To surrogate or not surrogate: an ancient dilemma without a happy ending

Haslam et al. performed an analysis of surrogate validation studies (1), in order to evaluate the strength of correlation between overall survival (OS) and surrogate markers. The analysis included 78 studies that according the inclusion criteria were meta-analyses of randomised controlled trials that investigated the validation as surrogate endpoint for survival of progression free survival or tumour response rate. Although the most part of the studies involved metastatic setting of disease, about one quart of the studies reported other setting such as adjuvant, neoadjuvant or immunotherapy. The criteria of the Institute of Quality and Efficiency in Health Care (2) and adapted by Prasad et al. (3) has been used to evaluate the strength of association between surrogate endpoints and OS. According this criterion, three levels of correlation has been adopted: low, medium or high according the value of r (≤0.7; >0.7 to <0.85 and ≥0.85, respectively). About the 40% of studies reported low correlation. In regard of the 4 studies that involved immunotherapy, no high correlation has been observed and low was the correlation of 3 studies. Then, the authors concluded the surrogate endpoints have generally a low or moderate correlation with OS.

The National Institutes of Health (USA) defines surrogate endpoint as “a biomarker intended to substitute for a clinical endpoint”. Surrogate endpoints may include biomarkers, behavioural/cognitive scores, radiological data or time to events. In oncological field, the surrogate endpoints should correlate with OS, therefore, both progression free survival and tumour response rate may be ideal surrogate endpoints in oncology, because they should allow lesser expensive and quicker studies. Unfortunately, the study by Haslam et al doesn’t validate the use of surrogate endpoints in medical oncology. It should speculate that progression free survival or tumour response rate failed the surrogacy for survival because of they are not cancers specific or drug-correlated. For example, decrease in serum prostate-specific antigen (PSA) value is universally considered a valid surrogate for survival in patients with prostate cancer (4,5); PD-L1 expression has been used as a selective criterion for pembrolizumab treatment of patients with non-small cell lung cancer (NSCLC) and rate of hypertension is historically related with efficacy during anti-angiogenic agents (6). All these data highlight the need of patient’s selection with selective biomarkers to guide treatment selection.

During the years, several anti-cancer drugs have been approved on the basis of successful trials with surrogate endpoints for OS (7,8). However, this approach raises several issues because successful phase 2 studies don’t translate in positive results on survival in further phase III or post-market studies (7,9,10). This speech is particularly true with novel immunotherapeutic agents, in fact, as reported by Haslam et al., based on a surrogate end-points, pembrolizumab received several approvals (11). However, immunotherapy has a well-known history of poor correlations between surrogate markers and OS (12-14).

This last may due to the pseudo-progression that is a unique event that characterizes the pattern of response and progression of novel immunotherapy compared with those of conventional chemotherapy or biological/molecular targeted therapies.

In conclusion, there is the need to identify surrogate endpoints that correlate with OS, however, several oncological drugs are approved with the use of surrogate markers for survival, therefore caution it should be used.

Acknowledgments

Funding: None.

Footnote

Provenance: This is an invited Editorial commissioned by the Section Editor Jianrong Zhang (MPH Candidate, George Warren Brown School; Graduate Policy Scholar, Clark-Fox Policy Institute, Washington University in St. Louis, St. Louis, USA).

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Jianrong Zhang (MPH Candidate, George Warren Brown School; Graduate Policy Scholar, Clark-Fox Policy Institute, Washington University in St. Louis, St. Louis, USA).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jhmhp.2019.02.01). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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