Overall Survival Should Be the Primary Endpoint in Clinical Trials for Advanced Non-Small-Cell Lung Cancer

Cheema, Parneet K.; Burkes, Ronald L.

doi:10.3747/co.20.1226

Cited by 38 publications

(35 citation statements)

References 54 publications

(70 reference statements)

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“…If the quality of life is not significantly compromised, an increase in the duration of patient OS remains the gold‐standard indicator of a successful treatment (Fig. 1A,B) . However, obtaining sufficient OS events to facilitate statistical analyses may require long follow‐up in settings (such as ovarian cancer) in which the duration of OS is long .…”

Section: Evaluation Of Clinical Trial Endpointsmentioning

confidence: 99%

Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Matulonis

Oza

et al. 2014

Cancer

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Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy.

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Section: Evaluation Of Clinical Trial Endpointsmentioning

confidence: 99%

Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Matulonis

Oza

et al. 2014

Cancer

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“…In addition, the inherent natural history of the specific tumor has also an impact on OS. That concern is based on the assumption that subsequent lines of therapy are more effective in the control arm than in the treatment arm, or that the biology of the treatment arm has changed because of exposure to the study drug; however, this is not supported by evidence [26]. Post-progression treatments that work better in the standard arm than the experimental arm will lead to a smaller OS difference.…”

Section: Discussionmentioning

confidence: 98%

Overall survival (OS) endpoint: an incomplete evaluation of metastatic breast cancer (MBC) treatment outcome

Raphael

Verma

2015

Breast Cancer Res Treat

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Overall survival (OS) has been debated as the most important clinical endpoint in metastatic breast cancer (MBC) trials mainly because survival could be influenced by treatment after progression in an era of effective subsequent-line agents. We conducted a search strategy using PubMed for all the phase 3 trials in the last two decades evaluating survival outcome in MBC. We investigated the frequency of trials reporting survival outcome and response/resistance to treatment beyond progression. One hundred fifteen trials met our eligibility criteria: 69 (60 %) evaluated chemotherapy regimens (group A), 32 (28 %) evaluated targeted therapies (group B), and 14 (12 %) focused on endocrine treatment (group C). An OS benefit was demonstrated in approximately 22 % of the trials in each group. Less than 10 % of the trials in group A and B reported response data after progression on trial therapy. Post-progression treatment resistance was only reported in group A in 3 % (2/69) of the trials. In addition, the number of lines of treatment used post-progression was reported in 14 % (10/69), 9.4 % (3/32), and 14 % (2/14) of the trials in group A, B, and C, respectively. Post-progression survival and its effect on OS was reported in only 1 % (1/69), 3 % (1/32), and 7 % (1/14) of the trials for group A, B, and C respectively. A clear paucity of post-progression treatment information is noted in the majority of the phase 3 trials for MBC. We do know that OS can be affected partially or directly by treatments used after progression. In order to assess the true clinical benefit of a new drug and to have a complete evaluation of OS outcome, a detailed collection of post-progression treatment information is required and should be mandated in MBC trials.

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“…16 Tumour size does not correlate with overall survival, 19 and the use of progression-free survival as a valid biomarker seems to depend on the type of cancer being treated. [19][20][21] The continued use of surrogate outcomes as the basis for approval of drugs to treat noninsulin-dependent diabetes seems difficult to justify given the lack of correlation between a reduction in concentration of glycated hemoglobin and cardiovascular events. 22 However, all 9 drugs approved for this indication were in the surrogate outcome group.…”

Section: Discussionmentioning

confidence: 99%

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study

Lexchin

Ahmed

2015

CMAJ Open

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Background: Health Canada approves drugs on the basis of evidence from clinical trials using clinical or surrogate outcomes. This study compares the postmarket safety of these 2 groups of drugs.Methods: Information about whether clinical or surrogate outcomes were used and the date of market approval were obtained from Health Canada's Summary Basis of Decision documents issued from Jan. 1, 20051, , to Dec. 31, 2014. Safety warnings and the dates they were issued were identified through advisories on the MedEffect Canada website. Kaplan-Meier survival curves were calculated to determine the likelihood that drugs in the clinical and surrogate outcome groups would receive a serious safety warning. The time from market authorization to first serious safety warning was compared for the 2 groups of drugs.Results: A total of 124 drugs were approved by Health Canada using clinical outcomes and 114 using surrogate outcomes. KaplanMeier curves did not differ between the 2 groups (p < 0.9). The median time from market authorization to first serious safety warning was 722 days in the clinical outcome group and 818 days in the surrogate outcome group (difference 96 days, 95% confidence interval -295 to 425). Interpretation:We found no statistically significant difference in postmarket safety between drugs approved using clinical outcomes and those approved using surrogate outcomes. Because drugs in the surrogate outcome group are approved before their benefit:harm ratio is fully established, these drugs should be used with caution until their clinical benefits are better understood. AbstractResearch CMAJ OPEN CMAJ OPEN, 3(3)

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Overall Survival Should Be the Primary Endpoint in Clinical Trials for Advanced Non-Small-Cell Lung Cancer

Cited by 38 publications

References 54 publications

Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Intermediate clinical endpoints: A bridge between progression‐free survival and overall survival in ovarian cancer trials

Overall survival (OS) endpoint: an incomplete evaluation of metastatic breast cancer (MBC) treatment outcome

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study

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