KEYNOTE-756 of Pembrolizumab/Chemotherapy Improves pCR in ER+HER2- Breast Cancer

KEYNOTE-756 is evaluating pembrolizumab with chemotherapy as neoadjuvant treatment, followed by adjuvant treatment with pembrolizumab plus endocrine therapy for high-risk, early-stage ER+/HER2- breast cancer: © SciePro [stock.adobe.com]

Pembrolizumab (Keytruda) in combination with chemotherapy met a primary end point of pathological complete response (pCR) rate following the neoadjuvant part of the neoadjuvant/adjuvant study regimen in patients with high-risk, early-stage estrogen receptor (ER)-positive, HER2-negative breast cancer, according to findings from the phase 3 KEYNOTE-756 trial (NCT03725059).¹

At a prespecified interim analysis, the combination led to a statistically significant improvement in pCR rate vs neoadjuvant placebo plus chemotherapy, as conducted by an independent Data Monitoring Committee (DMC). Regarding safety, the safety profile of pembrolizumab was consistent with that observed in previously reported studies, and no new safety signals were identified.

The DMC has now recommended that the trial continue without changes to evaluate the other dual primary end point of event-free survival (EFS), per the trial design. Results from the trial will be presented at an upcoming medical meeting.

“This is the first positive phase 3 study evaluating an immunotherapy-based regimen for patients with high-risk, early-stage ER-positive, HER2-negative breast cancer, and an important milestone in our efforts to advance research in early-stage breast cancer,” said Gursel Aktan, MD, vice president, global clinical development, Merck Research Laboratories, in a press release. "We look forward to sharing the detailed results with the medical community and thank the patients and investigators for their important contributions to this study.”

The randomized, double-blind, phase 3 KEYNOTE-756 study is evaluating the combination of pembrolizumab with chemotherapy as neoadjuvant treatment, followed by adjuvant treatment with pembrolizumab plus endocrine therapy for the treatment of patients with high-risk, early-stage ER+/HER2- breast cancer.²

The trial enrolled 1,240 patients who were randomized in a 1:1 to receive pembrolizumab with chemotherapy or placebo and chemotherapy. In the first arm, patients were given pembrolizumab 200 mg every 3 weeks (Q3W) plus chemotherapy for 4 cycles, followed by 4 additional cycles of pembrolizumab and chemotherapy as neoadjuvant therapy prior to surgery, followed by 9 cycles of pembrolizumab (Q3W) plus endocrine therapy as adjuvant therapy post-surgery. The second arm gave patients placebo Q3W with chemotherapy for 4 cycles, followed by 4 additional cycles of placebo in combination with chemotherapy as neoadjuvant therapy prior to surgery, followed by 9 cycles of placebo Q3W plus endocrine therapy as adjuvant therapy post-surgery.

Patients aged 18 years and older with localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist and centrally confirmed ER-positive/HER2-negative, grade 3 breast cancer of ductal histology were eligible for enrollment. Patients must have provided a new or recently obtained core needle biopsy taken from the primary breast tumor(s) for central determination of hormone receptor status, HER2, grade, and PD-L1 status, have adequate organ function, and an ECOG performance status of 0 or 1.

In addition to the dual primary end points of pCR rate and EFS, secondary end points of the study are overall survival and safety.

“While significant advancements have been made in the treatment of ER-positive, HER2-negative breast cancer, people diagnosed with high-risk disease as assessed by clinical and pathologic criteria typically have a worse prognosis and limited options before surgery,” said Fatima Cardoso, MD, director of the Breast Unit of the Champalimaud Clinical Centre, Lisbon, Portugal and co-principal investigator, in the press release.¹ “Data from KEYNOTE-756 suggest that adding pembrolizumab to neoadjuvant chemotherapy before surgery can significantly improve the pCR rate compared to neoadjuvant chemotherapy alone for people with high-risk, early-stage ER-positive, HER2-negative breast cancer.”

REFERENCES:

1. Merck announces phase 3 KEYNOTE-756 trial met primary endpoint of pathological complete response (pCR) rate in patients with high-risk, early-stage ER+/HER2- breast cancer. News release. Merck. July 28, 2023. Accessed July 31, 2023. https://tinyurl.com/287tnv7d

2. Study of pembrolizumab (MK-3475) versus placebo in combination with neoadjuvant chemotherapy & adjuvant endocrine therapy in the treatment of early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer (MK-3475-756/KEYNOTE-756). ClinicalTrials.gov Updated July 28, 2022. Accessed July 31, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03725059