Editor’s Note: On May 16, 2024, the European Society for Medical Oncology Breast Cancer Annual Meeting (ESMO BC) reported updated results from the CAPItello-291 study (183MO). The data showed that the AKT inhibitor capivasertib combined with fulvestrant provided benefits in second-line treatment without affecting the benefits of subsequent treatments. This further solidified capivasertib’s role in the post-CDK4/6 inhibitor (CDK4/6i) era, leading the way in precision therapy for HR+ breast cancer. Oncology Frontier interviewed Professor Yiding Chen from The Second Affiliated Hospital of Zhejiang University School of Medicine to analyze the progress of the CAPItello-291 study and discuss superior treatment options in the post-CDK4/6i era from mechanisms to clinical applications.
Oncology Frontier: The CAPItello-291 study updated its PFS2 data at this ESMO BC meeting. Could you summarize the main advancements brought by the CAPItello-291 study?
Professor Yiding Chen: For hormone receptor-positive (HR+) breast cancer, CDK4/6 inhibitors have become the first-line standard treatment. However, precise treatment strategies after resistance to CDK4/6i remain to be thoroughly explored. Among many precision therapy studies, the CAPItello-291 study is currently the only phase III clinical trial that has enrolled a large number of patients previously treated with CDK4/6i, about 70% of whom were in this group, bringing groundbreaking progress to precision therapy in the post-CDK4/6i era.
In the previously released overall data of the CAPItello-291 study, the capivasertib plus fulvestrant group had a median progression-free survival (mPFS) of 7.2 months, twice that of the placebo plus fulvestrant group, which was 3.6 months. In the AKT mutation population, the mPFS benefit was significant, with 7.3 months versus 3.1 months. The study also achieved consistent results in the Chinese patient population, providing new treatment options in clinical practice.
This ESMO BC meeting mainly presented PFS2 data (time from randomization to second progression) and TFSC data (time from randomization to first subsequent chemotherapy or any cause of death before the first subsequent chemotherapy). After PIK3CA/AKT1/PTEN screening, 155 patients in the capivasertib plus fulvestrant group and 134 patients in the placebo plus fulvestrant group were included in the analysis. Results showed that the capivasertib plus fulvestrant group had a longer mPFS2 of 14.7 months compared to 12.5 months in the placebo plus fulvestrant group, and an mTFSC of 11.0 months compared to 6.8 months. In the PIK3CA/AKT1/PTEN screened group, the mPFS2 was 15.5 months compared to 10.8 months, and the mTFSC was 11.0 months compared to 6.0 months.
This confirms that the application of capivasertib in the post-CDK4/6i era benefits the entire population, with more benefits in the PIK3CA/AKT1/PTEN screened population. The updated PFS2 results also showed that the use of capivasertib does not impact the benefits of subsequent treatments and may even bring more benefits, delaying the need for chemotherapy and alleviating patients’ fear of chemotherapy, thereby ensuring their quality of life and treatment experience.
Oncology Frontier: How has the continuous release of CAPItello-291 study data changed the treatment landscape for breast cancer in the post-CDK4/6i era?
Professor Yiding Chen: The emergence of CDK4/6 inhibitors has revolutionized the treatment model for HR+/HER2- advanced breast cancer. Clinical studies such as PALOMA, MONALEESA, MONARCH, and DAWNA have established CDK4/6 inhibitors as the standard first-line treatment. However, there is no standard treatment regimen for the post-CDK4/6i era, and the reasons for resistance are multifaceted and complex, including the loss of estrogen receptor (ER)/progesterone receptor (PR) expression, overexpression of cell cycle kinases such as Cyclin E, activation of other pathways, and changes in the microenvironment. Different resistance mechanisms require different strategies. Due to the lack of large-sample prospective data, current domestic and international guidelines have yet to provide first-line recommended treatment options after CDK4/6i progression, representing an unmet clinical need.
Among the possible strategies such as cross-line treatment with CDK4/6i or other endocrine-targeted therapies, cross-line treatment with CDK4/6i still faces challenges. The PACE and PALMIRA studies with palbociclib combined with fulvestrant failed, and only the MAINTAIN study achieved preliminary success, but it was only a phase II study with insufficient evidence strength. New endocrine therapy drugs like SERDs have shown mPFS ranging from 2 to 7 months in this context, but these studies are also phase II with small sample sizes and require further validation. Additionally, antibody-drug conjugates (ADCs) have been explored in patients with CDK4/6i progression, but clinical choices need to consider specific patient situations.
PAM pathway abnormalities are well-known as a core resistance mechanism for CDK4/6i. Multiple effective drugs targeting key points in this pathway have been developed, but current PI3K and mTOR inhibitors lack large-scale clinical data for the post-CDK4/6i population. The only phase III clinical study in this pathway, involving 70% of patients previously treated with CDK4/6i, is with the AKT inhibitor capivasertib, which has shown superior results, making it a true standard choice after CDK4/6i treatment, revolutionizing guidelines and clinical practice in the post-CDK4/6i era.
