SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years (Lancet Oncol. 2018;19:27-39).
The promising efficacy observed with single-agent checkpoint blockade for advanced HER2-negative breast cancer, and the significant benefit observed with PD-1 inhibitors combined with chemotherapy for lung cancer and other cancer types, led the researchers to evaluate the efficacy of adding Pembrolizumab to standard neoadjuvant chemotherapy. In the Phase 2 I-SPY2 trial, Pembrolizumab plus neoadjuvant chemotherapy improved estimated pathological Complete Response rates versus neoadjuvant chemotherapy alone, at 30% versus 13%, in patients with HR-positive, HER2-negative breast cancer.
Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity.
Pembrolizumab is approved for the treatment of patients with high-risk early-stage Triple Negative Breast Cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, as well as in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or more).
KEYNOTE-756 is a global, randomized, double-blind, Phase III trial, conducted to assess the efficacy and safety of Pembrolizumab versus placebo, in combination with neoadjuvant chemotherapy followed by adjuvant treatment with Pembrolizumab plus endocrine therapy, in adults with high-risk, early stage ER-positive HER2- negative breast cancer. In this study 1,278 enrolled patients (N=1278) were randomized 1:1 to receive Pembrolizumab 200 mg IV ever 3 weeks or placebo, both given with Paclitaxel weekly for 12 weeks, followed by 4 additional cycles of Doxorubicin or Epirubicin plus Cyclophosphamide (neoadjuvant treatment) prior to surgery. Following definitive surgery with or without radiation treatment, patients received Pembrolizumab or placebo every 3 weeks for 9 cycles plus endocrine therapy for up to 10 years, as adjuvant therapy post-surgery. Eligible patients had centrally confirmed T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, Grade 3, ER-positive, HER2-negative, invasive ductal carcinoma, and were treatment-naive. Both treatment groups were well balanced. The median age was 49 years, about 76% of patients in each treatment group had a PD-L1 CPS of 1 or higher, about 40% had a CPS of 10 or higher, and about 90% had nodal involvement. About 62% of patients had Stage II disease, and 38% had Stage III disease. The dual Primary endpoints were pathological Complete Response (pCR) rate (ypT0/Tis ypN0), defined as absence of invasive cancer in the breast and axillary lymph nodes at the time of surgery, and Event Free Survival (EFS). Secondary endpoints included Overall Survival and Safety.
With a median follow-up of 33.2 months, the study demonstrated a statistically significant improvement in pCR rates with Pembrolizumab compared to placebo. The pCR rate in the intention-to-treat (ITT) population was 24.3% with Pembrolizumab versus 15.6% with placebo (absolute difference 8.5%; P = 0.00005). Similar improvements were observed across various subgroups, including patients with Stage II or III disease, positive lymph nodes at baseline, and higher PD-L1 expression levels. Pembrolizumab demonstrated superior efficacy across geographic regions and exhibited a linear improvement in pCR rates with increasing PD-L1 expression.
Further analyses showed a greater pCR benefit with Pembrolizumab in patients with low estrogen receptor (ER) positivity (defined as less than 10% of ER-positive cells), node positive disease and those with higher PD-L1 expression. Pembrolizumab recipients who received full-dose chemotherapy had a greater pCR benefit compared to those who received reduced chemotherapy doses. Additionally, Pembrolizumab recipients were more likely to shift to lower Residual Cancer Burden (RCB) groups post-surgery. The trial also observed higher rates of immune-mediated adverse events with Pembrolizumab compared to placebo, with common events including hypothyroidism, hyperthyroidism, and pneumonitis.
It was concluded from this study that, the addition of Pembrolizumab to neoadjuvant chemotherapy followed by adjuvant Pembrolizumab plus endocrine therapy, significantly improves pCR rates in patients with early stage, high risk ER-positive, HER2-negative breast cancer. Further assessment of long term outcomes, including Event-Free Survival and Overall Survival is ongoing to fully evaluate the clinical benefit of this treatment approach. The study sponsors added that this is the first positive Phase III study, evaluating an immunotherapy-based regimen for patients with high risk, early stage ER-positive, HER2-negative breast cancer, and an important milestone in advancing research, in early stage breast cancer.
Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2- breast cancer: KEYNOTE-756. Cardoso F, O’Shaughnessy J, McArthur H, et al. Presented at SABCS 2023. December 5-9, 2023. San Antonio, TX. Abstract GS01-02.
