Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors.
Over the past 15 years, targeted therapy has revolutionized the systemic treatment of cancer. In parallel, there has been a growing debate on the choice of end points in clinical trials in oncology. This debate basically hinges on the choice between overall survival (OS) and progression-free survival (PFS). PFS is advantageous because it is measured earlier than OS, requires a smaller sample size than OS to achieve the desired power, and is not influenced by cross-over. On the other hand, PFS is prone to measurement error and bias, and may not capture the entire treatment effect on the outcomes of most interest to patients with an incurable disease: a prolonged survival and improved quality of life. Therefore, how can we choose between two imperfect end points? The answer to this question would certainly be made easier if PFS could be demonstrated to be a valid surrogate for OS. The validation of a surrogate end point is best made using individual-patient data (IPD) from randomized trials, which allows for standardized assessments of the patient-level and the trial-level correlations between surrogate and final end points. Proper IPD meta-analytical evaluations for targeted agents have still been rare, and to our knowledge only three studies on this topic are currently available in the metastatic setting: one in breast cancer, one in colorectal cancer and one in lung cancer. Although these three studies suffer from limitations inherent to the availability of IPD and the design of the original clinical trials, they have not been able to validate PFS as surrogate for OS, because only modest correlations were found between these two end points, both at the patient and at the trial level. Even if properly conducted surrogate-endpoint evaluations have thus far been unsuccessful, these evaluations are a step in the right direction and can be expected to be applied on a much larger scale in the era of data sharing of clinical trials.
Service de Biostatistique et d'Epidémiologie, Gustave Roussy, B2M RDC, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France. stefan.michiels@gustaveroussy.fr.|Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM U1018, 94805, Villejuif, France. stefan.michiels@gustaveroussy.fr.|Ligue Nationale Contre le Cancer Meta-Analysis Platform, Gustave Roussy, 94805, Villejuif, France. stefan.michiels@gustaveroussy.fr.
Stefan
http://orcid.org/0000-0002-6963-2968
S
Michiels
International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
Everardo D
ED
Saad
Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Hasselt, Belgium.|International Drug Development Institute (IDDI), San Francisco, CA, USA.
Marc
M
Buyse
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality; D008297:Male; D015201:Meta-Analysis as Topic; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate
D000970:Antineoplastic Agents