Poor correlation between progression-free and overall survival in modern clinical trials: Are composite endpoints the answer?

Amir, Eitan; Šeruga, Boštjan; Kwong, Ryan C.; Tannock, Ian F.; Ocaña, Alberto

doi:10.1016/j.ejca.2011.10.028

Cited by 91 publications

(76 citation statements)

References 25 publications

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“…Although the goal of cancer treatment is to improve the quantity and quality of life,1 2 3 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4 5 6 7 8 9 10 11 or quality of life4 6 11 12 13 in all settings, and two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low 814 Moreover, there is growing concern that the benefits offered by many new treatments for cancer—often discussed and promoted as “breakthroughs”15 16 17 18—are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs 19…”

Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

481

415

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Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

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Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

481

415

View full text Add to dashboard Cite

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“…In particular, PFS seems to be a poor surrogate for OS in patients with a long survival post-progression (SPP) compared with those with a shorter SPP [40,41]. It has been suggested that in tumors with long SPP, PFS is only clinically meaningful when it is also associated with an improvement in patient-reported outcomes (PROs).…”

Section: A Discussion Of the Strengths And Limitations Of End Points Usmentioning

confidence: 98%

Clinical trial end points relevant to patients and society for rare cancers

Khakoo¹,

Georgiou²,

Chau³

2015

Clinical Investigation

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In solid tumors, end points such as progression-free survival are increasingly utilized as primary end points, as the use of overall survival can often be confounded by the growing use of multiple lines of therapy. In rare cancers, the choice of end points is further complicated by small and heterogeneous patient populations. In the absence of confirmed overall survival benefit, it remains unclear as to whether extending progression-free survival provides a discernible clinical benefit. Inclusion of robust patient-reported outcomes may provide valuable supporting evidence when making decisions regarding the clinical value of new costly agents. We discuss recent trials in pancreatic neuroendocrine tumors to exemplify some of the challenges faced in the trial design for rare cancers.Keywords: end points • health related quality of life • objective response rate • overall survival • pancreatic neuroendocrine tumors • progression-free survival • rare cancers

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“…Most RCTs in the frontline treatment setting accept PFS at the primary end point to demonstrate the efficacy and as a surrogate for survival. However, PFS loses utility as a surrogate for OS in scenarios where survival is relatively prolonged, such as in FL [30]. Obviously, with a 15-20-year timeframe for results if OS is the chosen end point, probably due to the impact of other available salvage therapies on OS in FL, the prospects for controlled trials to answer these questions are modest at best.…”

Section: ■ Management In Flmentioning

confidence: 94%

Comparative effectiveness research in follicular lymphoma: current and future perspectives and challenges

Wudhikarn

Link

2014

J. Compar. Effect. Res.

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Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma in northern America. FL is an incurable disease with relapsing-remitting courses requiring serial intermittent treatments. Duration of remission will often become progressively shorter and most patients will die from refractory disease or transformation to aggressive lymphoma. Given the incurable nature of FL, current goals of treatment are focused on improving symptoms and survival by a variety of available treatment options, while considering potential adverse events. Although randomized controlled trials are universally perceived as the gold standard of clinical research, randomized controlled trials are not always practical and have several limitations. Therapeutic and diagnostic options of FLs are expanding faster than randomized controlled trials can test them, so employing comparative effectiveness research on other research designs are needed to efficiently improve global FL care. Implementing comparative effectiveness research with judicious use of appropriate research designs will hopefully fill current knowledge gaps and provide insights for FL managements.

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Poor correlation between progression-free and overall survival in modern clinical trials: Are composite endpoints the answer?

Cited by 91 publications

References 25 publications

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Clinical trial end points relevant to patients and society for rare cancers

Comparative effectiveness research in follicular lymphoma: current and future perspectives and challenges

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