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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
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. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant Endocrine Therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.
Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.
Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.
NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Safety, Quality of Life, and Overall Survival.
At a median follow up of 34 months, as of data cutoff, 74.7% of patients remained on study treatment, with 1,984 patients on Ribociclib and 1,826 patients on Endocrine Therapy alone. The addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%. The 3-year invasive DFS rates were 90.4% in the Ribociclib group, compared with 87.1% in the Endocrine Therapy alone. This invasive DFS benefit was generally consistent across stratification factors and other subgroups. There was a trend towards improvement in Overall Survival with the addition of Ribociclib, although further follow up is needed. This regimen had a favorable safety profile with no new safety signals.
It was concluded from this study that the addition of Ribociclib to Endocrine Therapy demonstrated a statistically significant, clinically meaningful improvement in invasive Disease Free Survival, with a well-tolerated safety profile. The authors added that this study results support the addition of Ribociclib to Endocrine Therapy as the treatment of choice in a broad group of patients with Stage II or III HR+/HER2-negative early breast cancer, including those with high risk node negative disease. The lower dose of Ribociclib chosen in this study and given over an extended 3-year period may be important to prolong cell cycle arrest and drive more tumor cells into senescence or death.
Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. DOI: 10.1200/JCO.2023.41.17_suppl.LBA500 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA500-LBA500.
