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. 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. 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. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first line treatment of advanced TNBC.
KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-Paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS-Combined Positive Score of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety.
In the primary analysis of the KEYNOTE-355 trial, the Overall Survival results after a median follow up of 44.1 months in the subgroup of patients with PD-L1 CPS (Combined Positive Score) of 10 or more was significantly better with first line KEYTRUDA® plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively; HR=0.73; P=0.0093). This represented a 27% reduction in the risk of death with the KEYTRUDA® combination. KEYTRUDA® in combination with chemotherapy, also significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. However, among patients with CPS of 1 or greater, the median PFS was not considered statistically significant, based on prespecified statistical criteria.
The researchers here in presented the results of a subgroup analysis, stratified by levels of PD-L1 expression, as assessed by CPS score. In the subgroups with CPS scores of less than 1 and 1-9, Overall Survival was similar for KEYTRUDA® plus chemotherapy and placebo plus chemotherapy. However, in subgroups with CPS 10-19 and CPS 20 or more, there was sustained separation of the Overall survival curves starting at approximately 10 months and the survival was improved by about 28%.
The authors noted that the general trend for PFS was consistent with that observed for Overall Survival, with improving PFS trend among those subgroups with PD-L1 enriched CPS of 10 or more. In the subgroup of patients with a CPS of 10-19 and CPS of 20 or more, the addition of KEYTRUDA® to chemotherapy resulted in a more sustained separation of PFS curves, beginning at approximately 4 months, compared with placebo plus chemotherapy. The Hazard Ratios for these two groups were 0.70 and 0.62, respectively. Toxicities of any grade were reported in 96% of the experimental group and 95% of the placebo plus chemotherapy group. The rate of Grades 3-5 treatment-related adverse events was 68.1% and 66.9%, respectively and the majority of treatment discontinuations in this study were for progressive disease.
The researchers based on this subgroup analyses concluded that a CPS of 10 or more is a reasonable cutoff to define the population of women with metastatic Triple Negative Breast Cancer, expected to derive treatment benefit from KEYTRUDA® plus chemotherapy, lending further support to KEYTRUDA® plus chemotherapy as a standard of care treatment regimen for this group of patients.
Final results of KEYNOTE-355: randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortés J, Cescon DW, Rugo HS, et al. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-02.
