Pembrolizumab in combination with chemotherapy is already FDA-approved for the treatment of patients with triple-negative breast cancer – in the setting of early or metastatic diseases.
Here we approach the main studies that led to these approvals. Annually in Brazil the breast cancer represents approximately 28% of new cases of cancer – being the second type of neoplasm more incident among women. The diseases are considered heterogenous and its molecular subtype differ in genomic complexity, major genetic alterations, and clinical prognosis.
The group of patients with the disease that expresses hormone receptors (HR+/HER2-) is the most prevalent – represents approximately 70% of cases. The group of patients HER2+ is the group referred triple-negative breast cancer (HR-/HER-), represent respectively about 20% and 15% of patients with this type of cancer.
In that regard, triple negative breast cancer (TNBC) differs from other types of breast cancer in that it grows and spreads faster, in addition to having limited treatment options and worse prognosis.
Pembrolizumab is a highly selective, humanized, PD-1-targeted monoclonal antibody. This drug has demonstrated robust antitumor activity and a favorable safety profile in several types of tumors, which has led to regulatory approval by ANVISA in at least 20 different indications. It has been investigated alone and in combination with other antitumors therapies.
Programmed death pathway 1 (PD-1) represents an immunological checkpoint used by tumor cells to avoid attack by tumor-targeted T cells. PD-1 is expressed on the surface of activated T cells, where it interacts with its ligands to attenuate signaling – which results in downregulation of T cell proliferation, inhibiting the antitumor immune response.
Therefore, tumors may express programmed death ligands 1 and 2 (PD-L1 and PD-L2, respectively) as a mechanism of adaptation to the immune system. In the case of breast cancer, although PD-L1 is rarely expressed in normal breast tissue, it can be expressed in some breast cancer cells and surrounding immune cells, where it can mediate inhibition of tumor-infiltrating lymphocytes (TILs). In this context, pembrolizumab becomes a drug with high therapeutic potential for patients with triple negative breast cancer.
In the phase Ib study KEYNOTE-012 (NCT02447003), pembrolizumab treatment showed durable antitumor activity and manageable safety in a subset of patients with TNBC metastatic (n=32) pre-treated and has PD-L1 positive.
The phase II study KEYNOTE-086 (NCT02447003) evaluated pembrolizumab monotherapy in two cohorts of patients with metastatic TNBC. Cohort A included 170 patients with metastatic TNBC previously treated, regardless of PD-L1 expression; and cohort B evaluated the use of pembrolizumab as monotherapy in 84 patients with metastatic TNBC previously untreated PD-L1 positive. In this study, pembrolizumab demonstrated the same safety profile and showed durable antitumor activity as a first-line therapy for this profile of patients.
Because of these promising results, the randomized, open-label, phase III study KEYNOTE-119 (NCT02555657) was designed to evaluate the use of pembrolizumab versus chemotherapy in participants with metastatic TNBC previously treated.
In this study, pembrolizumab did not improve the overall survival of patients in the second- or third-line setting compared with chemotherapy. However, through exploratory analyzes in subgroups with higher expression of PD-L1, it was observed that the effect of treatment with pembrolizumab increased as the enrichment of PD-L1 increased, and that the antitumor activity of pembrolizumab is better in the scenario of first-line treatment.
Based on the rationale that immunological checkpoint inhibition can enhance endogenous antitumor immunity following increased release of tumor-specific antigens with chemotherapy, the phase 3 study KEYNOTE-355 (NCT02819518) was designed.
This study aimed to compare the efficacy and safety of pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients previously untreated with inoperable locally recurrent or metastatic TNBC. According to the study design, the investigator could choose between three chemotherapies: nab-paclitaxel, paclitaxel or gemcitabine with carboplatin.
To be eligible in this study, patients had to be at least 18 years, centrally confirmed TNBC – as defined by ASCO guidelines, and at least one measurable lesion based on RECIST version 1.1.
Patients with de novo metastatic TNBC were eligible for the study. Patients who completed treatment for stage I-III breast cancer were eligible if at least 6 months had elapsed between completion of treatment with curative intent.
Chemotherapy with pembrolizumab showed significant improvement and clinical improvement in overall survival (HR, 0.73, 95% CI, 0.55 – 0.95, P=0.0093 [threshold P value, 0.0113]). Also achieving significant results and clinical improvement in progression-free survival versus chemotherapy and placebo in patients with metastatic TNBC with PD-L1 positive (CPS of 10 or greater) (HR, 0.65, IC 95% , 0.49–0.86; one-sided P =0.0012 [P value limit, 0.00411]). These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.
In the context of early TNBC disease, a phase 3 study KEYNOTE-522 (NCT03036488) was performed to assess the efficacy and safety of neoadjuvant chemotherapy with pembrolizumab compared to neoadjuvant chemotherapy with placebo followed by adjuvant pembrolizumab or placebo in patients with early triple negative breast cancer.
Patients were eligible for inclusion if they were at least 18 years, centrally confirmed TNBC in all focus, and newly diagnosed non-metastatic disease – previously untreated (tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2 by the AJCC).
This study demonstrated that 64.8% of patients in the pembrolizumab group (IC 95%, 59.9-69.5) versus 51.2% of patients (IC 95%, 44.1-58.3) in the placebo group achieved pathological complete response (difference between treatments in response rate: 13.6; IC 95% , 5.4-21.8; P<0.001). In addition, the 36-month event-free survival rate was 84.5% (IC 95% , 81.7-86.9) – in the pembrolizumab group versus 76.8% (IC 95% , 72.2- 80.7) – in the placebo group (HR 0.63; IC 95%, 0.48-0.82; P=0.0003). An event was defined as disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. Together, these data suggests a role for adding pembrolizumab to standard chemotherapy in the treatment of metastatic triple-negative breast cancer, in the early disease setting as well as in the metastatic setting. References:
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