The surrogacy value of a pCR in this setting is controversial, despite US Food and Drug Administration approval of the surrogate endpoint of disease-free survival, according to Dr. Fabio Conforti of the Institute of Oncology, IRCCS in Milan and colleagues, writing in The BMJ.
"In the last decade, pCR has been considered a good predictor of patients' survival, and several drugs obtained accelerated approval from regulatory agencies based on positive improvement in rates of pCR as compared with standard treatments," Dr. Conforti told Reuters Health by email.
"We demonstrated that pCR did not reliably predict whether a new experimental drug provides significant survival benefit to the patient population treated," he said. "This result holds true for chemotherapy as well as for new anti-cancer therapies such as targeted therapy, anti-vascular agents and immunotherapy."
"This means that pCR should no longer be used to grant expedited approval of experimental drugs, to spare patients from being exposed to potentially useless or harmful drugs, and clinical research from embarking on roads leading to a dead end," he said.
The team analyzed data from 54 randomized trials involving more than 32,000 patients. The trials tested neoadjuvant chemotherapy given alone or combined with other treatments, including anti-human epidermal growth factor 2 drugs, targeted treatments, antivascular agents, bisphosphonates, and immune checkpoint inhibitors.
A weak association was seen between the log (relative risk) for pCR and log (hazard ratio) for both disease-free survival (coefficient of determination, or R2, = 0.14,) and overall survival (R2 =0.08).
Similar results were found across all subgroups, independent of the definition used for pCR, experimental arm treatment type, and biological features of the disease.
The surrogate threshold effect was 5.19 for disease-free survival but was not estimable for overall survival.
The authors state, "Although this finding does not affect the role of (pCR) to estimate patients' residual risk of relapse after neoadjuvant treatment and to identify those patients who are candidates for further adjuvant treatments, use of (pCR) to predict long-term outcomes of patient populations enrolled in neoadjuvant randomized clinical trials is questionable."
Dr. Conforti added, "At the 2021 St. Gallen International Breast Cancer Consensus Conference, only 40% of experts supported pCR as an appropriate endpoint for defining standard neoadjuvant systemic treatments in early-stage breast cancer."
Further, he said, "recently, the FDA restricted the use of pCR in the accelerated approval pathway of new drugs, supporting it only when and if a large treatment effect is demonstrated. I hope that our results will push future research in the direction of exploring new and more reliable surrogate endpoints for the approval of new drugs for patients with early breast cancer."
One new surrogate endpoint under investigation is the residual cancer burden (RCB), he noted. "The RCB is a more comprehensive modality that assesses the amount of microscopic residual disease found at surgery performed at the end of systemic neoadjuvant treatments. If validated, this surrogate endpoint may achieve a reasonable trade-off between the two conflicting needs to have access to effective therapies faster than waiting for results of randomized clinical trials, and to reliably assess patients' clinical benefits."
SOURCE: https://bit.ly/3A5925D The BMJ, online December 21, 2021.
By Marilynn Larkin
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