preface
The 2024 European Society for Medical Oncology Annual Meeting (2024 ESMO) was held in Barcelona, Spain from September 13 to September 17, bringing together scholars from the global oncology field to share the latest research progress in cancer diagnosis and treatment. At this meeting, the announcement of the results of the randomized phase II ABIGAIL study has received widespread attention, and Yimaitong specially invited Professor Li Man from the Second Affiliated Hospital of Dalian Medical University to share and interpret the results.
Background:
CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the first-line treatment options for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. However, for patients with rapid disease recurrence or progression, visceral metastasis, and rapid tumor shrinkage, chemotherapy induction therapy is still one of the common clinical options. The ABIGAIL study was designed to evaluate the efficacy and safety of first-line abeciclib plus ET compared with sequential abeciclib plus ET after chemotherapy in HR+/HER2- advanced breast cancer with aggressive features and a poor prognosis.
Figure 1. Research progress of CDK4/6i
Figure 2. RIGHT CHOlCE study design
Research Methods:
The ABIGAIL study is an open-label, international, multicenter, randomized Phase II clinical study (NCT04603183) of patients with HR+/HER2- advanced breast cancer with measurable lesions who have not received other systemic therapies in the advanced stage, have an ECOG score of 0-1, and contain ≥ 1 aggressive features:
- Disease relapses during adjuvant therapy or progresses within 36 months of the end of adjuvant therapy;
- with visceral metastases;
- Histology grade 3;
- PR negative for primary or metastatic lesions;
- LDH > 1.5 times the upper limit of normal.
Patients were randomized 1:1, and group A received abeciclib (150 mg; 2 times daily; oral) + letrozole or fulvestrant (specific endocrine regimen is determined by the investigator), and group B received paclitaxel chemotherapy (90 mg/m2; Day 1, 8, 15; every 28 days) for 12 weeks, followed by abeciclib + letrozole or fulvestrant (the specific endocrine regimen is determined by the investigator), and the clinician can decide whether to extend paclitaxel to a maximum of 6 cycles after 12 weeks of initial treatment. The main stratification factor includes the presence or absence of visceral metastases. The primary endpoint of the study was the 12-week objective response rate (ORR) as assessed by a blinded independent review committee (BICR), which was designed for non-inferiority, and the secondary endpoints included progression-free survival (PFS), overall survival (OS), time to response (TTR), duration of response (DOR), and safety. The study used the Newcombe hybrid score, which was based on a dropout rate of 10% and a significance level of bilateral α = 0.05, and at least 160 patients needed to be included in order to achieve 80% power.
Figure 3. ABIGAIL Study Design
Findings:
Between June 2021 and January 2024, 162 patients from 29 centers were randomized to either group A (n=80; 72.5% letrozole) or group B (n=82). Baseline characteristics were balanced between groups: the median age of enrolled patients was 58 years (range 26-85 years), 64% had visceral metastases, 36% had ≥ 3 metastases, 30% had newly diagnosed stage IV breast cancer (De novo ABC), and 30% were premenopausal.
Figure 4. Patient baseline characteristics
In terms of primary endpoints, the 12-week ORR (as assessed by BICR) was 58.8% in the abeciclib + ET arm and 40.2% in the paclitaxel arm (p= 0.0193), showing significant efficacy compared to chemotherapy.
Figure 5. Efficacy Outcome: Primary endpoint
In terms of safety, it is also in line with the safety spectrum of their respective treatments, and the hematologic toxicity, alopecia and neurotoxicity of chemotherapy are more prominent, and abeciclib combined with ET is mainly gastrointestinal toxicity, and grade 1-2 is the main one, and the incidence of grade ≥ 3 diarrhea is only 3%.
Figure 6. Safety outcome (at 12 weeks)
Conclusions of the study
The ABIGAIL study demonstrated that the use of abeciclib plus ET in the first-line treatment of HR+/HER2- advanced breast cancer with aggressive profile had a higher objective response rate than sequential ET after paclitaxel chemotherapy.
Figure 7. Conclusions of the study
Professor Li Man's in-depth comments
The positive results of a number of large-scale phase III randomized controlled clinical studies around the world have established the status of CDK4/6 inhibitors combined with ET as the first-line standard treatment for HR+/HER2- advanced breast cancer. However, for those patients with rapid disease recurrence or progression, visceral metastasis, and rapid tumor shrinkage, chemotherapy sequential endocrine maintenance regimen is still one of the common clinical options, and it seems that chemotherapy has become a deep-rooted "little expert" for rapid tumor shrinkage for clinicians. As we all know, HR+ breast cancer is less sensitive to chemotherapy, and the toxicity of chemotherapy and the impact on quality of life should not be underestimated, so in the era of CDK4/6 inhibitor treatment, is it necessary for HR+/HER2- breast cancer patients with aggressive characteristics to undergo chemotherapy induction therapy? Can endocrine combined with CDK4/6 inhibitors completely replace chemotherapy? Previous RIGHT Choice, PEARL studies, or Young-Pearl studies all combined CDK4/6 inhibitors with ET versus full course of chemotherapy, and the results of chemotherapy were not sequential, so more high-quality evidence-based medical evidence is needed to provide answers.
The ABIGAIL study, the first head-to-head study comparing CDK4/6 inhibitors plus ET versus sequential ET after short-term chemotherapy, not only achieved non-inferiority results, but also demonstrated significant efficacy, with first-line abeciclib+ET demonstrating a higher ORR in patients with HR+/HER2- ABC with an aggressive profile (58.8 versus 40.2 percent; p=0.0193), and achieved good early tumor shrinkage. In terms of toxicity, the incidence of hematologic toxicity, alopecia and neurotoxicity of abeciclib was significantly lower than that of chemotherapy, and diarrhea was the main one, and it was mainly grade 1-2, which had a better safety profile. This suggests that induction therapy with chemotherapy may not be necessary, and that the pattern of sequential ET with chemotherapy is not optimal. For HR+/HER2- advanced breast cancer with aggressive characteristics, the results of the ABIGIAL study can be referred to in clinical practice, and the first-line treatment regimen of ET+abeclib can be selected with more confidence, so that more patients can delay the use of chemotherapy and obtain good safety and quality of life. The long-term follow-up results of the study are ongoing, and more results on the long-term efficacy and secondary study endpoints are also expected.
Expert Profile
Prof. Li Man
- Doctor of Medicine, Professor, Doctoral Supervisor
- Director of the Department of Oncology and Director of the Teaching and Research Department of the Second Affiliated Hospital of Dalian Medical University
- Distinguished Professor of Liaoning Province
- Liaoning Province has hundreds of thousands of talents and hundreds of people
- Director of the Chinese Society of Clinical Oncology (CSCO).
- Member of the Standing Committee of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology
- Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
- Vice Chairman of the Oncology Branch of Liaoning Medical Association
- Vice Chairman of the Breast Cancer Professional Committee of Liaoning Anti-Cancer Association
- Chairman of the Oncology Branch of Dalian Medical Association
Bibliography:
Juan De la Haba Rodríguez, et al. 2024 ESMO LBA23.
Editor: Prof. Li Man
Typography: Ryland
Execution: Uni
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