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. For patients who have progressed after CDK4/6 inhibitor therapy (post-CDK4/6i), remain suitable for endocrine therapy, and have no actionable genetic alterations, treatment options are particularly limited. Without biomarkers such as ESR1 mutations, alterations in the PI3K/AKT/mTOR (PAM) pathway, or germline BRCA1/2 mutations to guide treatment selection, these patients face substantial unmet medical needs.At the 2026 Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Oncology Frontier invited Professor Yanxia Shi of Sun Yat-sen University Cancer Center to discuss the unmet needs of mutation-negative patients after CDK4/6 inhibitor therapy, the clinical potential of triple CDK2/4/6 inhibition, and individualized treatment strategies. Drawing on evidence from studies including TQB3616-II-04 and CULMINATE-1, as well as her clinical experience, Professor Shi outlined potential approaches to optimizing endocrine-based treatment after CDK4/6 inhibitor progression, extending the duration of endocrine therapy, and appropriately delaying chemotherapy or antibody–drug conjugates (ADCs).
Oncology Frontier: Among patients who have progressed after CDK4/6 inhibitor therapy but remain suitable for endocrine treatment, options are limited for those without actionable genetic alterations. The benefits of continuing or switching CDK4/6 inhibitors are also reaching a plateau, leaving this group frequently perceived as having a “treatment gap.” What do you consider the most significant unmet treatment needs in these patients?
Professor Yanxia Shi: These patients are not without treatment options. Rather, what is missing is a second-line endocrine therapy (ET)-based combination regimen that does not depend on specific genetic alterations, can overcome resistance to CDK4/6 inhibitors, can delay the need for chemotherapy or ADCs, and offers good tolerability.
The most pressing unmet needs in this population fall into three areas.
First, there is a gap in targeted treatment options. Patients without actionable genetic alterations lack a matching biomarker for treatment selection, such as ESR1 mutations, PIK3CA/AKT1/PTEN alterations, or germline BRCA1/2 mutations. This limits access to precision treatment strategies involving oral selective estrogen receptor degraders (SERDs), PI3K/AKT/mTOR (PAM) pathway inhibitors, and PARP inhibitors. Although ADCs may be considered for patients with HER2-low or HER2-ultralow expression, these agents exert their effects by delivering cytotoxic drugs to kill cancer cells, so their adverse effects and accessibility must also be taken into account.
Second, the efficacy of sequential CDK4/6 inhibitor treatment remains limited. Rechallenge with CDK4/6 inhibitors may provide some benefit, but the overall effect is modest. Both the MAINTAIN and postMONARCH studies suggest that switching or rechallenging with a CDK4/6 inhibitor can be an option for selected patients. However, progression-free survival (PFS) in patients receiving subsequent CDK4/6 inhibitor-based treatment generally remains around five to six months, which falls short of current clinical needs.
Third, there is a gap in the time available for effective treatment throughout the disease course. Real-world data indicate that approximately 50% of patients receiving second-line treatment never proceed to another line of therapy. The second-line setting is therefore a critical transition point. We need regimens that are highly effective, minimally toxic, and capable of preserving quality of life, so patients can remain on treatment for as long as possible rather than discontinuing because of treatment-related toxicity.
Therefore, patients who have progressed after CDK4/6 inhibitor therapy, remain suitable for endocrine treatment, and have no actionable genetic alterations need regimens that do not rely on a single mutation, address mechanisms of CDK4/6 inhibitor resistance, have manageable toxicity, extend the duration of endocrine-based treatment, and delay chemotherapy.
Oncology Frontier: The TQB3616-II-04 study showed significant benefit with kermoxili combined with fulvestrant in patients previously treated with CDK4/6 inhibitors, regardless of which CDK4/6 inhibitor they had received. How do you view the clinical potential of triple CDK2/4/6 inhibition? Could this approach offer a broadly applicable treatment strategy for mutation-negative patients after CDK4/6 inhibitor therapy?
Professor Yanxia Shi: The findings from TQB3616-II-04 are indeed encouraging. This was a prospective, multicenter, single-arm phase II study that enrolled patients representative of current clinical practice. Participants included patients whose advanced disease had progressed following first-line CDK4/6 inhibitor treatment, as well as those whose disease had progressed during adjuvant CDK4/6 inhibitor therapy. Patients were permitted to have received no more than one line of chemotherapy for advanced disease and no more than two lines of endocrine therapy for advanced disease.
Among patients previously treated with CDK4/6 inhibitors, kermoxili plus fulvestrant demonstrated promising antitumor activity, with an objective response rate (ORR) of 32.4%, a disease control rate (DCR) of 88.2%, and a 10-month PFS rate of 61.8%. The benefit was observed regardless of the type of CDK4/6 inhibitor used previously. This suggests that patients may benefit from the regimen whether their previous treatment was palbociclib, ribociclib, or dalpiciclib. The overall safety profile was consistent with findings from previous studies, with no new safety signals identified.
Mechanistically, activation of the cyclin E–CDK2 pathway and CCNE1 overexpression are important mechanisms of resistance to CDK4/6 inhibitors. Studies have shown that the relative benefit of CDK4/6 inhibitor plus endocrine therapy is substantially reduced in patients with high CCNE1 expression. As a triple CDK2/4/6 inhibitor, kermoxili can simultaneously inhibit CDK2, CDK4, and CDK6. By incorporating CDK2—a key convergence point in resistance signaling—into the inhibition strategy, it may theoretically overcome or delay resistance to CDK4/6 inhibitors.
The randomized phase III CULMINATE-1 study also demonstrated a significant survival benefit with kermoxili plus fulvestrant compared with placebo plus fulvestrant. Median PFS reached 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 or death. Based on this study, 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.
For patients who have progressed after CDK4/6 inhibitor therapy, have no actionable genetic alterations, and remain suitable for endocrine treatment, kermoxili plus ET therefore has the potential to become a broadly applicable strategy that does not depend on a specific mutation.
However, we must also recognize the limitations of the evidence. TQB3616-II-04 was a small, single-arm phase II study that enrolled only 35 patients, so its findings require validation in phase III trials. For patients with visceral crisis or rapidly progressing disease, other treatment options should be selected promptly when appropriate.
In short, the absence of actionable genetic alterations does not mean that patients have no treatment options. Triple CDK2/4/6 inhibition may be an important strategy for addressing this gap.
Oncology Frontier: For mutation-negative patients who have progressed after CDK4/6 inhibitor therapy, should CDK2/4/6 inhibition be positioned as an “upgraded alternative” to switching CDK4/6 inhibitors, or as the “last line of endocrine defense” before chemotherapy or ADCs? How would you plan individualized treatment pathways in clinical practice to make the most of the treatment window without missing the optimal time to change therapy?
Professor Yanxia Shi: I do not think CDK2/4/6 inhibition should be assigned a simplistic role as either an “upgraded alternative” to switching CDK4/6 inhibitors or the “last line of endocrine defense” before chemotherapy or ADCs. Instead, we need to position treatment according to individual patient characteristics and reassess the disease dynamically.
As long as patients remain suitable for endocrine-based treatment, endocrine therapy with or without targeted agents should generally be prioritized to delay chemotherapy or ADC treatment whenever possible. If patients are no longer suitable for endocrine therapy or develop visceral metastases or visceral crisis, treatment should be switched to chemotherapy or an ADC in accordance with guideline recommendations.
I would stratify patients as follows.
1. Patients who remain suitable for endocrine therapy: Consider CDK2/4/6 inhibition plus ET as a preferred second-line option.
For these patients, I would recommend kermoxili plus fulvestrant. In TQB3616-II-04, this combination demonstrated promising antitumor activity in patients previously treated with CDK4/6 inhibitors.
In CULMINATE-1, 59% of patients had visceral metastases. The PFS benefit was also observed in the visceral metastasis subgroup, with an HR of 0.45, and in the liver metastasis subgroup, with an HR of 0.49. These findings suggest that CDK2/4/6 inhibition plus ET may offer an additional endocrine-based targeted treatment option even for patients with less favorable baseline characteristics.
2. Patients who are unsuitable for endocrine therapy or have visceral crisis: Chemotherapy or an ADC may be the more appropriate choice.
Guidelines continue to emphasize endocrine-based treatment as the preferred approach for patients with HR+/HER2− advanced breast cancer and visceral metastases, provided they do not have visceral crisis. For patients with visceral crisis who have not yet received treatment for advanced disease, or whose disease recurs or metastasizes at least 12 months after completing adjuvant endocrine therapy, chemotherapy has generally been the preferred first-line option. However, studies such as RIGHT Choice suggest that CDK4/6 inhibitor plus ET may be superior to chemotherapy in selected patients.
For patients whose disease has failed endocrine therapy or who are no longer suitable for endocrine-based treatment, chemotherapy or an ADC may be considered. ADCs should not automatically be the preferred second-line treatment for every patient, nor should they necessarily be used too early. If an ADC is administered prematurely in the second-line setting, the treatment options available after subsequent progression may be limited.
Determining the optimal treatment sequence for each patient requires further exploration. In clinical practice, I believe we should make the fullest appropriate use of endocrine therapy, reserve chemotherapy and ADCs for the right time, and continually reassess the patient’s condition and treatment response.
In summary, mutation-negative patients who have progressed after CDK4/6 inhibitor therapy do not represent a “treatment gap.” CDK2/4/6 inhibition offers an endocrine-based targeted treatment option that does not depend on a specific genetic alteration. The key is to stratify patients appropriately and reassess them dynamically, enabling them to remain on endocrine-based treatment for as long as possible and thereby delay the need for chemotherapy or ADCs.
Professor Yanxia Shi
