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Pathologic complete response (pCR) is not a reliable surrogate endpoint in trials evaluating neoadjuvant therapies for early breast cancer, according to a critical analysis of the literature.

A team of researchers pointed to their 2021 meta-analysis in BMJ, which found that the association between pCR and overall survival was weak — with a coefficient of determination, or R2, of 0.08. In other words, only 8% of the variability among treatment effects on overall survival could be explained by pCR — far from the optimal R2 cutoff value of 0.70 for a candidate surrogate endpoint.

This weak pCR surrogacy at the randomized controlled trial level “limits the possibility to use pCR as a surrogate endpoint to predict long-term outcomes of the patient populations enrolled in [these] trials,” Fabio Conforti, MD, with the European Institute of Oncology, crestor safe Milan, Italy, and colleagues wrote in JAMA Oncology.

However, regulatory agencies continue to accept pCR as a surrogate endpoint for long-term clinical outcomes when assessing new drugs for accelerated approval.

This decision may be partly based on the strong correlation observed between pCR and overall survival at the patient level; however, as Conforti and colleagues explained, this correlation does not exist at the trial level.

In other words, patients who achieve pCR have significantly better long-term survival compared with those who do not, but this benefit is not observed among patients enrolled in trials, which have consistently demonstrated a poor association between the degree of improvement in pCR rate and survival.

Further data from the team’s 2021 meta-analysis revealed that the association between pCR and disease-free survival was “similarly weak.”

Given the weak trial-level associations, “pCR should no longer be used to grant expedited approval of experimental drugs” in this setting “to spare patients from being exposed to potentially useless or harmful drugs, and clinical research from embarking on roads leading to a dead end,” Conforti told Reuters Health after the meta-analysis was published in BMJ.

In their commentary, the researchers proposed assessing alternative molecular biomarkers to use as surrogate endpoints. Analyses have shown, for instance, that circulating tumor DNA (ctDNA) assessed at diagnosis or during follow-up was significantly associated with disease-free survival in patients with early breast cancer.

If shown to be robust, other potential surrogate endpoints “could overcome limits of pCR and provide a reasonable trade-off between the two conflicting needs to have access to effective therapies rapidly, and to reliably assess patients’ clinical benefit,” Conforti and colleagues concluded.

This research mentioned no specific funding. Conforti reported no relevant disclosures.

JAMA Oncol. Published October 6, 2022. Full text

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