FDA Approves KEYTRUDA® for High Risk Early Stage Triple Negative Breast Cancer

SUMMARY: The FDA on July 26, 2021, approved KEYTRUDA® (Pembrolizumab) for high risk, early stage, Triple Negative Breast Cancer (TNBC), in combination with chemotherapy, as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment following surgery. The FDA also granted regular approval to KEYTRUDA® in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score – CPS 10 or more), as determined by an FDA approved test. FDA granted accelerated approval to KEYTRUDA® for this indication in November 2020.

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. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

KEYTRUDA® (Pembrolizumab) 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. Cytotoxic chemotherapy releases tumor-specific antigens and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Preliminary results from Phase I and II trials have shown that in patients with TNBC, KEYTRUDA® given along with chemotherapy in a neoadjuvant setting resulted in a high rate of pCR.

The present FDA approvals were based on KEYNOTE-522, which is an international, randomized, multicenter, double-blind, placebo controlled Phase III trial, conducted to evaluate the safety and efficacy of neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® or placebo, in patients with early stage TNBC. In this study, 1,174 patients were randomly assigned in a 2:1 ratio to receive neoadjuvant KEYTRUDA® 200 mg IV every 3 weeks (N=784) or placebo (N=390). All patients received 4 cycles of Carboplatin plus Paclitaxel, followed by 4 cycles of Doxorubicin or Epirubicin plus Cyclophosphamide, in the neoadjuvant setting. Following definitive surgery, adjuvant KEYTRUDA® or placebo was continued every 3 weeks for 9 cycles or until disease recurrence or unacceptable toxicity. Enrolled TNBC patients were newly diagnosed, early stage, high risk, treatment naïve, and included both node-negative and node-positive patients with nonmetastatic disease (Tumor Stage T1c, Nodal Stage N1-N2 or Tumor Stage T2-T4, Nodal Stage N0-N2, per AJCC criteria). Patients were enrolled regardless of tumor PD-L1 expression. Treatment groups were well balanced and patients were stratified according to nodal status, tumor size, and Carboplatin schedule (weekly versus every 3 weeks). The two Primary endpoints were pathological Complete Response (pCR) at the time of definitive surgery and Event Free Survival (EFS).

At the first interim analysis, at a median follow up of 15.5 months, the pCR among the first 602 patients who underwent randomization was 64.8% in the KEYTRUDA® plus chemotherapy group, compared with 51.2% in the placebo plus chemotherapy group (HR=0.63; P<0.001). At the median follow-up of 39 months, EFS data were made available, and this showed that KEYTRUDA® demonstrated a statistically significant EFS benefit compared with chemotherapy alone. The number of patients who experienced an EFS event was 16% and 24%, respectively (HR=0.63; P=0.00031). Among patients who were in the PD-L1 positive, defined as those with a CPS of 1 or higher, there was a 33% reduced risk of EFS events with KEYTRUDA® compared with the placebo group (HR=0.67). In the PD-L1 negative group, patients receiving the KEYTRUDA® combination had a reduced risk for EFS events by 52% compared with the placebo-chemotherapy group (HR=0.48). Across all treatment phases, Grade 3 or higher treatment-related toxicities were 78.0% in the KEYTRUDA® plus chemotherapy group and 73.0% in the placebo plus chemotherapy group

It can be concluded from this study that among patients with early stage Triple Negative Breast Cancer, the addition of KEYTRUDA® to neoadjuvant chemotherapy significantly increased the pathological Complete Response rate, compared to those who received placebo plus neoadjuvant chemotherapy, with a statistically significant Event Free Survival benefit. This KEYTRUDA® combination therapy is a meaningful milestone for breast cancer patients, and is the first immunotherapy regimen to be approved in high risk, early stage Triple Negative Breast Cancer.