times with adjustment for covariates leads to a reduction in the standard error of the estimated treatment effect relative to the unadjusted estimator or whether covariate adjustment provides no improvement in precision. Chen and Tsiatis suggest that precision will increase if covariates are chosen judiciously. We present results of simulation studies that compare unadjusted versus adjusted comparisons of restricted mean survival time between treatment arms in randomized clinical trials. Results: We find that for comparison of restricted means in a randomized clinical trial, adjusting for covariates that are associated with survival increases precision and therefore statistical power, relative to the unadjusted estimator. Omitting important covariates results in less precision but estimates remain unbiased. Conclusion: When comparing restricted means in a randomized clinical trial, adjusting for prognostic covariates can improve precision and increase power.

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