Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Therapy for Early Breast Cancer: Critical Analysis of Strengths, Weaknesses, and Misinterpretations.

IMPORTANCE

The pathologic complete response (pCR) is supported by regulatory agencies as a surrogate end point for long-term patients' clinical outcomes in the accelerated approval process of new drugs tested in neoadjuvant randomized clinical trials (RCTs) for early breast cancer (BC). However, a meaningful association between pCR and patients' survival has been proven only at the patient level (ie, significantly better survival of patients who achieved pCR compared with those who did not), but not at trial level (ie, poor association between degree of improvement in pCR rate and survival reported across trials).

OBSERVATIONS

We critically discuss the potential reasons of such discrepancy between pCR surrogacy value at the patient and trial level, as well as the relevant implications for both clinical research and drug regulatory policy. We also describe alternative surrogate end points, including combined end points that jointly analyzed pathological response and event-free survival data, or the assessment of circulating tumor DNA (ctDNA). Such proposed surrogate end points could overcome limits of pCR and provide a reasonable trade-off between the 2 conflicting needs to have access to effective therapies rapidly, and to reliably assess patients' clinical benefit.

CONCLUSIONS AND RELEVANCE

Using surrogate end points to grant drug approvals is justified only when they can provide accurate prediction of a drug's effect on the long-term patient outcomes. Evidence currently available does not support pCR used alone as a reliable surrogate end point in regulatory neoadjuvant RCTs for BC. The surrogacy value at trial level of potentially more robust surrogate end points needs to be urgently tested.