Nonsteroidal Aromatase Inhibitor Therapy Research Articles

Abstract PO2-20-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC treated with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (P) and fulvestrant (F). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. This Phase 3 multinational clinical trial will evaluate geda and F with or without P in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, P, and F), Arm B (geda and F), or Arm C (F). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, P, and F), Arm E (alpelisib and F), or Arm F (geda and F). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. Enrollment is ongoing. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022. Citation Format: Sara Hurvitz, Fabrice André, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-02.

A phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/ HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor (VIKTORIA-1).

TPS1118 Background: Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (palbo) and fulvestrant (FUL). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1 (NCT05501886). Methods: This Phase 3 multinational clinical trial will evaluate geda and FULwith or without palboin patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, palbo, and FUL), Arm B (geda and FUL), or Arm C (FUL). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, palbo, and FUL), Arm E (alpelisib and FUL), or Arm F (geda and FUL). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival, safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. The trial is open for enrollment. Clinical trial information: NCT05501886 .

Abstract OT3-26-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Background: Gedatolisib is a potent reversible dual inhibitor that selectively targets all Class I isoforms of phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). Two separate pivotal clinical trials demonstrated that PI3K and mTOR inhibitors are active in combination with endocrine therapy and prolong progression-free survival (PFS) among patients with hormone receptor positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) who had previously received endocrine therapy (SOLAR-1, BOLERO-2). CDK4/6 inhibitor (CDK4/6i) therapy has been approved in the front-line setting. However, patients eventually experience disease progression on CDK4/6i based therapy. Available data indicates that resistance to CDK4/6i is a transient adaptive mechanism that may be reversed by adding inhibitors of the PI3K/mTOR pathway (PI3K/mTORi). Thus, combination of PI3K/mTORi and CDK4/6i in patients whose disease progressed on prior CDK4/6i could potentially both restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021). Subjects with HR+/HER2- ABC who were CDK4/6i pretreated received gedatolisib (180 mg IV weekly for 3 weeks, then one week off) in combination with standard doses of palbociclib and fulvestrant. Median PFS was 12.9 months, and overall response rate was 63%. Grade 3-4 adverse events (AE) were observed at a low rate, and toxicity was overall easily managed with available standards of care, and few patients discontinued treatment due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. Trial design: This Phase 3, open-label, randomized, multinational two-part clinical trial will evaluate the efficacy and safety of gedatolisib and fulvestrant with or without palbociclib in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with non-steroidal aromatase inhibitor therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 and those with PIK3CA mutations will be assigned to Study 2. Study 1 will include up to 351 subjects randomized in a 1:1:1 ratio to Arm A (gedatolisib, palbociclib, and fulvestrant), Arm B (gedatolisib plus fulvestrant), or Arm C (fulvestrant). For subjects in Arm C whose disease progresses, crossover to Arm A or B is allowed. Study 2 will include up to 350 subjects randomized in a 3:3:1 ratio to Arm D (gedatolisib, palbociclib, and fulvestrant), Arm E (alpelisib plus fulvestrant), or Arm F (gedatolisib plus fulvestrant). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status for females, radiologically evaluable disease, and prior CDK4/6i treatment with non-steroidal AI. Prior therapy with SERD, including fulvestrant is allowed. Key exclusion criteria include prior treatment with a PI3K, protein kinase B (Akt), or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. This trial is open for enrollment. Citation Format: Sara Hurvitz, Fabrice Andre, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo S. Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Samuel Suzuki, Sarah C. Mutka, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-02.

Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal.
 Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020.
 Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052
 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal.
 Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020.
 Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052
 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.

This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10mg/day) + EXE (25mg/day) orally. A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.

Everolimus Plus Exemestane Treatment in Patients with Metastatic Hormone Receptor-Positive Breast Cancer Previously Treated with CDK4/6 Inhibitor Therapy.

The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of patients with metastatic hormone receptor-positive breast cancer (mHRBC) who progress on nonsteroidal aromatase inhibitor (NSAI) therapy. However, none of the patients enrolled in the trial that led to this approval (BOLERO-2) had previously received CDK4/6 inhibitors (CDK4/6is), which have since become a frontline standard of care for mHRBC. As such, the clinical benefit of EVE plus EXE in patients who have previously received CDK4/6is remains unknown. Adult patients with mHRBC at our institution who progressed on an NSAI plus CDK4/6i or NSAI therapy alone and were treated with at least one cycle of EVE plus EXE between 2012 and 2018 were analyzed. Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. Primary objectives were to compare progression-free survival (PFS) and overall survival (OS) between patients who received prior NSAI plus CDK4/6i therapy versus an NSAI alone. Among 43 patients, 17 had prior CDK4/6i exposure. With the exception of de novo metastatic disease, patient and disease characteristics were comparable across treatment cohorts. There was no significant difference in PFS (median, 3.6 vs. 4.2 months) or OS (median, 15.6 vs. 11.3 months) between patients who had received prior CDK4/6is and those who had not, respectively. Prior exposure to CDK4/6i therapy did not impact survival outcomes for patients with mHRBC taking EVE plus EXE. However, there was a trend toward improved OS in the CDK4/6i cohort that should be evaluated in larger cohorts. The use of CDK4/6 inhibitors in combination with a nonsteroidal aromatase inhibitor has become a standard frontline therapy in metastatic hormone receptor-positive breast cancer. An approved subsequent line of therapy is everolimus plus exemestane; however, the original data supporting this therapy predated approval of CDK4/6 inhibitors. As such, the clinical benefit of everolimus and exemestane in patients previously treated with a CDK4/6 inhibitor was unknown. This retrospective cohort study offers real-world data demonstrating prior CDK4/6 inhibitor exposure does not impact survival outcomes for everolimus plus exemestane.

Everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer patients previously treated with CDK4/6 inhibitor based therapies.

1058 Background: The combination of everolimus (EVE) and exemestane (EXE) is approved as second line endocrine therapy for metastatic hormone receptor positive breast cancer (mHRBC) patients who progressed on non-steroidal aromatase inhibitor (NSAI) therapy based on the BOLERO-2 trial. However, none of the patients in BOLERO-2 received prior CDK4/6 inhibitors, which have since become standard of care for metastatic HRBC. As such, the clinical benefit of EVE + EXE in mHRBC patients previously treated with CDK4/6 inhibitors remains unknown. Methods: We reviewed patients ≥18yo with mHRBC treated with EVE + EXE following NSAI alone or NSAI + CDK 4/6 inhibitor at our institution between 2012-2018. Data collected included patient and tumor characteristics, therapies in the metastatic setting, special interest adverse events, and clinical outcomes. The primary objective was comparing PFS for EVE + EXE therapy between patients who received prior CDK4/6 inhibitor therapy and those who did not. Secondary endpoints included overall survival (OS). Patient features were summarized with descriptive statistics and time-to-event measures were estimated using the Kaplan-Meier method. Differences between groups were tested with Fisher’s exact, Kruskal-Wallis, or log-rank test. Results: Thirty-three patients were included in the study; 17 had prior CDK4/6 inhibitor therapy and 16 did not. Subjects that took EVE + EXE for < 28 days were excluded. Patient characteristics, including prior therapies and sites of metastatic disease, were not significantly different. There was no significant difference in PFS (median 5.7 vs 4.7 months, p = 0.890) or OS (median 17.8 vs 11.4 months, p = 0.177) between patients who received prior CDK4/6 inhibitors and those who did not, respectively. Steroid mouthwash use was associated with a reduced incidence of stomatitis. Conclusions: EVE + EXE is well tolerated and shows similar efficacy in metastatic HRBC patients who received CDK4/6 inhibitor therapy and those who did not. There was a non-significant trend towards improved OS in the CDK4/6 inhibitor group that needs to be further evaluated in larger patient cohorts.

Prognostic role of serum thymidine kinase 1 activity in patients with hormone receptor–positive metastatic breast cancer: Analysis of the randomised phase III Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT)

BackgroundThymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. Patients and methodsThe Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on samples collected at baseline, after three and six months of endocrine therapy, and at disease progression. ResultsThe median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91–5.89) versus 2.57 months (95% CI: 2.04–3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14–4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01–6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. ConclusionsTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted.

Abstract P4-13-06: Real-world experience using exemestane and everolimus in patients with hormone receptor positive/HER2 negative breast cancer with and without prior CDK4/6 inhibitor exposure

Abstract Background: For patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who progress on a non-steroidal aromatase inhibitor (NSAI), exemestane plus everolimus (EE) has been shown to prolong progression-free survival in comparison to exemestane alone. In the current era, many patients are now receiving a CDK4/6 inhibitor with first-line NSAI therapy. There is limited data describing the utilization and effectiveness of treatments following hormonal therapy - CDK4/6 inhibitor combinations, including EE. The aim of this study was to describe the real-world clinical experience and outcomes associated with EE amongst patients with and without prior CDK4/6 inhibitor exposure treated in our provincial jurisdiction. Methods: All patients prescribed EE from January 1, 2016 through May 10, 2018 were obtained from the Alberta Health Services CancerControl Breast Data Mart (BDM). Patients with HER2+ disease, had received &amp;lt;1 cycle of EE or who had been on a placebo controlled trial of hormonal therapy +/- CDK4/6 inhibitor prior to EE were excluded. Review of the electronic medical record was undertaken to obtain detailed information on lines of treatment prior to EE, EE dosing and reason for EE discontinuation. The cohort was described and analyzed in total and by prior CDK4/6 inhibitor exposure. Time on treatment (TOT) was defined as start of EE to last dose or June 11, 2018 (censoring for data extraction) and was calculated using the Kaplan Meier method. The log rank test was used to compare TOT. Results: There were 110 patients extracted and 88 eligible for analysis (3 excluded for HER2+ disease, 14 for receipt of &amp;lt;1 cycle EE and 5 for participation on a placebo controlled trial of hormonal therapy +/- CDK4/6 inhibitor prior to EE. Median age 62.4 years (range 32.1-86.6 years). EE was administered first line in 12.5%, second line in 46.6% and third or greater line in 40.9%. Median time from start of first line therapy to start of EE was 19.3 months (range 0.3-72.1 months). Visceral metastases at start of EE in 62.5%. EE mean starting dose 7.3 mg (SD 2.5 mg) and mean last dose recorded 7.0 mg (SD 2.7 mg). At time of data extraction, 69 patients had stopped EE, 68.1% for progression and 31.9% for toxicity or other reason. Twenty patients had hormonal therapy + CDK4/6 inhibitor prior to EE. In the first line setting, 10 patients had letrozole and palbociclib. In the second line setting or greater, 5 patients had letrozole + palbociclib, 1 patient had tamoxifen + palbociclib and 4 patients had fulvestrant + palbociclib. Median time on hormonal therapy + CDK4/6 inhibitor was 12.0 months (range 4.0-20.9 months). Those with hormonal therapy + CDK4/6 inhibitor were more likely to have visceral metastases (p=0.02). Median time on treatment for the CDK4/6 exposed vs naïve groups was similar (5.8 vs 5.3 months, p=0.952). Median overall survival not yet reached. Conclusion: In a cohort of patients who have progressed on hormonal therapy + CDK4/6 inhibitor within 2 years, subsequent EE is a clinically meaningful treatment option in the setting of HR-positive/HER2-negative metastatic breast cancer. TOT was similar for CDK4/6 inhibitor exposed and naïve patients. Citation Format: Lupichuk SM, Recaldin B, Nixon NA, Mututino A, Joy AA. Real-world experience using exemestane and everolimus in patients with hormone receptor positive/HER2 negative breast cancer with and without prior CDK4/6 inhibitor exposure [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-06.

Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report

BackgroundChemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response.Case presentationA 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life.ConclusionsThis case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.

Abstract P2-08-03: Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer

Abstract Background: In vitro mechanisms link IL-6 to poor outcome in breast cancer via inflammatory pathways, activated JAK/STAT tumor signaling and upregulation of aromatase, leading to an aggressive tumor phenotype. Epidemiological data from our group and others support these mechanisms in women with ER-positive (+) disease. We therefore hypothesized that the JAK inhibitor, ruxolitinib (RUX, INCB018424; Incyte), would enhance activity of exemestane (EXE) in women with ER+ breast cancer who relapsed after non-steroidal aromatase inhibitor therapy, particularly among carriers of a germ-line polymorphism in IL-6, conferring elevated levels of IL-6 in the tumor microenvironment. Methods: The “JAKEE trial” is a phase II trial to determine the safety and efficacy of RUX + EXE in postmenopausal women with relapsed, ER+ advanced breast cancer. Eligible patients were required to have progressed on a non-steroidal AI and either measureable or bone-only disease. CRP, a putative biomarker of tumor microenvironment inflammation, was measured at baseline and serially during treatment. Using a Simon 2-stage design, we treated 15 patients with RUX at 25 mg BID and EXE at 25mg daily on a continuous 28-day schedule. First stage results were previously presented (AACR, 2014). Accrual proceeded to second stage after no patient met the pre-defined stopping rule of grade (G) 3/4 toxicity requiring discontinuation from the study within the first treatment cycle. Due to the substantial rate of anemia requiring dose reductions, however, RUX dose was reduced to 15 mg BID in second stage. Results: A total of 25 patients were enrolled; 24/25 had progressed on AI in metastatic setting; 1 relapsed on adjuvant AI. RUX+EXE was well-tolerated overall, with only 2 G4 events (creatinine elevation, hepatic failure); both were due to disease progression. 16% had G3 fatigue, anemia or hypertension; 12% had G3 neutropenia or depression. Other lower grade toxicities in &amp;gt;20% included musculoskeletal pain, increased ALT, and headache. Overall, patients stayed on therapy for a median of 3 cycles (range 2 – 21). There were no CR or PR, but 6/25 (24%) had prolonged disease control (SD&amp;gt; 6 months). Median CRP at study entry was 6.4 (range 0.3-38.9), with 8/25 (32%) having CRP&amp;gt;10. Achieving SD&amp;gt;6 months was not associated with baseline CRP (CRP&amp;gt;10 in 32% with vs. 33% without SD&amp;gt;6 months, p(exact)=1.0). A novel pharmacodynamic assay to assess STAT3 phosphorylation in peripheral blood mononuclear cells after RUX exposure demonstrated differential effects in patients with response. Conclusions: Targeting JAK/STAT signaling in AI-resistant breast cancer with RUX+EXE was safe and well-tolerated. 24% of patients had prolonged SD, but baseline CRP level did not predict response. Correlative studies to determine whether host and/or tumor biomarkers predict response to therapy, including germline IL-6 genotype, immune profiles, p-STAT3 and estradiol levels, are currently underway. Citation Format: DeMichele AM, Clark AS, Holmes R, Volpe M, Medrano C, Troxel A, Fox K, Domchek S, Matro J, Bradbury A, Shih N, Feldman M, Hexner E, Bromberg J. Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-03.

Treat ER+ight: Treatment of Canadian postmenopausal women with ER+ HER2- advanced breast cancer in the real-world setting with hormone therapy ± targeted therapy.

TPS614Background: Although randomized controlled trials (RCTs) provide evidence of efficacy, generalization of these results to patients in the real-world setting is challenging, given RCTs are conducted in highly selected patient populations. An understanding of the effectiveness and safety of approved cancer therapies in routine clinical practice is essential in order to optimize the management of these patients and to identify treatment and safety gaps. Treat ER+ight is the first Canadian study to describe real-world treatment patterns/sequencing, effectiveness and safety for postmenopausal HR+HER2- advanced breast cancer (aBC) patients. Methods: This registry incorporates an observational prospective cohort design and will enroll 320 postmenopausal HR+HER2- aBC women that have been previously exposed to non-steroidal aromatase inhibitor (NSAI) therapy being treated with: endocrine therapy (ET) alone or ET in combination with targeted therapy (ET+TT). Patients who are receiving chemotherapy, have had >...

Abstract OT2-01-04: E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group

Abstract Background: A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA. Methods: E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n=600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility: Postmenopausal women and men, ECOG 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy. Statistics: Both PFS (central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months). E2112 was activated in March 2014 and accrual is anticipated to complete in 40 months. Citation Format: Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-04.

Abstract P5-19-06: 4EVER - Final efficacy analysis of the phase IIIb, multi-center, open label study for postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer (BC) treated with everolimus (EVE) in combination with exemestane (EXE)

Abstract Introduction: The phase III BOLERO-2 trial showed a significant doubling of PFS benefit with EVE + EXE over EXE alone in postmenopausal women with hormone receptor positive advanced BC progressing after non-steroidal aromatase inhibitor (NSAI) therapy. The 4EVER trial further evaluated the combination of EVE+EXE with regard to efficacy and safety, quality of life and health resources utilization in a broader patient population, i.e. without limitations as to the number of previous chemotherapy lines, the time point of progression after NSAI therapy, and the previous EXE therapy. Methods: From May 2012 to November 2012 a total of 299 postmenopausal women with metastatic or locally advanced, hormone receptor positive, HER2 negative breast cancer, refractory to NSAI were recruited to this phase IIIb study. Here we report the results of the planned analysis of the primary and secondary endpoints. The primary endpoint was the overall response rate (ORR) at week 24. The secondary endpoints included: Progression-free survival (PFS), ORR at week 48, overall survival (OS), and quality of life. This study includes a broad exploratory translational research program e.g. changes in serum bone turnover biomarkers, the correlation of Interleukin-6 with anxiety and depression, presence and molecular characteristics of circulating tumor cells, the correlation of response to EXE+EVE with pharmacogenomics. Results: Trial database lock will occur in late June 2014, therefore, the final data concerning the primary and secondary efficacy and safety endpoints will be presented at SACBS 2014. The preliminary baseline analysis included 299 patients (data cut off 15 Nov 2013): HR status: ER+/PgR+ 78.1%, ER+/PgR- 20.9%, 0.7% ER-/PgR+, 0.3% ER-/PgR-. Tissue for receptor status analysis: 71.0% primary tumor, 29.0% metastasis. The mean time since initial diagnosis was 9.6 years, the mean time since first relapse/metastasis was 4.3 years. The mean time since last relapse/metastasis was 2.8 months. 68.1% of patients had bone lesions. Last anti-neoplastic therapy had been administered in the adjuvant (23.9%) and metastatic setting (73.0%). 25.9% of patients had no prior antineoplastic therapy in the metastatic setting, 16.3% had one, 12.2% two and 47.4% three or more prior therapies. Conclusion: The final analysis of the 4EVER study provides more important information on disease patterns and benefits of the combined treatment with EVE and EXE. Citation Format: Hans Tesch, Oliver J Stoetzer, Thomas Decker, Christian M Kurbacher, Romy Neumeister, Frederik Marmé, Andreas Schneeweis, Christoph Mundhenke, Andrea Distelrath, Peter A Fasching, Michael P Lux, Diana Lueftner, Peyman Hadji, Wolfgang Janni, Mathias Muth, Julia Kreuzeder, Claudia Weiss, Diethelm Wallwiener. 4EVER - Final efficacy analysis of the phase IIIb, multi-center, open label study for postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer (BC) treated with everolimus (EVE) in combination with exemestane (EXE) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-06.

Abstract P3-06-04: 4EVER: The impact of mTOR inhibition on bone health in postmenopausal women with hormone receptor positive (HR+) advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE)

Abstract Introduction: The BOLERO-2 study showed significant doubling of PFS benefit with the addition of EVE to EXE in postmenopausal women with hormone receptor–positive advanced breast cancer progressing after non-steroidal aromatase inhibitor (NSAI) therapy. The BOLERO-2 bone sub study indicated an immediate positive influence of EVE on bone health after 6 and 12 weeks of treatment. To further investigate the longer term effect of mTOR inhibition on bone health, we included this exploratory objective in the phase IIIb, multi-center, open label study 4EVER for postmenopausal women with hormone receptor positive advanced breast cancer treated with EVE +EXE. Methods: From May 2012 to November 2012 bone biomarker samples of 247 postmenopausal women with metastatic or locally advanced, hormone receptor positive, HER2 negative breast cancer refractory to NSAI were collected within this phase IIIb study. Here, we report the results of the planned exploratory analysis of biomarkers of bone turnover. The objective of the exploratory biomarker analysis of bone resorption and formation was to assess the effect of EVE on changes of biomarker levels of bone metabolism (CTX, P-I-NP, osteocalcin, vitamin D, testosterone, estradiol, DHEAS, SHBG, PTH,TSH and FSH) from day 1 to weeks 4, 12 and 24 to confirm potential protective effects of EVE on bone via inhibition of bone osteoclast resorption. Descriptive statistics were used to summarize the single bone resorption markers by visit and difference to baseline. Results: Trial data base lock will occur in late June 2014, therefore, the final biomarker analysis of bone resorption and formation and their influence on ORR, PFS and safety will be presented at SABCS 2014. The preliminary analysis on the changes of bone marker levels from baseline to week 24 included 247 patients. The measured changes from baseline to week 24 in biomarker levels revealed increasing levels of testosterone, DHEAS and FSH, while SHBG and PTH were significantly decreased from baseline to week 24. The combination of EVE to EXE resulted in stabilization of bone health as documented by a decrease of absolute P-I-NP levels at week 24 compared to baseline as well as a stabilization of bone resorption as measured by CTX. Conclusion: Our first preliminary results (data cut off 15 Nov 2013) on the changes in bone marker levels supported the hypothesis of EVE having direct impact on bone health, suggesting a decrease of bone turnover and a reversal of the increase in bone resorption associated with aromatase inhibitor therapy. The final analysis of the 4EVER sub study on bone marker levels in correlation with the efficacy data will provide more detailed insights into possible benefits of the combination of EVE plus EXE. Citation Format: Peyman Hadji, Hans Tesch, Oliver Stoetzer, Thomas Decker, Christian M Kurbacher, Romy Neumeister, Frederik Marmé, Andreas Schneeweiss, Christoph Mundhenke, Andrea Distelrath, Peter A Fasching, Micheal P Lux, Diana Lüftner, Wolfgang Janni, Mathias Muth, Julia Kreuzeder, Claudia Weiss, Eva-Maria Grischke. 4EVER: The impact of mTOR inhibition on bone health in postmenopausal women with hormone receptor positive (HR+) advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-04.

Abstract OT2-1-06: E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer

Abstract Background: Epigenetic alterations in the genome, including abnormal DNA methylation and histone hypoacetylation, initiate and promote cancerous changes. A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. Results from ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression on a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), the primary endpoint, and overall survival (OS), an exploratory endpoint. Based on the OS results, entinostat has been designated a Breakthrough Therapy by the FDA when used in combination with exemestane in HR-positive advanced breast cancer. Trial design: E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer who have experienced disease progression on a NSAI (n=600). Patients will receive exemestane 25mg po daily and entinostat/placebo 5mg po every week (28 day cycle). Staging every 12 weeks. Eligibility Criteria: Postmenopausal women and men (≥ 18 years), ECOG performance status 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy. Prior CDK inhibitor or everolimus permitted, but not exemestane or fulvestrant. One prior chemo permitted in metastatic setting. Specific Aims: Both PFS (defined by central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. Statistical Methods: One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months) Present and Targeted Accrual: This study was activated in March 2014 and accrual is anticipated to complete in 40 months. Contact Person: Dr. Roisin Connolly, Email: rconnol2@jhmi.edu Funding: ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute, and Syndax Pharmaceuticals. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Amye J Tevaarwerk, Lynne I Wagner, Min-Jung Lee, Judy Murray, Robert Gray, Richard L Piekarz, Jo Anne A Zujewski, Joseph A Sparano. E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-06.

Management of patients with hormone receptor-positive breast cancer with visceral disease: challenges and treatment options.

Endocrine therapy is an important treatment option for women with hormone receptor–positive (HR+) advanced breast cancer (ABC), yet many tumors are either intrinsically resistant or develop resistance to these therapies. Treatment of patients with ABC presenting with visceral metastases, which is associated with a poor prognosis, is also problematic. There is an unmet need for effective treatments for this patient population. Although chemotherapy is commonly perceived to be more effective than endocrine therapy in managing visceral metastases, patients who are not in visceral crisis might benefit from endocrine therapy, avoiding chemotherapy-associated toxicities that might affect quality of life. To improve outcomes, several targeted therapies are being investigated in combination with endocrine therapy for patients with endocrine-resistant, HR+ ABC. Although available data have considered patients with HR+ ABC as a whole, there are promising data from a prespecified analysis of a Phase III study of everolimus (Afinitor®), a mammalian target of rapamycin (mTOR) inhibitor, in combination with exemestane (Aromasin®) in patients with visceral disease progressing after nonsteroidal aromatase inhibitor therapy. In this review, challenges and treatment options for management of HR+ ABC with visceral disease, including consideration of therapeutic approaches undergoing clinical investigation, will be assessed.

A new era of improving progression-free survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer.

Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)), advanced breast cancer. Recent advances in elucidating the molecular mechanisms of disease progression have identified the existence of adaptive "cross-talk" between the estrogen receptor (ER) and various growth factor receptor and intracellular signaling pathways, allowing breast cancer cells to escape the inhibitory effects of endocrine therapy. These findings provide the clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against a compensatory pathway. In BOLERO-2, adding the mTOR inhibitor everolimus to endocrine therapy significantly improved progression-free survival (PFS) in patients with HR(+) advanced breast cancer previously treated with nonsteroidal aromatase inhibitor therapy. Notably, PFS benefits were comparable in subgroup analyses of first- and later-line settings. These results contrast with those of the large first-line HORIZON study, wherein adding the mTOR inhibitor temsirolimus to endocrine therapy did not improve PFS. Therefore, it is unclear whether a targeted agent should only be combined with endocrine therapy to restore endocrine sensitivity or whether it may also prevent or delay resistance in hormone-sensitive advanced breast cancer. Numerous additional targeted agents are currently being evaluated in combination with endocrine therapies, including PI3K, cyclin-dependent kinase 4/6, SRC, and histone deacetylase inhibitors. Appropriate patient selection based on prior treatment history will become increasingly important in maximizing the incremental benefit derived from these new agents combined with existing endocrine therapies in HR(+) advanced breast cancer.

Everolimus plus exemestane in patients with advanced invasive lobular carcinoma: Efficacy and safety results from BOLERO-2.

152 Background: In BOLERO-2 (NCT00863655), everolimus plus exemestane (EVE + EXE) more than doubled median progression-free survival (PFS) vs placebo (PBO) + EXE (by local assessment: 7.8 vs 3.2 mo; hazard ratio [HR], 0.45; P &lt; 0.0001; by central assessment: 11.0 vs 4.1 mo; HR, 0.38; P &lt; 0.0001) in patients (pts) with hormone-receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). This exploratory analysis assessed the efficacy and safety of EVE + EXE in a subset of pts with baseline invasive lobular carcinoma (ILC) (elderly pts with predominantly peritoneal, gastrointestinal, and ovarian metastases [mets]). Methods: Pts with HR+, HER2– ABC recurring or progressing on/after prior nonsteroidal aromatase inhibitor therapy were randomized 2:1 to receive EVE 10 mg/day + EXE 25 mg/day or PBO + EXE. Primary efficacy end point was PFS (by local assessment). Results: Of 724 pts, 77% (n = 556) had ductal carcinoma and 14% (n = 104; EVE + EXE, n = 64; PBO + EXE, n = 40) had ILC. In ILC subset, median age was 63 years, 47.1% had measurable disease, and majority of baseline characteristics were similar to overall study population with exception of main mets sites. In pts with ILC, 36% reported visceral mets (lung, liver, pleural, pleural effusions, peritoneum, and ascites), 10% lung mets, and 23% liver mets when compared with 59% visceral mets, 31% lung mets, and 33% liver mets in overall study population. Median PFS was higher with EVE + EXE vs PBO + EXE (6.9 vs 4.2 mo; HR, 0.59; 95% CI, 0.37-0.95). Objective response rates were 14.1% (EVE + EXE arm) and 0% (PBO + EXE arm) vs 12.6% and 1.7%, respectively, among overall study population. Clinical benefit rates were 45.3% (EVE + EXE arm) and 30.0% (PBO + EXE arm); 51.3% vs 26.4% in overall study population. The safety profile of EVE + EXE in pts with ILC was similar to overall study population. Most common adverse events (all grades) in EVE-treated pts with ILC were stomatitis (50%), diarrhea (41%), nausea (36%), fatigue (34%), and rash (33%). Conclusions: EVE + EXE prolonged PFS in pts with ILC who had different patterns of mets. Other outcomes were similar to those in overall study population. Clinical trial information: NCT00863655.