The results of a recently published study in eClinicalMedicine show that some of the so-called intermediate clinical endpoints (ICE) can predict changes in overall survival (OS) in patients with early-stage breast cancer who are receiving adjuvant therapy. Therefore, these ICE can effectively be considered surrogate endpoints for OS in this population, according to Eva Blondeaux, MD, of the epidemiology unit at IRCCS Ospedale Policlinico San Martino in Genoa, Italy, and colleagues.
"This is a nonobvious conclusion," Lorenzo Gerratana, MD, of the Department of Medicine at the University of Udine and the Department of Medical Oncology at IRCCS CRO in Aviano, Italy. "OS represents the primary endpoint par excellence, but we also have intermediate endpoints available. Blondeaux and colleagues' work aimed precisely to verify if these intermediate endpoints are also surrogates of OS, a condition that does not always occur," he said. Intermediate and surrogate endpoints aim to optimize timelines, logistics, and resources for clinical trials and therefore provide answers as soon as possible to guide clinical practice. "In early-stage breast cancer and in adjuvant treatment, one must wait a long time to observe a potential event, and fortunately, only a minimal proportion experience this possibility. Therefore, obtaining OS results requires studies with extremely long follow-up and with very large populations," said Gerratana.
Spotlight on ICE
The investigators' study analyzed individual patient data enrolled in phase 3 adjuvant therapy trials conducted by researchers from the Italian Breast Group and the Breast InterGroup. In total, 12,397 patients enrolled in six clinical trials from November 1992 to July 2012 were included in the analysis. The impact of each ICE was evaluated at the outcome level (ie, OS and ICE are correlated independently of treatment) and at the trial level (ie, the effects of treatment on ICE and the effect of treatment on OS are correlated, thus testing surrogacy).
Outcome analyses showed that more than 95% of the variability in OS observed at 5 years was attributable to the 5-year variation in ICE. The ICE evaluated and identified as surrogates are disease-free survival (DFS), distant DFS, recurrence-free survival (RFS), distant RFS, recurrence-free interval (RFI), distant RFI, breast cancer-free interval (BCFI), and invasive breast cancer-free survival. At the trial level, ICE and OS were found to be correlated. The strongest correlation was observed for RFS and DRFS and the weakest for BCFI.
The analysis provides evidence supporting the use of the evaluated ICE as primary endpoints in adjuvant studies on breast carcinoma, the authors wrote. "These results have potential implication in trial design and drug approval."
"These results, based on an extremely strong statistical analysis framework, confirm what we would have expected, namely that event-free survival (EFS) is indeed an indicator of OS," said Gerratana. Before the study, there was no specific confirmation. "Lately, clinical trials in the adjuvant setting are already registered based on EFS data because it would be extremely complex and counterproductive to wait for OS data, but the recent study allows us to proceed with greater confidence and certainty in this direction," he added.
Strength of Heterogeneity
In a diagnostic and therapeutic landscape that is rapidly and continuously evolving, one might think that data obtained from studies started more than 30 years ago should be considered obsolete, but it is essential to interpret the results correctly. "The major strength of Blondeaux and colleagues' analysis is that the studies are extremely heterogeneous: Patients have triple-negative disease but also hormone receptor-positive. Some are focused on chemotherapy and others on endocrine therapy, and so on. This is very important, in my opinion, and makes the result extremely robust and generalizable," said Gerratana. Although the basic chemotherapy treatment has remained almost unchanged, today's treatments are entirely different, and none of those used in the six studies considered in the recently published analysis represent today's standard therapy.
Gerratana also pointed out that today, in addition to treatment, the risk classification methods have changed significantly: The stage remains one of the most important parameters, but many others have been added, such as genomic analyses that guide adjuvant choice.
"From a certain point of view, this is undoubtedly a seminal study that tells us that, based on the data and treatments done in the past 30 years, there is a form of surrogacy. And this result is far from obvious," said Gerratana. "Now there is a need to refine the data, especially considering the new types of treatment and risk classifications, for which it would be interesting to have specific and updated data."
This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.