A Phase II Study of Fulvestrant 500 mg as Maintenance Therapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Patients with Advanced Breast Cancer After First-Line Chemotherapy
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Abstract
Lessons Learned
- Fulvestrant 500 mg maintenance therapy showed a clinical benefit rate of 76% and median progression-free survival of 16.1 months in patients who achieved objective responses or disease control after first-line chemotherapy.
- Adverse events with fulvestrant maintenance therapy were consistent with the known safety profile of the drug.
Background
Evidence for maintenance hormonal therapy after chemotherapy for estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer is scarce. This study aimed to evaluate the efficacy of fulvestrant 500 mg maintenance therapy in patients after first-line chemotherapy.
Methods
We enrolled postmenopausal women with ER-positive/HER2-negative advanced breast cancer who attained tumor responses or disease control with four to eight cycles of chemotherapy as first-line treatment. Fulvestrant 500 mg was injected on days 1, 15, and 29 and every 28 (±3) days thereafter. The primary endpoint was the clinical benefit rate (CBR); the secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and safety.
Results
We included 58 patients; the median follow-up duration was 32.6 months. The CBR since commencing fulvestrant maintenance therapy was 76% (95% confidence interval [CI], 63%–86%), and ORR was 14% (95% CI, 6%–25%); eight patients achieved partial response. The median PFS for fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3–21.0 months). Thirty-nine patients (67%) reported at least one adverse event, of which most were grade 1/2, whereas three patients (5%) reported grade 3 adverse events.
Conclusion
Fulvestrant 500 mg is a feasible and promising hormonal maintenance strategy in patients with ER-positive/HER2-negative advanced breast cancer who have no disease progression after first-line chemotherapy.
Discussion
For hormone receptor-positive, HER2-negative advanced breast cancer, the best treatment pattern remains uncertain, predominantly because of a paucity of evidence comparing different sequential treatment strategies. National and international treatment guidelines recommend hormone therapy for first-line treatment [1-3]; however, there are always some patients who need initial palliative chemotherapy to shrink bulky tumor or stop rapid tumor growth, especially those with visceral crisis.
Researchers have established the role of maintenance therapy in patients who achieved tumor control with first-line chemotherapy. The GEICAM 2001-01 trial of maintenance treatment with pegylated liposomal doxorubicin reported improvements in time to progression compared with observation [4]. Similarly, the KCSG-BR07-02 study showed significant prolongation of PFS and overall survival (OS) with maintenance paclitaxel and gemcitabine chemotherapy compared with observation [5]. Maintenance hormonal therapy after chemotherapy for advanced ER-positive/HER2-negative breast cancer is widely used and is considered a reasonable treatment option according to the Advanced Breast Cancer guidelines. However, there are little high-quality data to support this maintenance setting.
Fulvestrant is a pure ER antagonist with no known agonist effects [6]. Results from the FIRST study showed that fulvestrant 500 mg for advanced breast cancer achieved longer PFS and OS than anastrozole [7, 8]. Results from the FALCON study further substantiated the superior PFS achieved by fulvestrant compared with anastrozole in women with advanced breast cancer who were endocrine therapy naïve [9]. Given the absence of maintenance hormonal therapy recommendations after induction chemotherapy and considering the encouraging data regarding the superiority of fulvestrant over aromatase inhibitors, we performed this Fulvestrant After First-line Chemotherapy (FANCY) trial to prospectively evaluate the efficacy of fulvestrant 500 mg as a maintenance hormonal therapy in patients with ER-positive/HER2-negative advanced breast cancer exhibiting no progression of disease after first-line induction chemotherapy.
To the best of our knowledge, this study is the first prospective trial focusing on the efficacy of fulvestrant 500 mg as maintenance hormonal therapy in women with nonprogressive disease after first-line chemotherapy. This study showed a CBR of 76% and median PFS of 16.1 months with fulvestrant 500 mg maintenance therapy in patients who achieved objective responses or disease control after first-line chemotherapy (Fig. 1). Adverse events with fulvestrant maintenance therapy were consistent with the drug's known safety profile. Our study offers preliminary evidence to support its clinical use and provides insights for future development.

Abbreviations: CI, confidence interval; PFS, progression-free survival.
Trial Information
Disease | Breast cancer |
Stage of Disease/Treatment | Metastatic/advanced |
Prior Therapy | One prior regimen |
Type of Study | Phase II, single arm |
Primary Endpoint | Clinical benefit rate |
Secondary Endpoints | Overall response rate, progression-free survival, safety |
Additional Details of Endpoints or Study Design | |
The primary endpoint was CBR during fulvestrant maintenance therapy, defined as the proportion of no clinical or radiological progression of disease per RECIST version 1.1 [10]. The secondary endpoints included PFS since fulvestrant maintenance therapy, defined as the date of commencing fulvestrant treatment to the documented date of progression or death irrespective of the underlying cause, and ORR, defined as the proportion of patients with the best overall response, either complete or partial response. We also assessed the safety and tolerability by adverse events and clinical laboratory results. | |
Simon's two-stage minimax design was used for sample size calculation [11]. On the basis of the 6-month PFS rate of the observational group in the GEICAM 2001-01 [4] and KCSG-BR07-02 [5] studies, we hypothesized that the 6-month disease control rate without maintenance therapy after the first-line chemotherapy would be 30%. To reflect real-world clinical practice, a 20% improvement of CBR upon maintenance therapy was expected. Assuming a significance level of 5% (type I error) and a statistical power of 90%, we required 53 patients in two stages; assuming a 10% follow-up loss, we ultimately enrolled 58 patients. If seven or more of the first 24 patients in the first stage achieved response or stabilization, recruitment would be continued for the second stage. | |
Investigator's Analysis | Active and should be pursued further |
Drug Information
Generic/Working Name | Fulvestrant |
Trade Name | Faslodex |
Company Name | AstraZeneca |
Drug Type | Small molecule |
Drug Class | Estrogen receptor |
Dose | 500 mg milligrams (mg) per flat dose |
Route | Intramuscular |
Schedule of Administration | Fulvestrant 500 mg was administered as two 5-mL intramuscular injections, one in each buttock, on days 1, 15, and 29 and once monthly thereafter. |
Patient Characteristics
Number of Patients, Male | 0 |
Number of Patients, Female | 58 |
Stage | Metastatic breast cancer: 58 |
Age | Median (range): 49 (31–78) years |
Number of Prior Systemic Therapies | Median: 1 |
Performance Status: ECOG |
0 — 15 1 — 38 2 — 1 3 — 0 Unknown — 4 |
Cancer Types or Histologic Subtypes | Invasive ductal carcinoma, 46; invasive lobular carcinoma, 4; mucinous adenocarcinoma, 1; invasive micropapillary carcinoma, 1; invasive carcinoma, 6. Detailed patient characteristics are shown in Table 1. |
Primary Assessment Method
Number of Patients Screened | 58 |
Number of Patients Enrolled | 58 |
Number of Patients Evaluable for Toxicity | 58 |
Number of Patients Evaluated for Efficacy | 58 |
Evaluation Method | RECIST 1.1 |
Response Assessment CR | n = 0 (0%) |
Response Assessment PR | n = 8 (14%) |
Response Assessment SD | n = 41 (70%) |
Response Assessment PD | n = 9 (16%) |
Response Assessment OTHER | n = 0 (0%) |
(Median) Duration Assessments PFS | 16.1 months, CI: 10.3–21.0 |
Outcome Notes | |
During the first stage, 17 of the first 24 patients (71%; 95% CI, 49%–87%) experienced a clinical benefit, thus meeting the threshold for continuing enrolment. Overall, the CBR and ORR were 76% (95% CI, 63%–86%) and 14% (95% CI, 6%–25%), respectively. Of the 58 patients' best response, 8 (14%) achieved partial response, 19 (33%) had stable disease, and 22 (38%) neither achieved complete response nor had disease progression. Progressive disease was observed in nine patients (16%). In the investigator-based assessment, 35 patients still had measurable disease after first-line chemotherapy, of whom 8 (23%) had a partial response and 19 (54%) had stable disease as best response. The CBR among measurable patients was 69% (95% CI, 51%–83%), and the ORR was 23% (95% CI, 10%–40%). By the data cutoff date, the median follow-up was 32.6 months. No patients died during fulvestrant treatment. The median PFS since commencing fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3–21.0 months; Fig. 1), with 1- and 2-year PFS rates of 60% (95% CI, 46%–71%) and 35% (95% CI, 23%–47%), respectively. Twenty-three deaths had occurred at the time of data cutoff. The median duration of OS had not been reached at the time of data analysis. The rate of OS at 3 years was 51% (95% CI, 32%–67%). |
Adverse Events
All Cycles | |||||||
---|---|---|---|---|---|---|---|
Name | NC/NA, % | Grade 1, % | Grade 2, % | Grade 3, % | Grade 4, % | Grade 5, % | All grades, % |
Aspartate aminotransferase increased | 83 | 12 | 3 | 2 | 0 | 0 | 17 |
Injection site reaction | 50 | 47 | 3 | 0 | 0 | 0 | 50 |
Alanine aminotransferase increased | 79 | 16 | 2 | 3 | 0 | 0 | 21 |
Nausea | 88 | 12 | 0 | 0 | 0 | 0 | 12 |
Hot flashes | 74 | 26 | 0 | 0 | 0 | 0 | 26 |
Arthralgia | 61 | 34 | 3 | 2 | 0 | 0 | 39 |
Anorexia | 86 | 14 | 0 | 0 | 0 | 0 | 14 |
Fatigue | 60 | 40 | 0 | 0 | 0 | 0 | 40 |
Anemia | 90 | 10 | 0 | 0 | 0 | 0 | 10 |
Neutrophil count decreased | 92 | 5 | 3 | 0 | 0 | 0 | 8 |
Pain in extremity | 91 | 9 | 0 | 0 | 0 | 0 | 9 |
White blood cell decreased | 93 | 5 | 2 | 0 | 0 | 0 | 7 |
Insomnia | 93 | 7 | 0 | 0 | 0 | 0 | 7 |
Rash maculo-papular | 93 | 7 | 0 | 0 | 0 | 0 | 7 |
Hypertriglyceridemia | 95 | 5 | 0 | 0 | 0 | 0 | 5 |
Cough | 96 | 2 | 2 | 0 | 0 | 0 | 4 |
Bone pain | 97 | 3 | 0 | 0 | 0 | 0 | 3 |
Hyperglycemia | 96 | 2 | 2 | 0 | 0 | 0 | 4 |
Constipation | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Cholesterol high | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Chest wall pain | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Headache | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Myalgia | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Edema limbs | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
Upper respiratory infection | 98 | 0 | 2 | 0 | 0 | 0 | 2 |
Platelet count decreased | 98 | 0 | 2 | 0 | 0 | 0 | 2 |
Vaginal infection | 98 | 0 | 2 | 0 | 0 | 0 | 2 |
Pharyngolaryngeal pain | 98 | 2 | 0 | 0 | 0 | 0 | 2 |
- Adverse Events Legend Incidence of adverse events in patients on fulvestrant maintenance therapy.
- Abbreviation: NC/NA, no change from baseline/no adverse event.
Assessment, Analysis, and Discussion
Completion | Study completed |
Investigator's Assessment | Active and should be pursued further |
Our study confirms the suggestive findings of previously published studies on maintenance endocrine treatment in patients with estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Kloke and colleagues conducted the first phase III randomized study [12] to elucidate the role of hormonal therapy in the maintenance setting (with medroxyprogesterone acetate). The investigators reported markedly prolonged time to progression (the primary endpoint) with medroxyprogesterone compared with observation (4.9 months vs. 3.7 months; p = .02). However, although the 1.2-month improvement in median time to progression derived from medroxyprogesterone was statistically significant, its clinical significance was limited. In addition, the frequent side effects of medroxyprogesterone, such as swelling, weight gain, and deep vein thrombosis, further restrict its use as maintenance therapy in clinical practice.
Bertelli et al. reported a phase II, single-arm study of 58 patients with nonprogressive disease who were given letrozole after first-line chemotherapy [13]. The results were encouraging, with median time to progression of 18.5 months. Moreover, in a retrospective analysis of French patient cohorts [14], 560 patients with positive tumor hormonal receptor who received first-line chemotherapy and achieved disease control were studied. Maintenance hormonal therapy after first-line chemotherapy, predominately with aromatase inhibitor (50%) and tamoxifen (31%), was similarly associated with longer progression-free survival (PFS) (16.3 months vs. 7.77 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.57–0.72; p < .001) and overall survival (48.08 months vs. 30.03 months; HR, 0.81; 95% CI, 0.71–0.92; p = .001) compared with those without maintenance hormonal therapy. In real life, aromatase inhibitors are indeed the most commonly used maintenance therapy in ER-positive/HER2-negative advanced breast cancer. In our study, we showed a PFS of 16.1 months with fulvestrant 500 mg maintenance therapy. However, whether fulvestrant can challenge the predominance of aromatase inhibitor in maintenance setting still needs to be verified by randomized controlled trials.
Maintenance therapy in patients with advanced breast cancer with nonprogressive disease after first-line chemotherapy is a subject of ongoing research. However, whether switching a regimen (maintenance with another type of treatment, i.e., hormonal therapy) or choosing one or more drugs from the induction therapy favors survival more remains controversial. Chen and colleagues [15] reported a retrospective study comparing maintenance hormonal therapy (n = 59) and maintenance with capecitabine monotherapy (n = 79) after response to first-line capecitabine-based combination chemotherapy. Median time to progression was significantly prolonged in patients receiving maintenance hormonal therapy compared with those receiving capecitabine maintenance (13 months vs. 8 months, p = .011). However, in the phase III AROBASE trial [16], 117 patients were randomly assigned to receive either maintenance exemestane plus bevacizumab (n = 58) or continuation of taxane plus bevacizumab (n = 59) after first-line taxane and bevacizumab combination therapy; the PFS of patients who received maintenance exemestane plus bevacizumab therapy did not improve compared with those who continued taxane and bevacizumab (7.6 months vs. 8.1 months; HR, 1.0; 95% CI, 0.66–1.51; p = .998).
A part of our study rationale was that switching to maintenance hormonal therapy might eliminate residual tumors that were resistant to chemotherapy. This hypothesis was partially confirmed because additional tumor regression occurred in 8 (14%) patients. However, 24% of patients did not derive a benefit from switching to maintenance hormonal therapy; they may have benefited from the same treatment modality that achieved initial tumor control. Consequently, further studies to identify patients who will benefit from maintenance chemotherapy or endocrine therapy are necessary.
We noted that there have been some important advances in the management of ER-positive/HER2-negative advanced breast cancer during the study period. In particular, the selective inhibitors of cyclin-dependent kinases 4/6 (CDK4/6), including palbociclib [17, 18], ribociclib [19], and abemaciclib [20, 21], have shown potential for overcoming or delaying endocrine therapy resistance. Their combination with an aromatase inhibitor and fulvestrant has been recommended for first- and second-line therapy [2], respectively. The high activities of CDK4/6 inhibitors lead to a delay in the initiation of palliative chemotherapy in those who may be ineligible for endocrine monotherapy. However, there are many patients in many countries who cannot obtain or afford these new drugs. For them, chemotherapy remains a well-established option to shrink bulky tumors or stop rapid tumor growth.
This study included 25 patients (43%) who were deemed resistant to prior endocrine treatment because they had a relapse during or within 12 months after the completion or discontinuation of adjuvant therapy, and 36 (62%) patients had symptomatic visceral disease. All patients were not eligible for initial endocrine monotherapy. We demonstrated the preliminary efficacy and feasibility of fulvestrant 500 mg as maintenance hormonal therapy. Prospective randomized trials (NCT02383030, ChiCTR-IIR-17014036) are ongoing to evaluate the superiority of fulvestrant maintenance therapy. If confirmed in randomized trials, these findings have major implications for the use of fulvestrant in the maintenance setting.
This study did have limitations. The absence of a control group and the relatively small number of patients may limit the interpretation of the results. However, a single-arm, phase II study may be sufficient to provide insights on the efficacy and safety of fulvestrant in maintenance therapy because previous large clinical trials have demonstrated superiority of the investigational drug in other therapeutic settings. In addition, in the absence of consistent first-line chemotherapy regimens, various treatment backgrounds may influence subsequent PFS resulting from maintenance therapy.
In summary, our findings show that maintenance therapy with fulvestrant 500 mg is active and well tolerated in patients with ER-positive/HER2-negative advanced breast cancer who have no disease progression after first-line chemotherapy. Further studies to assess the long-term outcome of fulvestrant maintenance therapy are worth considering.
Acknowledgments
We thank all the patients who participated in the study and their families. We are grateful to all medical staff, staff nurses, and research nurses at the three medical centers. This work was partially supported by grants from Sci-Tech Project Foundation of Guangdong Province (2012B031800447, 2014A020212384, and 2016A020215079), National Natural Science Foundation of China (81272896), and Joint Funds of the National Natural Science Foundation of China and the Government of Guangdong Province (U1601224). AstraZeneca provided fulvestrant.
Disclosures
The authors indicated no financial relationships.
- ClinicalTrials.gov Identifier: NCT02000193
- Sponsor: AstraZeneca
- Principal Investigator: Shusen Wang
- IRB Approved: Yes
References
Table
Characteristics | n (%) |
---|---|
Hormone receptor status | |
ER(+), PR(+) | 42 (72) |
ER(+), PR(–) | 16 (28) |
Previous adjuvant endocrine therapy | |
Tamoxifen/toremifene | 29 (50) |
AI | 7 (12) |
OFS + tamoxifen | 3 (5) |
Tamoxifen followed by AI | 2 (3) |
No prior adjuvant endocrine treatment | 17 (29) |
Sensitivity to previous hormonal therapya | |
Yes | 33 (57) |
No | 25 (43) |
Disease-free interval after diagnosisb | |
De novo | 8 (14) |
Not de novo | 50 (86) |
≤2 years | 11 (19) |
>2 years | 39 (67) |
Metastatic sites | |
Local recurrence | 33 (57) |
Bone metastases | 38 (66) |
Any visceral disease | 36 (62) |
Lung metastases | 22 (38) |
Liver metastases | 10 (17) |
Pleura/peritoneum metastases | 12 (21) |
Pleural/pericardial effusion | 7 (12) |
Colon metastases | 2 (3) |
Ovary metastases | 2 (3) |
Adrenal metastasis | 1 (2) |
Retrobulbar metastasis | 1 (2) |
Metastatic organs, median (range), sites | 3 (1–7) |
First-line chemotherapy agent | |
Taxane-based | 42 (72) |
Not taxane-based | 16 (28) |
First-line chemotherapy response | |
Complete response | 0 (0) |
Partial response | 25 (43) |
Stable disease | 33 (57) |
Use of bisphosphonate | 33 (57) |
- a Patients were defined as having sensitivity to prior endocrine therapy if they had no prior endocrine therapy or had completed more than 12 months of adjuvant endocrine therapy for early disease, whereas patients were defined as having no sensitivity to prior endocrine therapy if they had a relapse during or within 12 months after the completion or discontinuation of adjuvant therapy.
- b Disease-free interval is defined as the time from initial diagnosis of early disease to first recurrence or progression.
- Abbreviations: AI, aromatase inhibitor; ER, estrogen receptor; OFS, ovarian function suppression; PR, progesterone receptor.