On October 20, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the first presentation of results from the neoadjuvant part of the Phase 3 KEYNOTE-756 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy as neoadjuvant treatment, followed by KEYTRUDA plus endocrine therapy as adjuvant treatment, for patients with high-risk, early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer (Press release, Merck & Co, OCT 20, 2023, View Source;Breast-Cancer/?feedref=JjAwJuNHiystnCoBq_hl-SZsvSFSeS2k6e-jDETKtk7rEQumBjqILHhqiwHg7GoJnkvYMqDDYxFrLs-oQ2BHQ-mJCMFkCosC_NGzuJ8TW18j0KvNpL5ik-rnXyj1_o5vU-QF2vCj0ELWlPt_oGwViA== [SID1234636183]). KEYTRUDA plus chemotherapy before surgery met one of its dual primary endpoints of pathological complete response (pCR), demonstrating a statistically significant improvement in pCR rate compared to placebo plus chemotherapy. The pCR rate increased from 15.6% in patients treated with neoadjuvant chemotherapy alone (n=100/643) to 24.3% in patients treated with neoadjuvant KEYTRUDA plus chemotherapy (n=154/635), an estimated increase of 8.5 percentage points (p=0.00005). A pCR rate is defined as a lack of all signs of cancer in tissue samples analyzed following completion of neoadjuvant therapy and definitive surgery (ypT0/Tis ypN0). The trial is currently continuing without changes to evaluate event-free survival (EFS), the other dual primary endpoint of the study, per the trial design.

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These pCR results are being featured today during a late-breaking proffered paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (abstract #LBA21). The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies.

"Results from KEYNOTE-756, together with our work across our oncology portfolio, demonstrate the progress we are making in earlier stages of certain cancers, including breast cancer," said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. "KEYNOTE-756 is the first positive Phase 3 trial with an immunotherapy regimen to demonstrate a statistically significant improvement in pCR rate in the neoadjuvant setting for patients with high-risk, early-stage ER-positive, HER2-negative breast cancer. These results support the potential of a KEYTRUDA-based regimen for more patients with difficult-to-treat types of early-stage breast cancer."

"With high rates of recurrence, patients with high-risk, early-stage ER-positive, HER2-negative breast cancer are in need of new treatment options," said Dr. Fatima Cardoso, director of the Breast Unit of the Champalimaud Clinical Centre, Lisbon, Portugal, and co-principal investigator. "While we await results from the dual primary endpoint of event-free survival, we are encouraged by data from KEYNOTE-756 in which the pembrolizumab-based regimen demonstrated a statistically significant improvement in pathological complete response rate compared to chemotherapy."

"The goal of neoadjuvant therapy is to reduce the size of the tumor prior to surgery," said Dr. Aditya Bardia, attending physician, medical oncology, Massachusetts General Hospital, director, breast cancer research, Massachusetts General Cancer Center, associate professor, Harvard Medical School and global co-principal investigator. "In KEYNOTE-756, 24.3% of patients treated with neoadjuvant pembrolizumab plus chemotherapy achieved a pathological complete response, a meaningful endpoint demonstrating there was no cancer in tissue samples analyzed and obtained at the time of definitive surgery following completion of neoadjuvant therapy for these patients. Overall, the study met one of its primary endpoints and we are looking forward to data for the other dual primary endpoint of event-free survival in the future."

As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at ESMO (Free ESMO Whitepaper) Congress 2023.

Study design and additional data from KEYNOTE-756

KEYNOTE-756 is a randomized, double-blind, Phase 3 trial (ClinicalTrials.gov, NCT03725059) that is fully accrued, evaluating KEYTRUDA in combination with chemotherapy as neoadjuvant treatment, followed by adjuvant treatment with KEYTRUDA plus endocrine therapy for the treatment of high-risk, early-stage ER+/HER2- breast cancer. The dual primary endpoints are pCR rate (ypT0/Tis ypN0) and EFS, and secondary endpoints include overall survival. The trial enrolled 1,240 patients who were randomized 1:1 to receive:

KEYTRUDA (200 mg every three weeks [Q3W]) plus chemotherapy (paclitaxel weekly) for four cycles, followed by four additional cycles of KEYTRUDA in combination with chemotherapy (doxorubicin or epirubicin plus cyclophosphamide) as neoadjuvant therapy prior to surgery, followed by nine cycles of KEYTRUDA (Q3W) plus endocrine therapy (for up to 10 years) as adjuvant therapy post-surgery; or,
Placebo (Q3W) plus chemotherapy (paclitaxel weekly) for four cycles, followed by four additional cycles of placebo in combination with chemotherapy (doxorubicin or epirubicin plus cyclophosphamide) as neoadjuvant therapy prior to surgery, followed by nine cycles of placebo (Q3W) plus endocrine therapy (for up to 10 years) as adjuvant therapy post-surgery.
Results from KEYNOTE-756 were consistent for secondary pCR definitions (ypT0 ypN0 and ypT0/Tis). In the neoadjuvant phase of the study, no new safety signals for KEYTRUDA were identified. Among all patients treated, 52.5% of those who received KEYTRUDA plus chemotherapy and 46.4% of those who received chemotherapy experienced Grade 3-5 adverse events (AEs). Treatment-related AEs in the neoadjuvant part of the study that led to discontinuation of any drug occurred in 19.1% of patients treated with KEYTRUDA plus chemotherapy and 10.1% who received chemotherapy. There was one death in the KEYTRUDA arm due to acute myocardial infarction; it was not related to KEYTRUDA.

About breast cancer

Breast cancer is one of the leading causes of cancer-related death in women worldwide, with more than two million patients diagnosed and approximately 685,000 deaths from the disease globally in 2020. In the U.S., it is estimated there will be approximately 298,000 patients diagnosed with breast cancer and 43,700 deaths from the disease in 2023. There are many different types of breast cancer and various subtypes. Of all breast cancer patients, about 70% will be diagnosed with hormone receptor-positive, HER2-negative disease. Cancer recurrence following surgery for this type of cancer is most common within five years, and patients with high-risk features have a greater chance of recurrence.