Neoadjuvant Pembrolizumab With Chemotherapy Boosts OS in Early TNBC


Pembrolizumab combined with chemotherapy significantly improved overall survival in patients with high-risk early triple-negative breast cancer, according to the prespecified interim analysis of the phase 3 KEYNOTE-522 trial.

3d rendered medically accurate illustration of a breast cancer: © SciePro -

3d rendered medically accurate illustration of a breast cancer: © SciePro -

The combination of neoadjuvant pembrolizumab (Keytruda) with chemotherapy led to a statistically significant and clinically meaningful improvement in overall survival (OS) vs neoadjuvant chemotherapy alone among patients with high-risk early-stage triple-negative breast cancer (TNBC), meeting a secondary end point of the phase 3 KEYNOTE-522 trial (NCT03036488).1

Findings from the prespecified interim analysis showed that the combination not only improved OS vs neoadjuvant chemotherapy followed by single-agent, adjuvant chemotherapy, but the safety profile of pembrolizumab was consistent with findings from prior studies. Additionally, there were no new safety signals observed.

KEYNOTE-522 marks the fourth study to evaluate a pembrolizumab-based regimen in an earlier stage of cancer and elicit a benefit in OS. The others included KEYNOTE-A18 (NCT04221945) in cervical cancer, KEYNOTE-671 (NCT03425643) in non-small cell lung cancer, and KEYNOTE-564 (NCT03142334) in renal cell carcinoma.

“This is a significant milestone, as it is the first time an immunotherapy-based regimen has demonstrated a statistically significant overall survival benefit compared to chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer,” said Gursel Aktan, MD, PhD, vice president, global clinical development, Merck Research Laboratories, in a press release. “To have achieved overall survival from this landmark study is highly encouraging and builds upon the positive pathological complete response and event-free survival results that led to approvals for this regimen around the world.”

“[I]n my opinion, unless there are specific contraindications, all patients with stage II or stage III triple-negative breast cancer should be considered for preoperative chemotherapy in combination with pembrolizumab for 6 months, followed by surgery, and then followed by adjuvant treatment,” Peter Schmid, FRCP, MD, PhD, professor, cancer medicine, center lead at the Centre of Experimental Cancer Medicine, and director of the Barts Breast Cancer Centre, previously told Targeted OncologyTM in an interview.

Additional data from the study are expected to be presented at an upcoming medical meeting and shared with regulatory authorities.

About KEYNOTE-522

The randomized, double-blind, phase 3 KEYNOTE-522 trial is evaluating pembrolizumab plus paclitaxel and carboplatin followed by pembrolizumab plus cyclophosphamide and either doxorubicin or epirubicin as neoadjuvant therapy before surgery, followed by adjuvant pembrolizumab alone postsurgery (n = 784) compared with placebo plus paclitaxel and carboplatin followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin as neoadjuvant therapy prior to surgery, followed by placebo alone as adjuvant therapy postsurgery (n = 390). A total of 1174 patients with previously untreated stage II or III TNBC were randomized in a 2:1 fashion.

To be eligible for this trial, patients must have had newly diagnosed, locally advanced TNBC confirmed by a central laboratory based on the latest guidelines from the American Society of Clinical Oncology and College of American Pathologists, previously untreated locally advanced nonmetastatic TNBC, an ECOG performance status of 0 to 1, and adequate organ function. Patients must have also provided a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory.

The dual primary end points of the study were pathologic complete response rate and event-free survival (EFS). A key secondary end point was OS.

Updated findings from the study were presented at the European Society for Medical Oncology (ESMO) 2023 Annual Congress.2 The 5-year results showed that chemotherapy plus pembrolizumab led to an EFS rate of 81.3% vs 72.3% for those in the placebo arm, resulting in a reduction in risk for recurrence, progression, complications, or death by 37% (HR, 0.63; 95% CI, 0.49-0.81). The EFS benefit was consistent across subgroups stratified by PD-L1 status, nodal status, tumor size, carboplatin schedule, age, and ECOG performance status.

Further, the median EFS was not achieved in either group, and the reduction in EFS events was seen regardless of pathologic complete response outcomes.

1. Merck announces phase 3 KEYNOTE-522 trial met its overall survival (OS) endpoint in patients with high-risk early-stage triple negative breast cancer (TNBC). News release. Merck. May 28, 2024. Accessed May 28, 2024.
2. Schmid P, Cortés J, Dent RA, et al. Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Onc. 2023;34(S2):S1256-S1257. doi:10.1016/j.annonc.2023.10.008.
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