Editor's Note: After CDK4/6i treatment failure in HR+/HER2- breast cancer patients, do you lean more towards a PI3K inhibitor or an AKT inhibitor? At the Northern Salon of the 2024 Summer Breast Cancer Forum, during the "In-Depth Analysis" segment, Dr. Yuhua Song from The Affiliated Hospital of Qingdao University and Dr. Jing Yao from Union Hospital Affiliated with Huazhong University of Science and Technology each presented their views. Professor Song expressed a preference for PI3K inhibitors, while Professor Yao favored AKT inhibitors. Following the session, Cancer Outlook invited both experts to elaborate on their perspectives.Presenting Views and Analyzing Reasons
Dr. Yuhua Song: Choosing PI3K Inhibitors
For HR+/HER2- breast cancer patients who have progressed after CDK4/6i treatment, I believe PI3K inhibitors should be prioritized for those with PI3CA mutations. The PI3K-AKT-mTOR signaling pathway is one of the most frequently mutated pathways in breast cancer, with a relatively high mutation rate of about 40%. We have entered the era of precision medicine in oncology, and new PI3K inhibitors, which are highly selective targeted therapies, can block the pathway at its source, offering better survival benefits for patients with alterations in the PAM signaling pathway.
Dr. Jing Yao: Choosing AKT Inhibitors
My view is that AKT inhibitors should be prioritized for HR+/HER2- breast cancer patients after progression on CDK4/6i treatment. Here’s why:
- SOLAR-1 Study Results: The SOLAR-1 study showed that, compared to fulvestrant combined with placebo, fulvestrant combined with the specific PI3K inhibitor alpelisib significantly extended median PFS (5.7 months vs. 11 months) in the PIK3CA-mutated population. However, only 6% of the patients in this study had received prior CDK4/6i treatment. Although this regimen was approved by the FDA at the time, the actual number of enrolled patients was small, making it less suitable for clinical application.
- BYLieve Study Results: Although the BYLieve study demonstrated the efficacy and safety of alpelisib combined with endocrine therapy in PIK3CA-mutated, HR+/HER2- advanced breast cancer patients, with 50.4% of patients not experiencing disease progression at 6 months and a median PFS of 7.3 months, it was an exploratory single-arm study. We cannot rely solely on PFS values to guide clinical practice. The results of the BYLieve study could be the basis for conducting RCTs to provide further evidence.
The CAPItello-291 study is the first global Phase III trial to include CDK4/6i-treated patients and achieve positive results. The study allowed the inclusion of at least 51% of patients who had received prior CDK4/6i therapy, with over 69% of the actual enrolled patients having been treated with CDK4/6i. Patients were randomized 1:1 to receive the AKT inhibitor capivasertib + fulvestrant or placebo + fulvestrant. The study met its dual primary endpoints, with significant PFS improvements observed in both the overall population (7.2 vs. 3.6 months, HR 0.60) and in patients with AKT pathway mutations (7.3 vs. 3.1 months, HR 0.50). From the overall data, AKT inhibitors currently offer more reliable data for patients who have progressed on CDK4/6i therapy.
The PI3K-AKT-mTOR signaling pathway is a critical intracellular signal transduction pathway, with AKT at its core. Inhibiting AKT activity can avoid the severe side effects caused by inhibiting upstream PI3K and the feedback mechanisms affecting drug efficacy when inhibiting downstream mTOR. Therefore, from a mechanistic perspective, finding effective and selective AKT inhibitors is a crucial focus in current oncology drug development.
In terms of adverse events, PI3K inhibitors have a higher incidence of hyperglycemia, stomatitis, and mucositis, whereas AKT inhibitors have a much lower incidence. Considering the mechanism of action, current clinical data, and adverse events, AKT inhibitors are the preferred choice for patients who have progressed after CDK4/6i treatment.
Debating and Sharpening Skills
Dr. Yuhua Song: The main safety issues with PI3K inhibitors include stomatitis, mucositis, and hyperglycemia, while AKT inhibitors may cause adverse reactions like rash and diarrhea, which can affect patients’ quality of life. Could you explain your choice from the perspective of quality of life?
Dr. Jing Yao: Many targeted therapies have diarrhea as a common side effect. The choice of AKT inhibitors also tests the clinician’s ability to manage diarrhea. Medications like montmorillonite powder can effectively help patients control diarrhea. Early prevention or intervention can significantly improve the patient’s quality of life.
Dr. Jing Yao: There is currently no unified standard for treating patients who have progressed after CDK4/6i therapy. With the data from the CAPItello-291 study now available, providing more detailed information, would you consider using AKT inhibitors based on this data?
Dr. Yuhua Song: For patients with PI3CA mutations, I prioritize PI3K inhibitors. However, I do not reject the use of AKT inhibitors, as they may be applicable to a broader population. For suitable patients, I would consider using AKT inhibitors.
Vote
For HR+/HER2- breast cancer patients who have progressed after CDK4/6i treatment, do you prefer PI3K inhibitors or AKT inhibitors? (Single choice)
- PI3K inhibitors
- AKT inhibitors
- No preference
Dr. Yuhua Song
- MD, Chief Physician, Master’s Supervisor
- Deputy Director of the Breast Center and Director of the Breast Oncology Department, Affiliated Hospital of Qingdao University
- Standing Committee Member, Breast Disease Committee, China Medical Education Association
- Member, CSCO Breast Cancer Expert Committee
- Member, Youth Committee, Breast Cancer Committee, Chinese Anti-Cancer Association
- Standing Committee Member, International Medical and Cooperation Committee, Beijing Breast Disease Prevention and Treatment Society
- Vice Chairman, Youth Committee, Breast Cancer Committee, Shandong Anti-Cancer Association
- Standing Committee Member, Breast Cancer Committee, Shandong Anti-Cancer Association
- Standing Committee Member, Tumor Targeting Committee, Shandong Anti-Cancer Association
- Member, Breast Disease Multidisciplinary Committee, Shandong Medical Association
- Vice Chairman, Breast Cancer Committee, Qingdao Anti-Cancer Association
Dr. Jing Yao
- Director, Breast Oncology Department, Tumor Center, Union Hospital Affiliated with Huazhong University of Science and Technology
- Chief Physician, Associate Professor, Master’s Supervisor, PhD in Oncology
Positions Held:
- Member, Breast Oncology Group, Chinese Medical Association Oncology Branch
- Member, Breast Cancer Committee, Chinese Anti-Cancer Association
- Standing Committee Member, Tumor Heterogeneity and Personalized Treatment Committee, Chinese Anti-Cancer Association
- Standing Committee Member, Integrative Tumor Medicine Committee, Chinese Anti-Cancer Association
- Member, Tumor Molecular Medicine Committee, Chinese Anti-Cancer Association
- Member, Multidisciplinary MDT Committee, Chinese Anti-Cancer Association
- Member, Youth Committee, Tumor Clinical Chemotherapy Committee, Chinese Anti-Cancer Association
- Member, Breast Specialty Committee, China Women Doctors Association
- Standing Committee Member, Translational Medicine Committee, Hubei Medical and Biological Immunology Society
- Chairman, Breast Oncology Committee, Hubei Medical and Biological Immunology Society
