Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high‐risk follicular lymphoma: CALGB 50904 (Alliance)

Blum, Kristie A.; Polley, Mei Yin; Jung, Sin Ho; Dockter, Travis; Anderson, Sarah; Hsi, Eric D.; Wagner‐Johnston, Nina D.; Christian, Beth; Atkins, Jim; Cheson, Bruce D.; Leonard, John P.; Bartlett, Nancy L.

doi:10.1002/cncr.32289

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…Five randomized studies (CALGB50904, 10 E2408, 11 FOLL05, 12,13 GALLIUM, 14 RELEVANCE 15 ) were included; four included rituximab during induction treatment (Table S1). The GALLIUM trial was split into three subunits according to chemotherapy regimen (CHOP n = 200, CVP n = 47, bendamustine n = 323) which was chosen by each enrolling site, and the RELEVANCE trial was split into two subunits based on sex (male n = 196, female n = 190) because all patients in the experimental arm received the R‐lenalidomide regimen.…”

Section: Resultsmentioning

confidence: 99%

End of induction positron emission tomography complete response (PET‐CR) as a surrogate for progression‐free survival in previously untreated follicular lymphoma

et al. 2022

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Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged followup. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [ 18 F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression (R 2 WLS) and bivariate Copula (R 2 Copula) models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation (R 2 WLS = 0.56, confidence interval [CI]: 0.20-0.88; R 2 Copula = 0.35, CI: 0.0-0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted.

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Section: Resultsmentioning

confidence: 99%

End of induction positron emission tomography complete response (PET‐CR) as a surrogate for progression‐free survival in previously untreated follicular lymphoma

et al. 2022

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“…To this end, it makes a distinction between the two potential censoring reasons, namely LTFU and administrative censoring. While Korn's paper is regularly cited in the literature by papers which analyze RCTs, the citation is typically used to refer to time to censoring (see, e.g., Blum et al 21 ). We are not aware of an actual computation of 6 in a trial.…”

Section: Quantities Used In the Literature To Quantify “Follow‐up”mentioning

confidence: 99%

“…Quantity 6, Korn's potential follow-up time, 20 is a generalization of time to censoring (Quantity 3) and estimates the probability to be under follow-up at a given time t. To this end, it makes a distinction between the two potential censoring reasons, namely LTFU and administrative censoring. While Korn's paper is regularly cited in the literature by papers which analyze RCTs, the citation is typically used to refer to time to censoring (see, e.g., Blum et al 21 ). We are not aware of an actual computation of 6 in a trial.…”

Section: Quantities Used In the Literature To Quantify " Follow-up"mentioning

confidence: 99%

Quantification of follow‐up time in oncology clinical trials with a time‐to‐event endpoint: Asking the right questions

Rufibach

Grinsted

Jiang³

et al. 2023

Pharmaceutical Statistics

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For the analysis of a time-to-event endpoint in a single-arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow-up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow-up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time-to-event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow-up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time-to-event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow-up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, for example, delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations.

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“…A 2015 phase II trial treated 49 indolent NHL patients with bendamustine and ofatumumab and found the ORR comparable to historical treatments with bendamustine and rituximab ( 98 ). A 2017 study by the Alliance found PFS was comparable between ofatumumab with bendamustine (OB) and historical rituximab with bendamustine in previously untreated FL, despite an initially improved CR with OB ( 99 ). Given conflicting reports of increased benefits, additional randomized phase III trials and more biologically representative in vitro assays are needed to fully assess the differences in efficacy between these CD20 mAbs.…”

Section: Shortfalls Of Rituximab and Alternativesmentioning

confidence: 99%

Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

2018

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Rituximab is a chimeric mouse/human monoclonal antibody (mAb) therapy with binding specificity to CD20. It was the first therapeutic antibody approved for oncology patients and was the top-selling oncology drug for nearly a decade with sales reaching $8.58 billion in 2016. Since its initial approval in 1997, it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. Despite widespread use, most mechanistic data have been gathered from in vitro studies while the roles of the various response mechanisms in humans are still largely undetermined. Polymorphisms in Fc gamma receptor and complement protein genes have been implicated as potential predictors of differential response to rituximab, but have not yet shown sufficient influence to impact clinical decisions. Unlike most targeted therapies developed today, no known biomarkers to indicate target engagement/tumor response have been identified, aside from reduced tumor burden. The lack of companion biomarkers beyond CD20 itself has made it difficult to predict which patients will respond to any given anti-CD20 antibody. In the past decade, two new anti-CD20 antibodies have been approved: ofatumumab, which binds a distinct epitope of CD20, and obinutuzumab, a mAb derived from rituximab with modifications to the Fc portion and to its glycosylation. Both are fully humanized and have biological activity that is distinct from that of rituximab. In addition to these new anti-CD20 antibodies, another imminent change in targeted lymphoma treatment is the multitude of biosimilars that are becoming available as rituximab’s patent expires. While the widespread use of rituximab itself will likely continue, its biosimilars will increase global access to the therapy. This review discusses current research into mechanisms and potential biomarkers of rituximab response, as well as its biosimilars and the newer CD20 binding mAb therapies. Increased ability to assess the effectiveness of rituximab in an individual patient, along with the availability of alternative anti-CD20 antibodies will likely lead to dramatic changes in how we use CD20 antibodies going forward.

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Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high‐risk follicular lymphoma: CALGB 50904 (Alliance)

Cited by 10 publications

References 20 publications

End of induction positron emission tomography complete response (PET‐CR) as a surrogate for progression‐free survival in previously untreated follicular lymphoma

End of induction positron emission tomography complete response (PET‐CR) as a surrogate for progression‐free survival in previously untreated follicular lymphoma

Quantification of follow‐up time in oncology clinical trials with a time‐to‐event endpoint: Asking the right questions

Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

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