FDA panel: Defer decision on pembrolizumab for early-stage triple-negative breast cancer
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An FDA advisory committee voted unanimously to recommend deferral of a regulatory decision on pembrolizumab for the treatment of patients with high-risk, early-stage triple-negative breast cancer.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) did not support accelerated approval of pembrolizumab (Keytruda, Merck), an anti-PD-1 monoclonal antibody, in combination with chemotherapy in the neoadjuvant setting and as a single agent in the adjuvant setting for this patient population, due in part to concerns about immature EFS and OS data from the KEYNOTE-522 trial.
“It is to be expected that [KEYNOTE-522] will turn out to be positive as the data mature. However, it is of interest that when the first interim analysis data were published, there was a difference in pathologic complete response rates between the two arms of about 14% — which is quite remarkable — but it is now down to 7%,” Philip C. Hoffman, MD, ODAC chairperson and professor of medicine at University of Chicago, said after the vote. “It is reasonably likely that this difference in pathologic complete response will lead to an improvement in EFS and OS, but data do change as they mature, and the fact that we are seeing trends toward improvement does not mean that the data cannot change with time. We should not underestimate the safety concerns, either.”
As previously reported by Healio, the placebo-controlled KEYNOTE-522 trial is the first phase 3 trial to evaluate immunotherapy for early-stage triple-negative breast cancer. Researchers evaluated the neoadjuvant pembrolizumab-chemotherapy combination followed by adjuvant pembrolizumab, vs. placebo and chemotherapy followed by placebo, among 1,174 patients with previously untreated, nonmetastatic, centrally confirmed triple-negative breast cancer.
Results of an interim analysis showed the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased the pathologic complete response rate (64.8% vs. 51.2%; percentage-point difference, 13.6%; P = .00055). The most recent interim analysis, including all randomly assigned patients, showed a percentage-point increase of 7.5% (95% CI, 1.6-13.4) with pembrolizumab (63% vs. 55.5%).
However, the FDA expressed concern that the improvement in pathologic complete response may not be adequate to predict improvement in long-term outcomes of patients with early-stage disease, and EFS and OS data remain immature for definitive analysis.
ODAC panelists also expressed concerns about immune-related adverse events observed with pembrolizumab among this patient population.
Nineteen percent of patients who received pembrolizumab in the KEYNOTE-522 trial had an unresolved immune-mediated adverse event at last assessment, including hypothyroidism (11%), adrenal insufficiency (2%) and hypophysitis (2%). Of note, 16% of patients initiated thyroid hormone replacement therapy during the study, and 14% remained on therapy at last study assessment.
Four patient deaths occurred that may have been due to immune-related adverse events. One patient died of adrenal crisis on day 1 after surgery and one patient died of autoimmune encephalitis while receiving adjuvant pembrolizumab.
“Our job is to always first protect the safety of our patients and second to protect the integrity of a clinical trial,” Daniel F. Hayes, MD, FASCO, FACP, ODAC temporary member and Stuart B. Padnos professor of breast cancer research and co-director of the breast oncology program at University of Michigan Comprehensive Cancer Center, said after the vote. “We owe it to the women who agreed to be a part of this trial to ensure that the integrity of the science is maintained so that we have a good answer when we are done, and it is unsure that we do have a good answer right now. On the trial, there was an approximate 1.3% mortality rate, which suggests that this is not a benign drug. My hope is that this will be a positive study, but we do not know yet.”
ODAC’s recommendation does not guarantee the FDA will defer a decision on pembrolizumab in this patient setting. The FDA often follows the guidance of the advisory committee when deciding on drug applications, but the agency is not required to do so.
Additional data from KEYNOTE-522 are anticipated later this year.
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