The NATALEE trial is currently underway to evaluate the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) compared with ET alone in a broad population of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC). This Phase III trial aims to address the unmet needs of a wider patient group, including those with stage II and III disease, who often experience recurrence despite standard endocrine therapy.
Background and Rationale
Approximately 80% of breast cancer cases are nonmetastatic, localized to breast tissue and regional lymphatics, and potentially curable with locoregional treatment. However, recurrence remains a significant challenge, with 27-37% of stage II and 46-57% of stage III estrogen receptor-positive (ER+) patients experiencing recurrence up to 20 years after diagnosis. While endocrine therapy is the backbone of adjuvant treatment, a considerable risk of recurrence persists, highlighting the need for more effective strategies.
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown promise in advanced breast cancer (ABC), with ribociclib demonstrating a statistically significant overall survival (OS) benefit. This success has prompted investigation into its potential in EBC. Previous trials with CDK4/6 inhibitors have yielded varying results. While abemaciclib showed a significant invasive disease-free survival (iDFS) benefit in the monarchE trial, it focused on patients with node-positive disease and high-risk clinical features, leaving an unmet need for a broader EBC population.
NATALEE Trial Design and Patient Population
The NATALEE trial includes patients with stage IIA N0 disease (with high-risk features), stage IIA disease with one to three positive nodes (N1), any stage IIB disease, and any stage III disease irrespective of nodal status. This broader inclusion criteria, compared to monarchE, allows for the evaluation of ribociclib in a more representative real-world patient population.
The trial's design incorporates a 3-year duration of ribociclib treatment, the longest among CDK4/6 inhibitor trials in EBC. This extended duration aims to maximize the time-on-target exposure of circulating tumor cells to ribociclib, potentially inducing senescence and preventing both early and late recurrences.
Ribociclib's Mechanism of Action and Potential Benefits
Ribociclib, a selective CDK4 and CDK6 inhibitor, exhibits preferential binding to CDK4, potentially leading to increased time on-target for CDK4 inhibition. Preclinical studies suggest that CDK4 inhibition can drive senescence and an immune response in cancer cell lines. These properties may contribute to a carryover effect, as observed in ABC, where ribociclib has demonstrated long-term OS benefit.
Safety and Tolerability Considerations
The NATALEE trial utilizes a reduced starting dose of 400 mg of ribociclib, compared to the 600 mg dose used in ABC. This dose reduction is expected to improve tolerability by minimizing dose-dependent toxicities, such as neutropenia and increased alanine aminotransferase or aspartate aminotransferase, without compromising efficacy. Maintaining quality of life (QOL) is a critical consideration in the adjuvant setting, and the reduced dose aims to minimize adverse events that could impact adherence and overall outcomes.
Addressing Unmet Needs and Future Directions
The NATALEE trial has the potential to address many important unmet needs in the treatment of HR+/HER2- EBC. Its results could provide an additional option for a broader range of patients, including those with node-negative disease and stage II/III disease. Furthermore, ongoing research endeavors are exploring whether ribociclib-based regimens could potentially spare the need for chemotherapy in certain patients, offering a more personalized treatment approach.
The results of the NATALEE trial are eagerly awaited, as they could significantly impact the treatment landscape for HR+/HER2- EBC and provide valuable insights into the role of CDK4/6 inhibitors in preventing recurrence and improving long-term outcomes.
