Editor’s Note:
Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for over 70% of all breast cancers[1]. The use of CDK4/6 inhibitors has brought about a breakthrough in the survival of these late-stage patients. However, some recurrent metastatic patients may develop endocrine resistance, reducing the efficacy of treatment. The European Society for Medical Oncology (ESMO) 2023 Annual Congress, held in Madrid, Spain, on October 20, 2023, featured Professor Xiaojia Wang’s poster presentation on the combination of anlotinib and fulvestrant (452P), providing new hope for these patients. Oncology Frontier invited Professor Xiaojia Wang from Zhejiang Cancer Hospital to share insights.
Endocrine therapy for HR+ breast cancer has evolved from the era of ovarian ablation and tamoxifen to the era of third-generation aromatase inhibitors and, in advanced breast cancer, the era of fulvestrant, an estrogen receptor downregulator. With the advent of CDK4/6 inhibitors in recent years, the entire landscape of endocrine therapy for breast cancer has entered the CDK4/6 inhibitor era, extending from the advanced stage to adjuvant therapy. Since third-generation aromatase inhibitors (AIs) have become the primary adjuvant endocrine therapy for most breast cancer patients, when these patients experience a relapse or progression (most of them being patients who progressed or developed resistance to third-generation aromatase inhibitors), we used to resort to fulvestrant. However, after AI resistance, patients’ progression-free survival (PFS) with fulvestrant was only around 6 months, which clearly did not meet clinical needs. Fortunately, several CDK4/6 inhibitors have been developed and most of them are covered by medical insurance, leading to an overall PFS of 1 to 2 years for these patients.
In 2023, major guidelines, including CSCO-BC, have comprehensive recommendations:
- l Untreated with endocrine therapy: Grade I recommendation adjusted to AI+CDK4/6i (palbociclib, abemaciclib); Grade II recommendation adds AI+ribociclib;
- l TAM treatment failure: Grade I recommendation adjusted to AI+CDK4/6i (palbociclib, abemaciclib); AI+ribociclib is downgraded from Grade I to Grade II; Grade II recommendation adds “AI+palbociclib,” “AI+ribociclib,” “AI+ribociclib”;
- l NSAI treatment failure: Grade I recommendation adjusted to fulvestrant+CDK4/6i (palbociclib, abemaciclib, ribociclib); SAI+ribociclib is downgraded from Grade I to Grade II, and Grade II recommendation adds “FUL+ribociclib”; fulvestrant is adjusted from Grade II to Grade III recommendation.
- l SAI treatment failure: Grade I recommendation adjusted to fulvestrant+CDK4/6i (palbociclib, abemaciclib, ribociclib); Grade II recommendation adds “fulvestrant+ribociclib,” “fulvestrant+abemaciclib”; fulvestrant is adjusted from Grade II to Grade III recommendation.
The strategy of CDK4/6 inhibitor combined with endocrine therapy (AI or fulvestrant, etc.) has been proven to prolong progression-free survival (PFS) and overall survival (OS) in HR+/HER2- advanced breast cancer (MBC) patients. Numerous pivotal Phase III clinical trials such as the PALOMA series, MONALEESA series, Monarch series, and the domestic DAWNA series have demonstrated better efficacy with AIs or fulvestrant in combination with CDK4/6 inhibitors compared to single-agent endocrine therapy, irrespective of being first-line or second-line, premenopausal, perimenopausal, or postmenopausal.
However, once patients progress on CDK4/6 inhibitors (i.e., after CDK4/6 inhibitor treatment progression), they can develop resistance to many endocrine therapy drugs. Endocrine resistance is one of the treatment challenges in hormone receptor-positive advanced breast cancer, and based on the mechanism of resistance, the introduction of targeted therapies in endocrine treatment holds promise in reversing or delaying resistance, with positive results seen in clinical studies. Additionally, the search for molecular biomarkers and identifying the patient populations that benefit is an important direction in this field.
Although observational studies have shown potential clinical benefits in continuing CDK4/6 inhibitor use and changing endocrine therapy regimens when disease progresses, there have also been several unsuccessful attempts. Therefore, this year’s guidelines have adjusted the sequence of “another CDK4/6i+endocrine therapy” in Grade II recommendations for cases of CDK4/6i treatment failure. The original “ribociclib+endocrine therapy” has been adjusted to “other targeted therapies (such as abemaciclib, ribociclib, apalutamide)+endocrine therapy,” among other changes.
Several preclinical experiments have indicated that angiogenesis is one of the crucial factors in breast cancer invasion or metastasis. Breast cancer metastatic lesions must establish their own vascular network to overcome the host’s intrinsic microenvironmental influences, and the initiation of the tumor’s metastatic process begins with angiogenesis. Therefore, targeting tumor angiogenesis at its source offers the potential to reduce the risk of distant metastasis and improve the prognosis of breast cancer patients. Early clinical trials have also demonstrated that when anti-angiogenic drugs are combined with endocrine therapy, patients experience improved survival. The CALGB 40503 study showed that, compared to letrozole monotherapy, the addition of bevacizumab significantly prolonged first-line treatment PFS for patients with HR+/HER2- advanced breast cancer, with PFS of 15.6 months and 20.2 months, respectively, and a 25% reduction in the risk of disease progression (HR 0.75, 95% CI 0.59-0.96, P=0.016). Another LEA study compared PFS between fulvestrant (or letrozole) in combination with bevacizumab and fulvestrant (or letrozole) monotherapy. The results indicated that in first-line treatment of HR+/HER2- advanced breast cancer, the clinical benefit rate (CBR) was 77% for the combination therapy group and 67% for the endocrine monotherapy group, with median PFS of 19.3 months and 14.4 months, respectively. This suggests that the combination of the anti-angiogenic drug bevacizumab with endocrine therapy has a certain therapeutic effect in HR+/HER2- MBC patients.
Anlotinib is a multitarget small molecule tyrosine kinase inhibitor (TKI) that exerts potent anticancer effects by inhibiting multiple targets, including VEGFR, PDGFR, FGFR, RET, c-Kit, and c-Met. It has great potential in late-stage breast cancer. This study is a prospective, single-arm, open-label, single-center, exploratory Phase II clinical trial aimed at evaluating whether the combination of anlotinib and fulvestrant can delay resistance in patients with HR+/HER2- advanced recurrent metastatic breast cancer previously treated with AIs, as well as assess its efficacy and safety in patients previously treated with CDK4/6 inhibitors.
The study included histologically confirmed HR+/HER2- breast cancer patients who had previously progressed after AI therapy and received no more than one course of systemic therapy for metastatic disease. They received treatment with fulvestrant in combination with anlotinib, with efficacy assessments conducted every 8 weeks. During the study, the dosage of anlotinib could be reduced due to anlotinib-related adverse events (starting from 12 mg, reduced to 10 mg, and then to 8 mg, with no cross-dose adjustments allowed), and patients who could not tolerate the 8 mg dose had to discontinue the study. The fulvestrant dosage was not adjusted in this study. The primary endpoint was PFS, and secondary endpoints included ORR, CBR, OS, and safety.
As of September 13, 2023, a total of 27 patients were enrolled, with 26 evaluable patients (those with at least one tumor assessment). The median follow-up time was 10.7 months (95% CI 8.8 months to 12.6 months). The ORR was 19.2% (95% CI 6.6%-39.4%), the DCR was 76.9% (95% CI 56.4%-91.0%), and only four patients maintained SD for at least 6 months, resulting in a CBR of 34.6% (95% CI 17.2%-55.7%). The median PFS for the entire group was 7.6 months (95% CI 3.1 months to 12.1 months). Subgroup analysis showed that patients who had not received CDK4/6 inhibitors in the past (14.8 months, 95% CI 1.7 months to 27.9 months) had a better mPFS compared to patients who had received CDK4/6 inhibitor treatment (4.6 months, 95% CI 2.6 months to 6.7 months) (HR 2.88, P=0.055).
The major adverse events (≥10%) included high blood pressure (50.0%), weight loss (23.0%), proteinuria (19.2%), increased thyroid-stimulating hormone (19.2%), hand-foot syndrome (19.2%), and decreased platelet count (15.3%). Eight patients experienced grade 3 hypertension (30.8%), one patient had grade 3 hand-foot syndrome (3.8%), and one patient had grade 3 weight loss (3.8%).
The results indicate that the combination of anlotinib and fulvestrant for metastatic breast cancer previously treated with AIs shows good efficacy and acceptable adverse reactions. Subgroup analysis revealed that patients who had not received CDK4/6 inhibitors in the past had a better mPFS compared to patients who had received CDK4/6 inhibitor treatment. Their respective mPFS was 14.8 months and 4.6 months. Currently, due to issues of accessibility and tolerance, a significant number of patients have been unable to receive first-line treatment with CDK4/6 inhibitors, and this study provides new treatment options for these patients.
References:
1. Xu BH. Progress and future of CDK4/6 inhibitor treatment for hormone receptor-positive, HER2-negative advanced breast cancer. Chinese Journal of Oncology, 2021, 43(4): 431-442.
2. X. Wang, et al. A phase II trial of anlotinib and fulvestrant in patients with metastatic breast cancer previously treated with an aromatase inhibitor. ESMO 452P.
Zhejiang Cancer Hospital
Doctor, Chief Physician (Secondary), Doctoral Supervisor and Postdoctoral Supervisor
Director of Breast Department, Zhejiang Cancer Hospital
Vice Chairman of Zhejiang Provincial Immunology Society
Deputy Director of Zhejiang Cancer Hospital Intelligent Diagnosis and Molecular Technology Research Center
Deputy Director and Chairman of the Breast Cancer Quality Control Expert Committee of Zhejiang Cancer Treatment Quality Control Center
Vice Chairman of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO)
Committee Member of the Chinese Anti-Cancer Association Breast Cancer Professional Committee, and Ethics Committee
Member of the Chinese Medical Association Cardio-Oncology Group
Chairman of the Zhejiang Medical Association Oncology Department
Chairman of the Breast Cancer Professional Committee, Vice Chairman of the Anticancer Association of Zhejiang Province, and former Chairman of the Oncology Department Professional Committee, and Head of the Oncology Cardiology Professional Committee (in preparation)
Vice Chairman and President of the Precision Medicine Branch of the Zhejiang Society of Translational Medicine
