Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review

Savina, M.; Gourgou, Sophie; Italiano, Antoîne; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin‐Pélissier, Simone; Bellera, Carine

doi:10.1016/j.critrevonc.2017.11.014

Cited by 38 publications

(37 citation statements)

References 86 publications

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“…Therefore, theoretically millstone survival could be a great intermediate endpoint in oncological RCTs with immunotherapies, which is well supported by the results in our included meta-analyses. Nowadays, one acceptable recommendation for evaluating the strength of the association between endpoints is the criteria proposed by the German Institute of Quality and Efficiency in Health Care (IQWiG) guidelines (13)(14)(15)32). According to the criteria, if we score the strength as low, medium and high correlations when the R 2 value is lower than or equal to 0.49, between 0.49 and 0.72, as well as equal to or higher than 0.72, the value of 1-year survival is also convincing: most indications demonstrated a high correlation between OS and 1-year survival, not just based on trial-level treatment effects (75%; 3/4), but also based on absolute results within experimental arm (80%; 4/5).…”

Section: Discussionmentioning

confidence: 99%

“…Another four systematic reviews of meta-analyses were conducted subsequently, also focusing on the association between OS and surrogate endpoints in oncological RCTs. A low triallevel correlation can be found in 62.5% (10/16), 51.6% (32/62), 56.2% (73/130), 38% (34/89) of indications from included meta-analyses, respectively (11)(12)(13)(14)(15). Furthermore, the systematic review of meta-analyses conducted by Haslam et al (15) also provided a subset of results based on immunotherapies: none of the four meta-analyses focusing on immunotherapies indicated high correlation; among these four meta-analyses, three (75%) indicated low correlation, based on the IQWiG criteria.…”

Section: Discussionmentioning

confidence: 99%

“…For such a low correlation of the trial-level association between OS and traditional surrogate endpoints (PFS and ORR), several considerations have been well explained by the five previous systematic reviews of meta-analyses (11)(12)(13)(14)(15) as well as our 11 included meta-analyses (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Their considerations involve the issues of study design, such as the availability of subsequent treatment(s) after tumor progression (especially based on a cross-over study design), sample size, time of follow-up, and the time interval as well as the accuracy of tumor assessment.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in colorectal cancer and extensive small cell lung cancer, the association between OS and PFS tended to be strong; however, such a strong association was hard to be found in other cancer diseases (11)(12)(13)(14)(15). Also, the association could be different due to different treatments; interestingly, we found that our study based on the setting of immunotherapies has a higher proportion of indications with a low correlation between OS and traditional surrogate endpoints, compared to the previous five systematic reviews mostly based on the settings of targeted therapies and chemotherapies (11)(12)(13)(14)(15), according to the IQWiG criteria. This indicates that using traditional surrogate endpoints to predict patients' final survival lacks of sufficient evidence in the setting of immunotherapies (34).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, meta-analyses that evaluated the validation of endpoint surrogacy for OS have been published consistently during the past 10 years (10-15). These meta-analyses were conducted mostly in the settings of targeted therapies or chemotherapies (10)(11)(12)(13)(14)(15); surprisingly, most of them indicated a low strength of association between OS and traditional surrogate endpoints.…”

Section: Introductionmentioning

confidence: 99%

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Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Zhang

Liang

et al. 2019

Ann. Transl. Med

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Few cancer drugs or their indications achieved survival benefit in subsequent trials during postmarket period after approval based on surrogate endpoints. This causes a concern of using surrogate endpoints instead of overall survival (OS) as the primary endpoint for trial design, implementation and regulation approval. We conducted a systematic review to summarize the findings from published metaanalyses which have evaluated endpoint surrogacy for OS in oncological randomized controlled trials (RCTs) with immunotherapies. After searching articles indexed in PubMed prior to 24 February 2019, we identified a total of 11 meta-analyses for advanced multiple tumors, non-small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, melanoma; most (91%; 10/11) focused on immune checkpoint inhibitors. Although the evaluation criteria adopted by these meta-analyses for validating endpoint surrogacy were not consistent (ranging from R 2 ≥0.60 to R 2 ≥0.80), the results were consistent. Few studies show an association between OS and progression-free survival (PFS)/objective response rate (ORR) that met the lowest evaluation criteria (R 2 ≥0.60), based on treatment effects (8%; 2/26 indications) or absolute results from experimental arm (0%; 0/11 indications). However, the association between OS and 1-year survival rate met the lowest criteria based on both the trial-level results (4/4 indications) and the arm-level results (5/5 indications). In lieu of this finding, we are supportive of an alternative endpoint, e.g., 1-year survival rate, rather than the more conventional choices PFS and ORR, as promising surrogate endpoint for OS in immunotherapy RCTs. We encourage further investigation on endpoint surrogacy based on the same or different settings, especially an assessment on survival rate at milestone time (e.g., 1-year), which has been demonstrated valuable for predicting OS in meta-analyses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Zhang

Liang

et al. 2019

Ann. Transl. Med

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Association Between Adjuvant Chemotherapy Duration and Survival Among Patients With Stage II and III Colon Cancer

et al. 2019

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Key Points Question Are shortened durations of adjuvant chemotherapy associated with decreased survival among patients with stage II and III colon cancer? Findings In this systematic review and meta-analysis of 22 studies comprising 43 671 patients, shortened durations of adjuvant chemotherapy were not associated with worse survival in studies involving combination regimens (the current standard of care) among patients with stage III colon cancer. Conversely, the standard 6 months of chemotherapy was associated with improved survival among patients prescribed monotherapy. Meaning Shorter durations of adjuvant chemotherapy may not adversely alter survival among patients with stage III colon cancer treated with combination therapy; patients prescribed monotherapy should be encouraged to complete the entire 6 months of treatment.

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Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: A systematic review

et al. 2021

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Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event‐defined endpoints in 91 studies (60.3%) and response‐based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re‐analysis.

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Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review

Cited by 38 publications

References 86 publications

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

Association Between Adjuvant Chemotherapy Duration and Survival Among Patients With Stage II and III Colon Cancer

Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: A systematic review

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