Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: A Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Original Investigation
July 2018

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: A Clinical Trial

Author Affiliations
  • 1University of New Mexico Comprehensive Cancer Center, Albuquerque
  • 2Breast Cancer Unit and the Clinical Trial Unit, Centre Léon Bérard, Lyon, France
  • 3Service d'Oncologie Médicale, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France
  • 4Department of Oncology, Cerrahpaşa School of Medicine, Istanbul University, Istanbul, Turkey
  • 5Oncology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
  • 6Instituto Brasileiro de Controle do Câncer, São Paulo, Brazil
  • 7Département d'Oncologie Médicale, Institut Bergonié, Bordeaux, France
  • 8Centro de Referência da Saúde da Mulher, Hospital Pérola Byington/Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  • 9Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
  • 10University of Alabama Comprehensive Cancer Center, Birmingham
  • 11Department of Surgery, Breast Cancer Center, Yonsei University Health System, Seoul, Republic of Korea
  • 12Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • 13Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 14Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
  • 15Global Medical Affairs Biostatistics, Novartis Pharma S.A.S., Rueil-Malmaison, France
  • 16Breast Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
JAMA Oncol. 2018;4(7):977-984. doi:10.1001/jamaoncol.2018.0060
Key Points

Question  Does first-line everolimus plus endocrine therapy provide a clinical benefit for patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer?

Findings  In this phase 2, single-arm study, 202 patients treated with everolimus plus letrozole in the first-line setting achieved a median progression-free survival of 22.0 months; median overall survival was not reached. For 50 patients whose cancer progressed and who received continued treatment with everolimus plus exemestane, median progression-free survival was 3.7 months.

Meaning  These results suggest a rationale for providing first-line everolimus plus letrozole therapy to patients with estrogen receptor–positive advanced breast cancer.

Abstract

Importance  Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer.

Objective  To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor–positive, human epidermal growth receptor 2–negative advanced breast cancer.

Design, Setting, and Participants  In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016).

Interventions  Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator’s discretion upon initial disease progression.

Main Outcomes and Measures  The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment.

Results  A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer).

Conclusions and Relevance  The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer.

Trial Registration  clinicaltrials.gov Identifier: NCT01698918

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