Is ribociclib plus endocrine therapy effective for high-risk early breast cancer?
Takashi Kuwayama
, Masakazu Toi
Keywords: Ribociclib; endocrine therapy; adjuvant; breast cancer
Received: 01 July 2024; Accepted: 05 September 2024; Published online: 15 October 2024.
doi: 10.21037/actr-24-114
Breast cancer is the most common cancer among women worldwide. Approximately 23,000,000 new cases are diagnosed annually, with 685,000 deaths each year in the world, second only to lung cancer (1). And half of the new cases are diagnosed in Asian countries (2). In Japan, 56.7% of newly diagnosed breast cancer were hormone receptor-positive, HER2-negative (3). Hormone receptor-positive breast cancer is considered to be a type of breast cancer with a relatively good prognosis, as it responds well to endocrine therapy. However, in approximately 20% of hormone receptor-positive breast cancers, the effectiveness of endocrine therapy is low, and these cases are considered to be at high risk of recurrence. In hormone receptor-positive, HER2-negative metastatic breast cancer, the combination of endocrine therapy and cyclin-dependent kinase (CDK)4/6 inhibitors has shown a significant improvement in progression-free survival (PFS) compared to endocrine therapy alone (4-12) and this therapeutic option was recommended in many guidelines (13-16). However, the efficacy of CDK4/6 inhibitors as adjuvant therapy in high-risk recurrent estrogen receptor-positive breast cancer has been inconsistent.
In high-risk hormone receptor-positive HER2-negative breast cancer, previous trials include the monarchE trial using abemaciclib, the PALLAS trial using palbociclib, and the PENELOPE-B trial. A summary of each trial is shown in Table 1. In the monarchE trial, a significant improvement in 3-year invasive disease-free survival (IDFS) was observed with the combination group at 88.9%, compared to 83.8% for the endocrine therapy alone group. Moreover, disease-free survival of the combination group was better one year after randomization, the separation became more pronounced. This indicates at least a carry-over effect for two years following the treatment (17). However, the PALLAS (18) and PENELOPE-B (19) trials did not show an improvement in IDFS with the combination therapy. In the PALLAS trial, the 3-year IDFS was 89.4% for the combination group and 89.3% for the endocrine therapy alone group. In the PENELOPE-B trial, the 3-year IDFS was 81.2% for the combination group and 77.7% for the endocrine therapy alone group. In these studies, low feasibilities, among other factors, were pointed out as a cause of results.
Table 1
| Author | Year | CDK4/6 | N | Menopausal status | Stage | Nodal status | Grade | Chemotherapy | Duration (months) | Endocrine treatment | Median follow-up (months) | AE and SAE | Discontinuation | Dose reduction |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Johnston et al. (17) | 2020 | Abemaciclib | 5,637 | Pre 44% | 2A: 12% | 0 0% | 1: 7.5% | 98% | 24 | TAM 30% | 42 (abemaciclib: 24) | AE 97.9% | Abemaciclib + endocrine therapy 6.4% | Abemaciclib + endocrine therapy 43.6% |
| Post 56% | 2B or 3: 88% | 1–3: 40% | 2: 49.2% | AI 70% | SAE 13.3% | |||||||||
| 4–9: 40% | 3: 38.0% | |||||||||||||
| ≥10: 20% | NA: 5.0% | |||||||||||||
| Mayer et al. (18) | 2021 | Palbociclib | 5,761 | Pre 45.6% | 1 or 2A: 17.9% | N0: 13.0% | 1 or 2: 67.6% | 82.5% | 24 | TAM 32% | 31 | AE 99.5% | – | – |
| Post 54.4% | 2B or 3: 82.1% | N1: 49.3% | 3: 27.9% | AI 67% | SAE 13.0% | |||||||||
| N2: 24.5% | NA: 4.4% | |||||||||||||
| N3: 13.2% | ||||||||||||||
| Loibl et al. (19) | 2021 | Palbociclib | 1,250 | Pre 49.3% | N0: 5.4% | 1: 5.4% | 100% | 12 | TAM 49.8% | 42.8 | AE 98.5% | – | – | |
| Post 50.7% | N1: 44.5% | 2: 55.5% | AI 50.2% | SAE 16.9% | ||||||||||
| N2: 36.9% | 3: 39.1% | |||||||||||||
| N3: 13.2% | ||||||||||||||
| Slamon et al. (20) | 2024 | Ribociclib | 5,101 | Pre 43.9% | 1 or 2A: 19.9% | N0: 28.1% | 1: 9.0% | 88.1% | 36 | AI 100% | 30 (ribociclib: 27.7) | – | Ribociclib + endocrine therapy 18.9% | Abemaciclib + endocrine therapy 21.9% |
| Post 55.7% | 2B or 3: 80.1% | N1: 41.1% | 2: 57.0% | |||||||||||
| N2 or 3 18.6% | 3: 21.0% | |||||||||||||
| NA: 10.8% |
AE, adverse event; SAE, serious adverse event; TAM, tamoxifen; AI, aromatase inhibitor; NA, not available.
An interim analysis of the NATALEE trial was reported, which evaluated the additive effect of ribociclib for three years to endocrine therapy alone as adjuvant therapy in hormone receptor-positive, HER2-negative high-risk recurrent breast cancer. The primary endpoint of this trial is IDFS, with secondary endpoints including distant disease-free survival, overall survival, and safety (20).
A total of 5,101 participants participated in this study. The average follow-up period at the time of the interim analysis was 30 months, with an average observation period of 27.7 months from the start of ribociclib. Among patients undergoing treatment, 45% continued treatment with ribociclib plus nonsteroidal aromatase inhibitor (NSAI), 13.1% continued NSAI alone, and 19.7% continued after completing ribociclib. In the NSAI alone group, 71.6% continued treatment, and 24.2% discontinued treatment. The 3-year IDFS was 90.4% in the ribociclib plus NSAI group and 87.1% in the NSAI alone group, with a statistically significant improvement (hazard ratio 0.75, 95% CI: 0.62–0.91, P=0.003). The 3-year distant disease-free survival was 90.8% in the ribociclib plus NSAI group and 88.6% in the NSAI alone group (hazard ratio 0.74: 95% CI: 0.60–0.91). The 30-month overall survival event rates were 2.4% vs. 2.9%, showing consistent results.
Ribociclib plus NSAI group treatment is considered highly effective as adjuvant therapy for high-risk HR+HER− breast cancer. However, Kaplan-Meier estimates of disease-free survival varied in this trial and monarchE trial, the difference in treatment outcome started to open after two years, but that did not open much after that. Some differences in patient background and the treatment might cause this. While menopausal status is similar (pre-menopausal 43.9%, post-menopausal 55.7%), there are relatively more N0 cases (28.1%) and fewer histological grade 3 cases (21.0%). The risk of patients participating in this study was slightly lower than in the monarchE trial and was slightly higher than in the PALLAS trial. In PENELOPE-B (add palbociclib in 1 year), PALLAS (add palbociclib in 1 year), and monarchE (add abemaciclib in 2 years) trials, the duration of CDK4/6 inhibitor administration in this trial is longer at 3 years. Additionally, all cases in this trial used NSAI, and ovarian function suppression was conducted in 48% of cases for menopausal women. The absence of tamoxifen usage, noted in other trials (monarchE: 30%, PALLAS: 32%), is notable, suggesting a slightly higher treatment intensity compared to another trial. Chemotherapy administration was 88.1%, slightly less than in the monarchE trial (98%).
Adverse events were reported in 97.9% of the ribociclib plus NSAI group and 87.1% of the NSAI group. Grade 3 or higher adverse events were 62.6% vs. 17.9%, and early discontinuation was 18.9% vs. 3.3%. The median time to early discontinuation of ribociclib was four months. The most common adverse event in the ribociclib plus NSAI group was neutropenia (62.1%, G3 or higher 43.9%). QT prolongation, a characteristic side effect of ribociclib, was observed in 5.2% of the ribociclib plus NSAI group, lower than in previous trials (10-12) for recurrent breast cancer. Discontinuation due to adverse events was similar in both groups. Despite dose reduction (600 to 400 mg/day) compared to recurrence trials, the high discontinuation rate due to adverse events (477/2,549) is concerning.
At this point in the interim analysis, with 45% of patients remaining on ribociclib plus NSAI treatment, the completion rate may decrease. This could potentially impact long-term follow-up and overall survival. The median time to discontinuation due to adverse events is short, at 4 months, so future analyses will need to clarify how the actual treatment intensity (such as the relative dose of ribociclib and the discontinuation of ribociclib treatment will affect IDFS and other outcomes. It is possible that reducing the dose of ribociclib might have improved the treatment continuation rate. While ribociclib plus NSAI treatment is considered highly effective as adjuvant therapy for high-risk hormone receptor-positive, HER2-negative breast cancer, longer-term follow-up is necessary due to the short observation period so far.
Acknowledgments
Funding: None.
Footnote
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References
- Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast 2022;66:15-23. [Crossref] [PubMed]
- Lim YX, Lim ZL, Ho PJ, et al. Breast Cancer in Asia: Incidence, Mortality, Early Detection, Mammography Programs, and Risk-Based Screening Initiatives. Cancers (Basel) 2022;14:4218. [Crossref] [PubMed]
- Tada K, Kumamaru H, Miyata H, et al. Characteristics of female breast cancer in japan: annual report of the National Clinical Database in 2018. Breast Cancer 2023;30:157-66. [Crossref] [PubMed]
- Finn RS, Boer K, Bondarenko I, et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat 2020;183:419-28. [Crossref] [PubMed]
- Rugo HS, Finn RS, Diéras V, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 2019;174:719-29. [Crossref] [PubMed]
- Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-39. [Crossref] [PubMed]
- Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR(+)/HER2(-) Metastatic Breast Cancer. Clin Cancer Res 2017;23:5218-24. [Crossref] [PubMed]
- Sledge GW Jr, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020;6:116-24. [Crossref] [PubMed]
- Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019;5:5. [Crossref] [PubMed]
- Im SA, Lu YS, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019;381:307-16. [Crossref] [PubMed]
- Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020;382:514-24. [Crossref] [PubMed]
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022;386:942-50. [Crossref] [PubMed]
- NCCN.Clinical Practice Guideline Breast Cancer Version 3.2024. 2024.
- Burstein HJ, DeMichele A, Fallowfield L, et al. Endocrine and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer-Capivasertib-Fulvestrant: ASCO Rapid Recommendation Update. J Clin Oncol 2024;42:1450-3. [Crossref] [PubMed]
- Im SA, Gennari A, Park YH, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer. ESMO Open 2023;8:101541. [Crossref] [PubMed]
- Iwata H, Saji S, Ikeda M, et al. The Japanese Breast Cancer Society Clinical Practice Guidelines, 2018 edition: the tool for shared decision making between doctor and patient. Breast Cancer 2020;27:1-3. [Crossref] [PubMed]
- Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol 2020;38:3987-98. [Crossref] [PubMed]
- Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2021;22:212-22. [Crossref] [PubMed]
- Loibl S, Marmé F, Martin M, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol 2021;39:1518-30. [Crossref] [PubMed]
- Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390:1080-91. [Crossref] [PubMed]
Cite this article as: Kuwayama T, Toi M. Is ribociclib plus endocrine therapy effective for high-risk early breast cancer? AME Clin Trials Rev 2024;2:71.
