Adding the targeted therapy drug ribociclib (Kisqali®; Novartis) to hormonal (endocrine) therapy showed a significant improvement in invasive disease-free survival (iDFS) for people with HR-positive, HER2-negative early-stage breast cancer.

This conclusion is based on the outcome of the NATALEE study (NCT03701334), which was funded by Novartis Pharmaceuticals.  The results of the study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in Chicago, Illinois. [1]

HR-positive, HER2-negative breast cancer is the most common subtype of the disease, making up nearly 70% of all breast cancer cases in the United States.[2]

“Currently approved targeted treatments can only be used in a small population of patients diagnosed with HR-positive, HER2-negative early breast cancer, leaving many without an effective treatment option for reducing risk of the cancer returning,” said lead author Dennis J. Slamon, MD, PhD, Director of Clinical/Translational Research and Director of the Revlon/UCLA Women’s Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, California.

“Thus, 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,” Slamon added.

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The NATALEE study investigated the addition of ribociclib to standard-of-care adjuvant endocrine therapy and was specifically designed to address these unmet needs,” he further noted.

HR-positive breast cancer makes up about two-thirds of breast cancers and is more common after menopause.[3] According to the authors, about one-third of people with stage II HR-positive, HER2-negative disease experience a recurrence following standard-of-care treatment and more than one-half of people with stage III disease experience a recurrence. If a recurrence occurs, it is often at a more advanced stage.

Targeted therapy
Ribociclib is a type of targeted therapy called a small molecule inhibitor. It works by targeting proteins in breast cancer cells called CDK4 and CDK6, which modulate cell growth, including the growth of cancer cells.

Ribociclib is currently approved by the U.S. Food and Drug Administration (FDA) to treat HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor for premenopausal people or in combination with fulvestrant (Faslodex®; AstraZeneca) for postmenopausal people. While ribociclib has previously shown survival benefits in people with metastatic disease, in this study, researchers showed that it may also improve outcomes for people with earlier-stage disease, including those with cancer that has not yet spread to the lymph nodes.

Study Design
The NATALEE phase 3 clinical trial included 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.

Participants were randomly assigned (1:1) to receive either 400 milligrams (mg/day; 3 wk on/1 wk off for 3 y) of adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years (2,549 patients; letrozole (Femara®; Novartis) 2.5 mg/day or anastrozole (Arimidex®; AstraZeneca) 1 mg/day, for ≥ 5 y) or hormonal therapy alone for at least 5 years (2,552 patients).

Men and premenopausal women also received goserelin (Zoladex®; AstraZeneca/TerSera Therapeutics), an ovarian suppression drug.

Prior hormonal therapy use was allowed if it was initiated no more than 1 year before the start of the study.

The current recommended starting dose of ribociclib for people with metastatic disease is 600 mg. However, an extended duration of treatment can help to stop cells from duplicating and dividing and destroy any remaining cancer cells. Because of this, study authors chose a 3-year treatment duration of ribociclib at a dose of 400 mg to reduce side effects while maintaining efficacy.

Study participants were randomly assigned to receive either adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years or hormonal therapy alone. At a median follow-up of 34 months, 20.2% of participants in the ribociclib group had completed 3 years of treatment and 56.8% had completed 2 years of treatment. Overall, 74.7% of participants remained on the study treatment at data cutoff, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone.

The study found that adding ribociclib to hormonal therapy led to a significant improvement in invasive disease–free survival (iDFS; a primary endpoint) compared with hormonal therapy alone.

Researchers evaluated iDFS after 426 iDFS events occurred, a number that was prespecified for the interim analysis. Of those events, 189 occurred in the ribociclib group (7.4% of patients) vs. 237 in the hormonal therapy alone group (9.2% of patients).

The ribociclib group demonstrated significantly longer iDFS than hormonal therapy alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014), with 3-year iDFS rates in this group at 90.4% compared with 87.1% in the hormonal therapy alone group.

Overall, the addition of ribociclib reduced the risk for recurrence by 25%. The iDFS benefit seen in the ribociclib group was generally consistent across clinically relevant patient subgroups. Ribociclib also showed more favorable outcomes in overall survival, recurrence-free survival, and distant disease-free survival.

Adverse events
For patients receiving ribociclib, the most common adverse effects were neutropenia and joint pain. Rates of gastrointestinal adverse effects and fatigue were low in patients receiving ribociclib. For patients receiving hormonal therapy alone, the most common adverse effects were joint pain and hot flash.

Next Steps
Researchers will continue to evaluate how the addition of ribociclib to hormonal therapy impacts quality of life and will follow patients to observe long-term outcomes.

Clinical trials
A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (NATALEE) – NCT03701334

Highlights of Prescribing Information
Ribociclib (Kisqali®; Novartis)[Prescribing Information]
Fulvestrant (Faslodex®; AstraZeneca)[Prescribing Information]
Letrozole (Femara®; Novartis)[Prescribing Information]
Anastrozole (Arimidex®; AstraZeneca)[Prescribing Information]
Goserelin (Zoladex®; AstraZeneca/TerSera Therapeutics)[Prescribing Information (10.9 mg)][Prescribing Information (3.6 mg)]

[1] Slamon DJ, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: Primary results from the phase III NATALEE trial. J Clin Oncol 41, 2023 (suppl 17; abstr LBA500). DOI 10.1200/JCO.2023.41.17_suppl.LBA500
[2] Cancer Stat Facts: Female Breast Cancer Subtypes. National Cancer Institute (SEER database). Online. Last accessed June 2, 2023.
[3] Breast Cancer: Introduction. Cancer.Net. Online. Last accessed on June 2, 2023.

Featured image: ASCO Annual Meeting, 2023, McCormick Place, Chicago, IL  Photo courtesy: © 2023 ASCO/Scott Morgan. Used with permission.

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