Ribociclib plus endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer

The NATALEE trial met its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in invasive disease-free survival with ribociclib plus endocrine therapy as compared to endocrine therapy alone in patients with HR+/HER2− early breast cancer. Furthermore, the three-year regimen of ribociclib at the 400 mg starting dose in the adjuvant setting was well tolerated.

To date, the majority of breast cancer cases are diagnosed at early stages. The current standard-of-care (SOC) for patients with HR+/HER2- early breast cancer (EBC) is surgery, with or without chemotherapy or radiation, followed by 5-10 years of adjuvant endocrine therapy (ET). However, even after receiving adjuvant ET, one-third of patients with stage II and more than half of patients with stage III HR+/HER2- EBC will experience disease recurrence up to decades after cancer diagnosis. Ribociclib is a CDK4/6 inhibitor that improved overall survival (OS) while maintaining or improving quality of life in patients with HR+/HER2- advanced breast cancer. The NATALEE study was specifically designed to assess ribociclib plus SOC ET in patients with HR+/HER2- EBC with the aim of addressing the unmet needs for this broad patient population.

Study design

The phase III multicentre, randomised, open-label NATALEE trial evaluated the efficacy and safety of ribociclib plus ET as adjuvant treatment in patients with HR+, HER2– EBC. Eligible women (any menopausal status) and men aged ≥ 18 years are randomised to ribociclib 400 mg/day (3 weeks on/1 week off) + ET or ET alone. ET consists of daily continuous letrozole 2.5 mg/day or anastrozole 1 mg/day. Both men and premenopausal women also receive goserelin 3.6 mg once every 28 days. Treatment with ribociclib will last for three years whereas treatment with ET (in both arms) will last for five years. Patients must have had American Joint Committee on Cancer (8th ed.) Anatomic Stage II (either N0 with grade 2-3 and/or Ki67 ≥ 20% or N1) or III EBC, with an initial diagnosis ≤ 18 months prior to randomisation, and completed chemotherapy and radiotherapy (if indicated). Patients receiving standard (neo)adjuvant ET are eligible only if this treatment was initiated within 12 months of randomisation. Stratification factors were menopausal status, anatomical stage, prior (neo)adjuvant chemotherapy, and geographic region.

Results

Patients were randomised to receive either adjuvant ribociclib with hormonal therapy (N= 2,549) or hormonal therapy alone (N= 2,552). After a median follow-up of 34 months, 20% of patients in the ribociclib arm had completed three years of treatment and 57% had completed two years of treatment. The three-year iDFS rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group (HR[95%CI]: 0.748[0.618-0.906], p= 0.0014). Overall, the addition of ribociclib thus reduced the risk of recurrence by 25%. Moreover, the iDFS benefit was generally consistent across patient subgroups, regardless of disease stage, menopausal status or nodal status. Furthermore, the risk of distant disease was reduced by 26.1% in the ribociclib arm as compared to the hormonal therapy alone group. Finally, ribociclib showed a trend for improved overall survival (HR[95%CI]: 0.759[0.539-1.068], p= 0.0563).

In terms of safety, it should be noted that patients received a reduced dose of 400 mg/day, as compared to the current recommended starting dose of ribociclib for patients with metastatic disease of 600 mg. Study authors chose a three-year treatment duration of ribociclib of 400 mg/day to reduce side effects while maintaining efficacy. This extended duration of treatment is crucial to prolong cell cycle arrest and drive more tumour cells into irreversible senescence. The most frequent all-grade adverse events (ribociclib + ET vs. ET alone) leading to discontinuation were liver-related adverse events (8.9% vs. 0.1%) and arthralgia (1.3% vs. 1.9%). Compared with ribociclib at a starting dose of 600 mg, the SOC in the advanced setting, the 400 mg starting dose in the adjuvant setting demonstrated lower rates of neutropenia and QTc prolongation.

Conclusion

The improvement in iDFS that was observed with the addition of ribociclib to ET is statistically significant and clinically meaningful. In addition, this benefit was consistent across patient subgroups, including patients with node-negative disease. The three-year regimen of ribociclib at a 400 mg starting dose in the adjuvant setting was well tolerated. All together, results from the NATALEE trial support ribociclib plus ET as a new treatment of choice in a broad population of patients with stage II or III HR+/HER2- early breast cancer at risk of recurrence.

Reference

Slamon D, 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. Presented at ASCO 2023; Abstract LBA500.