New hope for certain breast cancer patients comes in the form of findings presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. 

The research, published in Therapeutic Advances in Medical Oncology, regards the ongoing phase 3 New Adjuvant Trial with Ribociclib [LEE011] (referred to as NATALEE). The trial looked at the efficacy of adjuvant ribociclib (also known as Kisqali) and endocrine therapy (ET)—a small molecule inhibitor designed to target and disrupt cell growth–modulating proteins CDK4 and CDK6 in breast cancer cells—in patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) early nonmetastatic breast cancer.

CDK4/6 Inhibitors. Susan G. Komen®.

  

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2− early breast cancer. Therapeutic Advances in Medical Oncology.

 

The findings showed that ribociclib, along with ET, could reduce cancer recurrence risk by 25%.

PM TAPSP 6/2/2023 2:48:00 PLU 6/2/2023 1:54:27. Adding ribociclib to endocrine therapy may reduce recurrence risk in patients with hr-positive, her2-negative early-stage breast cancer - the asco post.

 

 

 

Treating HR+/HER2− breast cancer

 

HR+/HER2− early breast cancer is the most common type of breast cancer, accounting for 70 to 75% of cases. Patients are typically treated with adjuvant endocrine therapy (ET) over five years—with additional treatment if necessary. Patients with this type of breast cancer may also require chemotherapy, depending on the risk of cancer recurrence and whether the treating physician sees specific benefits for a given patient.

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2− early breast cancer. Therapeutic Advances in Medical Oncology.

 

 

This is where ribociclib enters the picture. Initially, ribociclib was shown to benefit patients with metastatic breast cancer. However, the NATALEE trial suggests that the drug can also improve results in patients with early-stage breast cancer and in patients with cancer that hasn’t spread to the lymph nodes.

Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of breast cancer. ASCO.

 

 

 

A closer look at the NATALEE trial

 

The NATALEE trial includes “men and premenopausal or postmenopausal women from 20 different countries with stage IIA, IIB, or III HR-positive, HER2-negative breast cancer at risk for recurrence,” according to an ASCO news release.

Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of breast cancer. ASCO.

 

 

A total of 2,549 participants received 400 milligrams (mg) of adjuvant ribociclib for three years, along with ET for at least five years, while 2,552 patients received only ET for at least five years.

Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of breast cancer. ASCO.

 

 

During an interim analysis of invasive disease–free survival (iDFS) events, the researchers found that 189 participants taking ribociclib experienced cancer recurrence versus 237 patients undergoing only ET.  “Adding ribociclib to hormonal therapy led to a significant improvement in iDFS. The 3-year iDFS rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group,” the ASCO press release noted. Additionally, it stated, “Ribociclib also showed more favorable outcomes in overall survival, recurrence-free survival, and distant disease-free survival.”

Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of breast cancer. ASCO.

 

“Use of a CDK4/6 inhibitor with endocrine therapy has become a standard of care in the treatment of this population of breast cancer patients,” Andrew Hertler, MD, FACP, Chief Medical Officer at New Century Health, tells MDLinx.

 

How does the drug work, exactly?  

 

“The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vivo studies of ribociclib showed that it led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation,” Hertler explains. 

The researchers said that giving ribociclib to participants for three years was the longest time that CDK4/6 inhibitors for early breast cancer were tested. The length of time was chosen to “maximize time-on-target exposure of any circulating tumor cells to ribociclib. This is intended to move these cells from a cell cycle arrest stage to a state of senescence (stable cell cycle arrest), even after ribociclib treatment is stopped. Prolonged cell cycle arrest may decrease recurrences that can occur up to 20 years after diagnosis due to circulating tumor cells.”

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2− early breast cancer. Therapeutic Advances in Medical Oncology.

 

 

The drug is also not without side effects. ASCO noted that common adverse outcomes for patients receiving ribociclib included neutropenia and joint pain. Low rates of gastrointestinal issues and fatigue were also present.

Adding ribociclib to hormonal therapy reduces risk of recurrence for people with most common subtype of breast cancer. ASCO.

 

 

 

How is ribociclib changing the landscape? 

 

Lead study author Dennis Slamon, MD, director of Clinical/Translational Research and director of the Revlon/UCLA Women's Cancer Research Program at the University of California, Jonsson Comprehensive Cancer Center, stated in the ASCO news release that, “Currently approved targeted treatments can only be used in a small population of patients diagnosed with [hormone receptor]-positive, HER2-negative early breast cancer, leaving many without an effective treatment option for reducing risk of the cancer returning.” 

Thus, Slamon says, there is a “significant unmet need for both reducing the risk of recurrence and providing a tolerable treatment option that keeps patients cancer-free without disrupting their daily life. The NATALEE study investigated the addition of ribociclib to standard-of-care adjuvant endocrine therapy and was specifically designed to address these unmet needs.”

The researchers also noted, "All three ribociclib Phase III trials have reported a statistically significant and clinically meaningful OS [overall survival] benefit in pre-and postmenopausal patients. Ribociclib has set a new benchmark for survival, with an unprecedented median OS of  >5 years when combined with letrozole or fulvestrant in the first-line setting in ABC [advanced breast cancer].”

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2− early breast cancer. Therapeutic Advances in Medical Oncology.

 

Ribociclib is currently approved by the U.S. Food and Drug Administration (FDA), in combination with an aromatase inhibitor “for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer,” according to the FDA.

Research C for DE and. Ribociclib(Kisqali). FDA. Published online May 3, 2023.

 

As Hertler says, “If ribociclib receives FDA approval for adjuvant use in early-stage breast cancer without nodal involvement, this could give it an advantage compared to abemaciclib, another CDK4/6 inhibitor [that] requires patients to have node-positive, early breast cancer at high risk of recurrence.”