The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics

Menis, Jessica; Litière, Saskia; Tryfonidis, Konstantinos; Golfinopoulos, Vassilis

doi:10.21037/atm.2016.06.19

Cited by 17 publications

(14 citation statements)

References 77 publications

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“…Since many ICBs have entered mainstream oncology in the last few years, their use in patients that were treated with IR has become common. Many retrospective studies that analyzed the interaction between IR and ICBs found at least some evidence of abscopal responses, but in cancers responsive to ICBs it cannot be ruled out that these responses reflect a later activity of the immunotherapy itself, which can manifest slowly [71]. Two retrospective studies are of particular interest in supporting the hypothesis that IR can increase responses to ICB: one study analyzed 98 NSCLC patients treated in a pembrolizumab trial and found that progression-free survival was significantly longer in patients who previously received radiotherapy than in patients who did not [72].…”

Section: Partnership Of Radiotherapy and Immunotherapymentioning

confidence: 99%

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

Rodríguez-Ruiz

Vanpouille-Box

Melero

et al. 2018

Trends in Immunology

377

289

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Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.

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Section: Partnership Of Radiotherapy and Immunotherapymentioning

confidence: 99%

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

Rodríguez-Ruiz

Vanpouille-Box

Melero

et al. 2018

Trends in Immunology

377

289

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“…However, nonproportional hazards situations are increasingly common in clinical trials. One area is cancer immunotherapies targeting immune cells instead of targeting the cancer cell, as did traditional chemotherapies and targeted therapies (eg, Menis et al). Many clinical trials have shown that immunotherapy as a monotherapy generally has (a) a delayed treatment effect (ie, the survival curves overlap at the start of the study and then separate) and (b) a durable anticancer effect, resulting in a long, flat tail of the survival curve (eg, Huang).…”

Section: Use Of the Win Ratio With Nonproportional Hazardsmentioning

confidence: 99%

The win ratio: Impact of censoring and follow‐up time and use with nonproportional hazards

Dong¹,

Huang

Chang³

et al. 2019

Pharmaceutical Statistics

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The win ratio has been studied methodologically and applied in data analysis and in designing clinical trials. Researchers have pointed out that the results depend on follow-up time and censoring time, which are sometimes used interchangeably. In this article, we distinguish between follow-up time and censoring time, show theoretically the impact of censoring on the win ratio, and illustrate the impact of follow-up time. We then point out that, if the treatment has long-term benefit from a more important but less frequent endpoint (eg, death), the win ratio can show that benefit by following patients longer, avoiding masking by more frequent but less important outcomes, which occurs in conventional time-to-first-event analyses. For the situation of nonproportional hazards, we demonstrate that the win ratio can be a good alternative to methods such as landmark survival rate, restricted mean survival time, and weighted log-rank tests. KEYWORDS hazard ratio, landmark survival rate, log-rank test, prioritized pairwise comparisons, restricted mean survival time 1 | INTRODUCTIONMuch interest has focused on composite time-to-event endpoints when the component outcomes can be prioritized according to their clinical importance. The win ratio 1 takes into account the clinical importance order among the components, and its simple and intuitive derivation make it attractive, compared with other methods for prioritized multiple outcomes such as weighted composites and rank tests. The net benefit 2-4 (proportion in favor of treatment) is the difference in win proportion between the two groups, so the two methods are closely related.The win ratio method has received much attention in methodological research. 5-14 One possible drawback is that it depends on follow-up time and censoring. [5][6][7][8]15 To reduce the impact of censoring (or follow-up) time, Oakes 7 proposed to calculate the win ratio from the time-to-event information as of a common time, c. Further, Rauch et al 16 argued that the win ratio should not be used in the presence of censoring, and they gave an illustrative example under proportional hazards (see Section 5.2 of Rauch et al 16 ). Also, some discussions of the win ratio have used censoring time and followup time interchangeably in a broad sense.In practice, the win ratio method has been used for many retrospective analyses of clinical trials and applied in study designs. In particular, together with the Finkelstein-Schoenfeld test, 17 the win ratio was used in the primary analysis for the tafamidis Phase III transthyretin amyloid cardiomyopathy (ATTR-ACT) study. 18,19 On the composite primary endpoint of all-cause mortality and frequency of cardiovascular(CV)-related hospitalization, the (stratified) win ratio

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“…The melanoma trial of tremelimumab versus chemotherapy mentioned in the Methods section is sometimes taken as a prime example of the problematic nature of futility monitoring when there is a delayed treatment effect 3,11 : The trial was stopped for futility at the second interim analysis (when 340 deaths had occurred) and the OS HR was 0.96. 21 However, little harm was done by this early stopping (performed 8 months after the last patient was enrolled), because the investigators were able to perform the regularly scheduled final analysis when there were 534 deaths, observing an OS HR of 0.88 (P = .127).…”

Section: Discussionmentioning

confidence: 99%

Interim Futility Monitoring Assessing Immune Therapies With a Potentially Delayed Treatment Effect

Korn

Freidlin

2018

JCO

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Purpose Introduction of new immune therapies that may have a delayed beneficial effect necessitates re-evaluation of traditional clinical trial designs in oncology. A key design feature of randomized trials is interim futility monitoring, which allows stopping early if the accruing data convincingly demonstrate that the experimental treatment is detrimental or is unlikely to be shown superior to the standard treatment. The appropriateness of futility monitoring is frequently questioned when the effect of the experimental treatment may be delayed (eg, in trials of many immune agents). We examine the advisability of using futility monitoring when there is potential for a delayed treatment effect and make recommendations concerning its use. Methods We evaluated the loss of statistical power when using some common futility interim monitoring rules and a new proposed conservative rule via simulation under varying amounts of treatment-effect delay and varying accrual periods. We also considered scenarios where the experimental treatment starts out being worse than the standard treatment but ends up being better, as may sometimes be the case when an immune therapy is compared with an active standard therapy. Results Some standard methods of futility monitoring can result in an unacceptable loss of power when there is a delayed treatment effect, especially if the accrual period is rapid or the experimental treatment is initially worse. The proposed conservative futility rule has a negligible loss of power in the situations considered. Conclusion Although care must be taken with the choice of futility monitoring when there is a delayed treatment effect, inclusion of appropriate rules can reduce the exposure of patients to ineffective therapies without reducing the probability of correctly identifying effective treatments.

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The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics

Cited by 17 publications

References 77 publications

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

The win ratio: Impact of censoring and follow‐up time and use with nonproportional hazards

Interim Futility Monitoring Assessing Immune Therapies With a Potentially Delayed Treatment Effect

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