Open-label phase II study of everolimus plus endocrine therapy in postmenopausal women with ER+, HER2-metastatic breast cancer (Chloe trial)

e13052 Background: In the treatment of ER-positive metastatic breast cancer (MBC), the addition of molecularly targeted drugs overcoming resistance to aromatase inhibitors (AI) improves outcomes. It is not clear, however, whether this drug is necessary in the first line treatment for all cases. Whether it should be administered before acquiring resistance, especially for MBCs with sensitivity to AI, is debatable. In this study, we prospectively investigated whether early additional administration of mTOR inhibitor to an AI-sensitive MBC regimen can delay the acquisition of resistance and extend the duration of AI efficacy. Methods: This was a multicenter, open-label, randomized, phase II study comparing patients with ER-positive postmenopausal MBC responsive to first-line treatment with AI for six months, and randomized to either continue to receive AI (standard group; SG) or add the 10 mg/day of mTOR inhibitor (experimental group; EG). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival, response rate (RR), disease control rate (DCR), adverse events (AE), and time to treatment failure (TTF). The planned number of registrations was 130 (65 cases in each group) with a registration period of 2 years. Results: The total enrollment was 44, with 21 in the SG and 22 in the EG (one patient did not receive treatment). As to patient backgrounds, 9.5% (2 patients) in SG and 22.7% in EG (5 patients) were PgR negative. Late recurrence (DFS＞5 years after surgery) was observed in 10 (47.6%) SG patients and 12 (54.5%) EG patients. Three SG patients (14.3%) and two EG patients (9.1%) had a history of chemotherapy after recurrence. Treatment was discontinued in 14 (66.7%) SG patients and 12 EG (54.5%) patients during follow-up. Progressive disease was observed in 12 (57.1%) and 4 (18.2%) patients, respectively, while in the EG we noted discontinuation due to AE (4 patients (18.2%)) and discontinuation at the patient's request (4 patients (18.2%)). There was no significant difference in PFS between the two groups. There was no significant difference in the DCR in patients with target lesions (62.5% in SG and 78.6% in EG). The frequency of AE greater than G2 was low in SG: only 3 with hyperglycemia and 1 with leukopenia. In contrast, numerous toxicities were observed in multiple patients in EG (68.2%). Conclusions: Early addition of an mTOR inhibitor for AI-sensitive MBC did not achieve significant PFS prolongation. Although the addition of mTOR inhibitors may have suppressed the deterioration of patient status, several cases required discontinuation due to AE associated with the drug. Further study with a larger sample size may be required to determine a significant difference between the two groups. Clinical trial information: jRCTs061180075 .