Editor's Note: CDK4/6 inhibitors combined with endocrine therapy have become the standard first-line treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer. However, resistance is almost inevitable, making the selection of subsequent treatment strategies a pressing clinical challenge. At the 2026 Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Oncology Frontier interviewed Professor Biyun Wang of Fudan University Shanghai Cancer Center. Drawing on clinical trial data for kermoxili, the world's first CDK2/4/6 inhibitor, and her own clinical experience, Professor Wang reviewed treatment strategies stratified by patient characteristics after CDK4/6 inhibitor resistance and identified patient populations who may benefit from CDK2/4/6 inhibition. The discussion aims to inform individualized treatment decisions for patients with HR+/HER2− advanced breast cancer receiving later-line therapy, helping improve survival and quality of life.Oncology Frontier: What treatment strategies are available in clinical practice after resistance to CDK4/6 inhibitors develops?
Professor Biyun Wang: The question of how to select treatment after resistance to first-line CDK4/6 inhibitor plus endocrine therapy (ET) in HR+/HER2− advanced breast cancer has remained a major topic for several years. It regularly features prominently at major oncology conferences and in leading journals, with ongoing debate and a growing number of clinical studies evaluating new agents.
In clinical practice, there are several main treatment approaches. First, we can continue with an endocrine-based combination regimen but switch to a different combination partner. Second, we can move directly to chemotherapy. Third, with the emergence of antibody–drug conjugates (ADCs), some agents have demonstrated better efficacy than chemotherapy in later-line settings for selected patients. For these patients, ADC treatment can be considered at an appropriate time based on individual characteristics, such as in those with HER2-low expression.
Our choice among these options is guided by multiple factors, including the patient’s clinical response to previous treatment and the duration of CDK4/6 inhibitor plus ET therapy.
Based on my clinical experience, if a patient previously achieved a sufficiently durable benefit from endocrine therapy, I would generally continue to favor an endocrine-based combination approach. I also tend to favor endocrine-based treatment for patients without visceral metastases, such as those with bone-only disease. However, if the disease progresses rapidly or the symptom burden requires prompt and reliable tumor shrinkage, chemotherapy or an ADC may be appropriate, depending on the patient’s treatment history and clinical condition.
Oncology Frontier: Among the available strategies after CDK4/6 inhibitor resistance, what endocrine-based targeted combination regimens are currently used for patients who remain suitable for endocrine therapy?
Professor Biyun Wang: For patients with HR+/HER2− advanced breast cancer whose disease has progressed after first-line CDK4/6 inhibitor plus ET but who remain suitable for endocrine-based treatment, we generally have several options.
The first is to continue using CDK4/6 inhibitors through a switching strategy. Changing to a different CDK4/6 inhibitor may still provide meaningful benefit for some patients. In addition, the availability of kermoxili, a CDK2/4/6 inhibitor, has introduced a new treatment option for patients whose disease has progressed after CDK4/6 inhibitor therapy.
In patients previously treated with CDK4/6 inhibitors, the TQB3616-II-04 study showed that kermoxili plus fulvestrant had promising antitumor activity, with an objective response rate (ORR) of 32.4%, a disease control rate (DCR) of 88.2%, and a 10-month progression-free survival (PFS) rate of 61.8%. These results were observed regardless of which CDK4/6 inhibitor patients had previously received. The regimen may therefore help overcome resistance to CDK4/6 inhibitors and extend survival.
Second, as breast cancer treatment increasingly moves toward precision medicine, genomic testing has become particularly important for selecting appropriate therapies. For patients with alterations in the PI3K/AKT/mTOR (PAM) pathway, PI3K, AKT, or mTOR inhibitors can be combined with endocrine therapy.
The use of PI3K and AKT inhibitors requires identification of the corresponding actionable molecular alterations. In China, the PI3K inhibitor inavolisib and the AKT inhibitor capivasertib have entered clinical practice and have been included in the national medical insurance system, making them important options for patients with the relevant alterations. However, these drugs can also cause toxicities and new adverse events, which require careful monitoring and management. Clinicians must continue updating their knowledge and accumulating clinical experience in this rapidly evolving field.
The mTOR inhibitor everolimus has been used in clinical practice for many years. Combining everolimus with exemestane after endocrine therapy failure does not require the presence of a specific actionable mutation. Nevertheless, its use has been limited by adverse events such as stomatitis and noninfectious pneumonitis.
For patients with ESR1 mutations, options include oral selective estrogen receptor degraders (SERDs) as monotherapy or in combination with a CDK inhibitor. The emergence of oral SERDs has provided additional treatment opportunities and encouraging efficacy, and one agent in this class has already received approval in China.
Oncology Frontier: Which patient populations are the main candidates for the new CDK2/4/6 inhibitor kermoxili in clinical practice?
Professor Biyun Wang: CULMINATE-1 was designed to evaluate the efficacy and safety of kermoxili plus fulvestrant versus placebo plus fulvestrant in patients with HR+/HER2− advanced breast cancer whose disease had progressed following previous endocrine therapy and who had received no more than one line of chemotherapy.
The results showed a significant PFS benefit with kermoxili plus fulvestrant compared with placebo plus fulvestrant. Median PFS was 16.62 months versus 7.46 months, respectively, with a hazard ratio (HR) of 0.36, corresponding to a 64% reduction in the risk of disease progression.
Based on the CULMINATE-1 results, kermoxili has received approval from China’s National Medical Products Administration (NMPA) for patients with HR+/HER2− locally advanced or metastatic breast cancer previously treated with endocrine therapy. It provides a new option for second-line treatment of HR-positive advanced breast cancer. The introduction of CDK2/4/6 inhibition also offers a new approach to addressing endocrine treatment resistance.
In current clinical practice, most patients have already received a CDK4/6 inhibitor. When considering kermoxili rather than switching to another CDK4/6 inhibitor, I take into account the possibility that a drug with a different mechanism of action may produce better outcomes. However, this remains a clinical consideration that requires confirmation in direct head-to-head studies. Such comparative clinical evidence is not yet available.
Overall, if a patient has an actionable molecular alteration—such as an ESR1 mutation, a PAM pathway alteration, or a germline BRCA1/2 mutation—I may prioritize a therapy directed at that target.
For patients without an actionable molecular alteration, options include kermoxili, everolimus, and chidamide, which do not require a specific molecular target to guide their use. In my clinical practice, some patients cannot undergo genomic testing for various reasons, while others cannot afford certain newer targeted therapies. In these circumstances, I may consider kermoxili as an initial option.
Professor Biyun Wang
