Therapy For Advanced Breast Cancer Research Articles

Targeted combination therapy with fulvestrant (FUL) for second-line (2L) treatment of hormone receptor-positive (HR+) advanced breast cancer (ABC).

e12527 Background: FUL is the recommended 2L treatment for patients whose HR+ ABC progressed after aromatase inhibitor (AI) therapy. In first line ABC adding targeted therapy, eg. cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib or ribociclib, or mammalian target of rapamycin inhibitor (mTORi) everolimus (EVE), to endocrine therapy (ET) has shown superior efficacy vs ET alone. The use of similar strategies to delay disease progression on ET in the 2L setting is an area of active research. Methods: PubMed and ClinicalTrials.gov were searched for trials investigating FUL + targeted therapies in 2L HR+ ABC. Search terms: (advanced OR metastatic) AND (breast cancer) AND (FUL OR faslodex) AND (2L OR relapse OR refractory OR resistant OR progression). Efficacy, adverse events (AEs) and quality of life were assessed. Results: 28 studies of FUL + targeted therapies in 2L ABC were found. Key randomized trials include 8 studies exploring FUL + CDK4/6i: palbociclib, ribociclib or abemaciclib. Palbociclib + FUL significantly improved progression-free survival (PFS) vs FUL in 2L HR+ ABC (p < 0.0001; PALOMA-3), AEs were manageable. Assessment of FUL + ribociclib (MONALEESA-3) or FUL + abemaciclib (MONARCH-2) in 2L HR+ ABC is ongoing. Ten studies are evaluating FUL + phosphatidylinositol 3-kinase (PI3K)/AKT/mTORi in 2L HR+ ABC. FUL + EVE significantly prolonged PFS vs FUL (p = 0.02; PrECOG 0102). Two trials evaluated buparlisib (pan-PI3K inhibitor [PI3Ki]) + FUL in HR+ ABC post-AI (BELLE-2) and post-mTORi (BELLE-3). In both trials, buparlisib + FUL improved PFS vs FUL in patients with PIK3CA-mutated tumors, FUL alone led to a poor response in this subgroup. However, pictilisib (pan-PI3Ki) + FUL did not improve PFS vs FUL even in the PIK3CA-mutated subgroup (FERGI). Ongoing phase 3 trials are exploring FUL + alpelisib (α-specific PI3Ki; SOLAR-1) or FUL + taselisib (β-sparing PI3Ki; SANDPIPER) in PIK3CA-mutant HR+ ABC. Pts who have progressed on AI, CDK4/6i or (neo)adjuvant chemotherapy are eligible for these studies. Data on FUL + other targeted therapies will also be discussed. Conclusions: Addition of targeted therapy to FUL demonstrates promising efficacy beyond first line.

Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC).

1038 Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC.1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10-5. Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.

Abstract P4-22-05: First-line ribociclib plus letrozole in patients with de novo HR+, HER2– advanced breast cancer (ABC): A subgroup analysis of the MONALEESA-2 trial

Abstract Background: Around 15,000 US patients per year are diagnosed with de novo ABC. Due to the absence of prior systemic treatment for breast cancer, tumors of patients with de novo ABC may exhibit a different disease biology, which could result in different tumor responses compared with patients who have relapsed breast cancer. Ribociclib is an orally bioavailable cyclin-dependent kinase (CDK) 4/6 inhibitor. Results from MONALEESA-2, a double-blind, placebo-controlled, randomized Phase 3 trial (NCT01958021), demonstrated that first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) vs placebo + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC. Many patients with de novo ABC receive endocrine therapy in the first line and in subsequent lines; here we present results from the MONALEESA-2 study in a subpopulation of patients with de novo ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had no prior systemic therapy for ABC were randomized 1:1 (stratified by liver and/or lung metastases) to receive ribociclib (600 mg/day; 3-weeks-on/1-week-off) + letrozole (2.5 mg/day; continuous) or placebo + letrozole. Patients with de novo ABC were eligible. Additional eligibility criteria included measurable disease or ≥1 predominantly lytic bone lesion, Eastern Cooperative Oncology Group performance status ≤1, and adequate bone marrow/organ function. Prior CDK4/6 inhibitors or systemic therapy for ABC were prohibited. Patients may have received ≤14 days of letrozole or anastrozole for ABC. The primary endpoint was locally assessed PFS; a predefined subgroup analysis evaluated PFS in patients with de novo ABC. Results: In total, 227 patients with de novo ABC were enrolled. Patients with de novo ABC were equally distributed with 114 (34%) and 113 (34%) in the ribociclib + letrozole and placebo + letrozole arms, respectively. Median duration of exposure to study treatment in the ribociclib + letrozole vs placebo + letrozole arms was 14.1 vs 12.8 months. Treatment was discontinued in 84 (37%) patients with de novo ABC (ribociclib + letrozole vs placebo + letrozole, n [%]; 34 [30%] vs 50 [44%]). Reasons for treatment discontinuation (ribociclib + letrozole vs placebo + letrozole, n [%]) included disease progression (21 [18%] vs 41 [36%]), patient/physician decision (5 [4%] vs 6 [5%]), and adverse events (6 [5%] vs 3 [3%]). PFS was increased in patients with de novo ABC who received ribociclib + letrozole vs placebo + letrozole (hazard ratio=0.448 [95% confidence interval: 0.267–0.750]). The 12-month PFS event-free probability in patients with de novo ABC was 82% in the ribociclib + letrozole arm vs 66% in the placebo + letrozole arm. Conclusions: The combination of ribociclib + letrozole significantly improved PFS compared with placebo + letrozole in postmenopausal women with HR+, HER2– de novo ABC at diagnosis and therefore may become an important treatment option in the de novo ABC setting. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: O'Shaughnessy J, Petrakova K, Sonke GS, André F, Conte P, Arteaga CL, Cameron DA, Hart LL, Villanueva C, Jakobsen EH, Lindquist D, Souami F, Li X, Germa C, Hirawat S, Hortobagyi GN. First-line ribociclib plus letrozole in patients with de novo HR+, HER2– advanced breast cancer (ABC): A subgroup analysis of the MONALEESA-2 trial [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 P4-22-05.

Abstract P4-22-10: Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc

Abstract Background: PAL , an oral cyclin dependent kinase (CDK) 4/6 inhibitor, is under investigation in multiple oncologic clinical trials and is currently approved for use in multiple countries in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC). International Conference on Harmonization guidance recommends that all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most non-adjuvant anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in patients [pts] is required in the registration dossier. The phase 3 PALOMA-2 study (N=666) confirmed the superior clinical benefit of PAL+LET vs placebo (P) + LET in postmenopausal women with estrogen receptor positive/HER2– ABC who have not received any prior systemic anticancer therapies for ABC. One of the secondary objectives of the study was to evaluate the effects of PAL+LET on QTc. Methods: 12 lead (with a 10 second rhythm strip) tracings were performed in triplicate ∼2 min apart but within 10 min for all 3 ECGs. On the day preceding the initiation of treatment (Day 0), triplicate ECGs were obtained at time 0, 2, 4, 6, and 8 hrs (baseline). On Cycle 1 Day 14, when PAL concentrations were at steady-state, triplicate ECGs time-matched to baseline ECGs collected on Day 0 (±35 min) were obtained following PAL or P dosing. All ECGs were sent to a central laboratory for blinded manual adjudication and these data were used for analysis. ECG measurements included PR interval, QT interval, RR interval and QRS complex. The QT interval was corrected for the effect of heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). Approximately 60 pts were to be included for QTc evaluation to ensure 40 evaluable pts in the PAL+LET arm (2:1 randomization) of PALOMA-2 and thus, to establish noninferiority between post-baseline and baseline (ΔQTc) at all 5 QTc sampling timepoints on Cycle 1 Day 14 with 90% power. The test was based on a 1-sided difference in means t test for paired ΔQTc (α= 0.05). The difference in means between ΔQTc under the alternative hypothesis is 10 ms, assuming a noninferiority margin of 20 ms and the standard deviation of the paired differences equal to 16 ms based on PALOMA-1 study. If the upper bounds (UB) of 1-sided 95% confidence intervals (CI) of ΔQTc for all 5 QTc time points were <20 ms, the post-baseline QTc will be considered noninferior to baseline and PAL+LET effect on QTc will be concluded to be not of clinical relevance. Results: A total of 77 pts were enrolled for intensive QTc assessment in PAL+LET arm. No pts had a post-baseline absolute maximum QTcF, QTcS or QTcB ≥500 ms or a ΔQTc ≥60 ms during the intensive QTc assessment period. A random effect analysis of the mean ΔQTc data demonstrated that the UB of the 1-sided 95% CI for QTcF, QTcS, and QTcB were <8 ms at all 5 QTc sampling time points. Conclusion: PAL+LET does not have a clinically relevant effect on QTc. Sponsor: Pfizer Citation Format: Ruiz A, Gauthier E, Durairaj C, Huang X, Hoffman J, Finn RS, Moulder S, Joy AA, Ettl J, Rugo HS, Wang D. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [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 P4-22-10.

Abstract P4-22-16: First-line ribociclib + letrozole in patients with HR+, HER2– advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial

Abstract Background: Patients with ABC who present with visceral metastases have a worse outcome than patients with non-visceral disease, while patients with bone-only disease tend to have a better prognosis. Ribociclib (LEE011) is an oral, selective inhibitor of cyclin-dependent kinase (CDK) 4/6. In a Phase 3, placebo-controlled, randomized trial (MONALEESA-2; NCT01958021), first-line ribociclib (R) + letrozole (L) significantly prolonged progression-free survival (PFS) vs placebo (P) + L in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, with a hazard ratio of 0.556 (95% confidence interval [CI]: 0.429–0.720; p=0.00000329) at the interim analysis cut-off date (Jan 29, 2016). Here, we present subgroup analyses in patients with visceral metastases, and those with bone-only disease. Methods: Postmenopausal women with HR+, HER2– ABC were randomized 1:1 to receive R (600 mg/day; 3-weeks-on/1-week-off) + L (2.5 mg/day; continuous) or P+L, stratified by the presence of liver and/or lung metastases. No prior CDK4/6 inhibitors or systemic therapy for ABC were allowed. Eligible patients had Eastern Cooperative Oncology Group performance status ≤1, baseline alanine/aspartate aminotransferase levels <5× upper limit of normal (ULN) or <2.5× ULN for patients with or without liver metastases, respectively, and ≥1 predominantly lytic bone lesion at baseline for patients with bone-only disease. Locally assessed PFS was analyzed for all patients (primary endpoint), and for predefined patient subgroups. Results: Overall, 668 patients were randomized; 393 had visceral metastases and 147 had bone-only disease. Visceral metastasesBone-only disease n=393n=147 R+LP+LR+LP+L n=197n=196n=69n=78Median age, years (range)63 (23–91)63 (29–88)65 (37–85)63 (37–84)De novo metastatic disease, n (%)53 (27)55 (28)28 (41)24 (31)Non-de novo disease-free interval, n (%)≤24 months12 (6)15 (8)5 (7)6 (8)>24 months132 (67)126 (64)36 (52)48 (62)Discontinued treatment, n (%)83 (42)111 (57)29 (42)40 (51)Reason for discontinuation, n (%)Disease progression56 (28)93 (47)17 (25)31 (40)Patient/physician decision10 (5)15 (8)7 (10)6 (8)Adverse events16 (8)3 (2)4 (6)2 (3)Protocol deviation001 (1)1 (1)Death1 (<1)000 In patients with visceral metastases: Median PFS was not reached in the R+L arm (95% CI: 19.3–not estimable [NE]) vs 13.0 months (95% CI: 12.6 –16.5) in the P+L arm, with hazard ratio 0.535 (95% CI: 0.385–0.742). Median duration of exposure was 12.0 and 13.0 months (R and L, respectively) in the R+L arm, and 12.1 and 12.2 months (P and L, respectively) in the P+L arm. In patients with bone-only disease: Median PFS was not reached in the R+L arm (95% CI: NE–NE) vs 15.3 months (95% CI: 13.8–NE) in the P+L arm, with hazard ratio 0.690 (95% CI: 0.381–1.249). Median duration of exposure was 12.1 and 12.6 months (R and L, respectively) in the R+L arm, and 12.7 and 12.9 months (P and L, respectively) in the P+L arm. Conclusions: First-line R+L was well tolerated and significantly prolonged PFS vs P+L in postmenopausal women with HR+, HER2– ABC, both in patients with visceral metastases and those with bone-only disease. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: Burris HA, Chan A, Campone M, Blackwell KL, Winer EP, Janni W, Verma S, Burdaeva O, Alba E, Favret AM, Mondal S, Miller M, Germa C, Hirawat S, Yap YS. First-line ribociclib + letrozole in patients with HR+, HER2– advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial [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 P4-22-16.

Abstract P4-22-07: Long-term safety of palbociclib in combination with endocrine therapy in treatment-naive and previously treated women with HR+ HER2– advanced breast cancer: A pooled analysis from randomized phase 2 and 3 studies

Abstract Background: Palbociclib (PAL) is a selective and reversible oral cyclin-dependent kinase 4 and 6 inhibitor. Large randomized phase (ph) 2 and 3 trials showed significant improvement in progression-free survival (PFS) when PAL was combined with endocrine therapy (ET) vs ET alone in treatment (trt)-naive and previously treated hormone receptor?positive human epidermal growth factor receptor 2?negative (HR+ HER2–) advanced breast cancer (ABC) patients (pts). The median PFS with PAL+ET is >2 years as a first-line therapy for ABC and 11.2 mo in endocrine-resistant ABC. We evaluated the long-term safety in PALOMA-1, -2, and -3. Methods: We analyzed the tolerability of PAL in combination with ET in 3 randomized trials. Pts untreated for ABC were randomized to receive PAL+letrozole (LET) vs LET alone in PALOMA-1 (ph 2, open-label; 1:1) or randomized to receive PAL+LET vs placebo (PBO)+LET in PALOMA-2 (ph 3, double-blind; 2:1). PALOMA-3 included pts who progressed on prior ET, randomized to receive PAL+fulvestrant (FUL) or PBO+FUL (ph 3, double-blind; 2:1). Safety assessments, including a complete blood count, were done at baseline, on D1 of each cycle, and on D14 of the first 2 cycles. We evaluated adverse events (AEs) by 6-mo intervals (out to 36 mo) and cumulatively (12-, 24-, and 36-mo time points), and assessed latency (event onset) of pertinent adverse drug reactions (ADRs) in all pts treated in PALOMA-1, -2, and -3. Results: A total of 1352 pts were pooled for this analysis; 872 pts received PAL+ET (527 pts, PAL+LET; 345 pts, PAL+FUL). Median duration of trt was 421 days in PALOMA-1 (January 2015), 603 days in PALOMA-2 (February 2016), and 330 days in PALOMA-3 (July 2015). PAL+LET was received by 119 pts as first-line trt in PALOMA-1 and 2 for 24–<30 months and 11 pts were treated for >36 mo. PAL+FUL was received by 140 pts for >12 mo as second-line trt in PALOMA-3. The most commonly reported ADRs across all studies were neutropenia, fatigue, nausea, anemia, and leukopenia. The 6-mo-interval analyses of the most common (>15%) AEs (by preferred term [PT]) from PALOMA-1, -2, and -3 indicated that these AEs were reported with the highest frequency during the first 6-mo interval and typically decreased in incidence over time to 30–<36-mo; the most common hematologic AEs (clustered PTs) are shown (Table). The cumulative incidence of AEs after the first vs the second and third years showed similar frequencies of most AEs, including the most common ADRs. Conclusions: Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicity resulting from prolonged trt with PAL+ET for HR+ HER2– ABC. This supports the ongoing investigation of PAL+ET in early breast cancer (NCT02513394). Table. Pooled hematologic AEs: all grades and all causality clustered PTs reported for ≥10% of PAL+ET (LET/FUL)-treated ptsTime interval, mo0–<66–<1212–<1818–<2424–<3030–<36≥36Patients, N8726764912891192711TEAEs, % Neutropenia75.758.649.349.842.937.054.5Leukopenia40.027.416.711.87.611.118.2Anemia20.812.710.011.19.211.118.2Thrombocytopenia15.18.76.15.55.914.836.4TEAEs=treatment-emergent adverse events. Sponsor: Pfizer. Citation Format: Diéras V, Rugo HS, Gelmon K, Finn RS, Cristofanilli M, Loi S, Colleoni M, Lu D, Gauthier E, Huang-Bartlett C, Turner NC, Schnell P. Long-term safety of palbociclib in combination with endocrine therapy in treatment-naive and previously treated women with HR+ HER2– advanced breast cancer: A pooled analysis from randomized phase 2 and 3 studies [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 P4-22-07.

Abstract OT2-01-05: TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor

Abstract Background: There is extensive crosstalk between the cyclin D–CDK4/6–inhibitor of CDK4–retinoblastoma and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways at the G1/S cell-cycle checkpoint. Both pathways are frequently dysregulated in hormone receptor-positive (HR+) breast cancer and have been associated with endocrine therapy (ET) resistance. CDK4/6 and PI3K/mTOR inhibitors have demonstrated clinical activity in combination with ET. Although CDK4/6 inhibitors combined with ET significantly improve progression-free survival (PFS) in ABC, disease progression eventually occurs, highlighting the need for effective treatment options following doublet therapy. Ribociclib (LEE011; CDK4/6 inhibitor; 3-weeks-on/1-week-off) + EVE (mTOR inhibitor) + EXE triplet therapy has shown preliminary clinical activity in heavily pretreated HR+, human epidermal growth factor receptor 2-negative (HER2–) ABC including patients (pts) with prior exposure to CDK4/6 inhibitors, suggesting this combination may restore sensitivity to CDK4/6 inhibitor-based therapy. Trial design and objectives: TRINITI-1 (NCT02732119) is a US-based, phase I/II, single arm, open-label study of ribociclib (continuous daily dosing) + EVE (2.5 mg/day) + EXE (25 mg/day) in men and postmenopausal women with HR+, HER2– ABC refractory to ≥1 line of ET. Phase I dose escalation consists of 2 ribociclib dose-level cohorts (250 and 300 mg/day), followed by a Simon Two-Stage phase II trial in pts with disease progression on prior CDK4/6 inhibitor-based therapy. No more than 3 lines of therapy for ABC, including ≤1 prior chemotherapy regimen, are permitted. Previous EXE treatment of >28 days for metastatic disease, prior mTOR inhibitors, and progression on >1 CDK4/6 inhibitor are prohibited. All pts in phase II must have progressed on a CDK4/6 inhibitor as the last regimen before study entry. Additional eligibility criteria include measurable disease or lytic/mixed bone lesions and Eastern Cooperative Oncology Group performance status of ≤1. Exclusion criteria include visceral crisis, unstable CNS metastases, and clinically significant heart disease. Phase I primary objective: maximum tolerated dose and/or recommended phase II dose of the triplet combination. Phase II primary objective: clinical benefit rate (CBR) at 24 weeks (0.1 significance level, 80% power to test CBR ≤15% against CBR ≥30%) with centrally-assessed PFS as a key secondary objective. Other secondary objectives include preliminary antitumor activity (phase I), safety and pharmacokinetics (phase I/II), and overall response rate, overall survival, and duration of overall response (phase II). Tumor assessments (RECIST v1.1) will be performed every 8 weeks for the first 12 months, and every 12 weeks thereafter until disease progression. Exploratory analyses include biomarkers potentially predictive of response and mechanisms of resistance. Target accrual: Approximately 52 pts at ∼30 sites; 3–6 pts per cohort in phase I, an initial 19 in phase II with another 20 enrolled upon demonstration of clinical benefit in ≥4 pts. Citation Format: Bardia A, Hurvitz S, Yardley DA, Zelnak A, DeMichele A, Clark AS, Warsi G, Small T, Tucci C, Moulder S. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor [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 OT2-01-05.

Experimental Therapy of Advanced Breast Cancer: Targeting NFAT1-MDM2-p53 Pathway.

Advanced breast cancer, especially advanced triple-negative breast cancer, is typically more aggressive and more difficult to treat than other breast cancer phenotypes. There is currently no curable option for breast cancer patients with advanced diseases, highlighting the urgent need for novel treatment strategies. We have recently discovered that the nuclear factor of activated T cells 1 (NFAT1) activates the murine double minute 2 (MDM2) oncogene. Both MDM2 and NFAT1 are overexpressed and constitutively activated in breast cancer, particularly in advanced breast cancer, and contribute to its initiation, progression, and metastasis. MDM2 regulates cancer cell proliferation, cell cycle progression, apoptosis, migration, and invasion through both p53-dependent and -independent mechanisms. We have proposed to target the NFAT1-MDM2-p53 pathway for the treatment of human cancers, especially breast cancer. We have recently identified NFAT1 and MDM2 dual inhibitors that have shown excellent in vitro and in vivo activities against breast cancer, including triple-negative breast cancer. Herein, we summarize recent advances made in the understanding of the oncogenic functions of MDM2 and NFAT1 in breast cancer, as well as current targeting strategies and representative inhibitors. We also propose several strategies for inhibiting the NFAT1-MDM2-p53 pathway, which could be useful for developing more specific and effective inhibitors for breast cancer therapy.

NEW ADVANCES IN THE TREATMENT OF BREAST CANCER: THE ROLE EPOTHILONES

The review considers information about the efficacy and safety of Ixabepilone as a monotherapy and as a component of combination therapy for advanced breast cancer. Successful treatment of metastatic breast cancer is often confounded by resistance to chemotherapy, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially important. A therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer and “intensivelytreated” variant. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease.

18F-Fluoroestradiol Positron Emission Tomography in Breast Cancer Patients: Systematic Review of the Literature & Meta-Analysis.

The aim of the study was to determine the correlation between 16α-18F-fluoro- 17β-estradiol (18F-FES) uptake and the expression and functionality of estrogen receptors (ERs), as well as to evaluate the ability of 18F-FES PET to predict the response to hormonal therapy (HT) in patients with locally advanced or metastatic breast cancer (BC). Literature searches in the major literature databases were carried out in order to select English-language articles dealing with 18F-FES PET and BC. Studies that included patients with BC undergoing 18F-FES PET alone or in combination with other imaging modalities and included the absolute numbers of true-positive, true-negative, false-positive and false-negative test results were selected. We found 23 journal articles, published between 1988 and December 2014, that critically evaluated the role of 18F-FES PET in BC patients. Two separate meta-analyses were carried out: 1- to assess the correlation between 18F-FES uptake and ER expression and 2- to determine the predictive value of 18F-FES in response to HT. For the first, we considered nine selected studies with a total of 238 patients. A pooled sensitivity of 82% (95% CI: 74-88%) and a pooled specificity of 95% (95% CI: 86-99%) for the evaluation of ER functional status by 18F-FES PET were found. Seven studies, with a total of 226 patients, were considered eligible for the analysis of prediction for response. The pooled sensitivities and specificities were 63.9% (95% CI: 46.2-79.2%) vs. 66.7% (95% CI: 52.1-79.2%), and 28.6% (95% CI: 17.3-42.2%) vs. 62.1% (95% CI: 48.4-74.5%), for a SUV cutoff of 1.5 and 2.0, respectively. A good correlation between 18F-FES uptake and ER expression by immunohistochemistry emerges, while the role of 18F-FES in predicting the response to endocrine therapy in advanced BC remains undetermined.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer

BackgroundThe inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).MethodsIn this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10−5.ResultsThe duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10−6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.ConclusionsAmong patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021.)

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

Estimation of Premature Deaths From Lack of Access to Anti-HER2 Therapy for Advanced Breast Cancer in the Brazilian Public Health System.

PurposePatients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients.MethodsOn the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow-up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions.ResultsIt was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab.ConclusionTrastuzumab is included in the WHO’s list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil.

Abstract LB-069: ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials

Abstract Background. ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy for advanced breast cancer. We addressed the impact of ESR1 mutations on sensitivity to standard therapies in SoFEA and PALOMA3, two phase III randomised trials that represent the trends in the current therapy for estrogen receptor positive advanced breast cancer. Methods. We assessed plasma DNA ESR1 mutations in the SoFEA trial that compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to non-steroidal AI, and in the PALOMA3 trial that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression on prior endocrine therapy. We developed and validated multiplex digital droplet PCR assays to detect ESR1 mutations in circulating free DNA. Plasma had been immediately processed in PALOMA3 but there was a delay of up to 9 days before processing of EDTA samples in the SoFEA trial. Results. In SoFEA we demonstrated that delayed processing of plasma samples had no effect on detection rate of ESR1 mutations (p = 0.71), which were found in 39.1%(63/161) patients. Patients with ESR1 mutations had improved progression free survival (PFS) on fulvestrant compared to exemestane (HR = 0.52, 95%CI 0.30 to 0.92, p = 0.02), while patients with wild type ESR1 had similar PFS on either treatment (HR = 1.07, 95%CI 0.68 to 1.67, p = 0.77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3%(91/360) patients. ESR1 mutations were almost exclusively found in patients with prior AI exposure with or without tamoxifen, and were very rare with prior tamoxifen exposure only (28.9% (90/311) versus 2.0% (1/49) respectively, p&amp;lt;0.001). ESR1 mutations were strongly associated with sensitivity to prior endocrine therapy (sensitive to prior endocrine therapy, 29.8% (85/285) versus resistant 8.0% (6/75), p&amp;lt;0.001), bone metastases (p = 0.001), prior lines of therapy for metastatic disease (p = 0.01), and with a trend towards ER and PR positive disease as opposed to ER positive but PR negative disease. Fulvestrant plus palbociclib improved PFS compared to fulvestrant plus placebo in both ESR1 mutant (HR = 0.43, 95%CI 0.25 to 0.74, p = 0.002) and ESR1 wild type patients (HR = 0.49 95%CI 0.35 to 0.70, p&amp;lt;0.001). ESR1 mutations were polyclonal in up to 49% of patients, with outcome on fulvestrant similar for polyclonal and monoclonal mutations. In an exploratory analysis there was no association between specific mutations and outcome on fulvestrant. Conclusions. ESR1 mutation analysis in plasma after progression on prior AI therapy has clinical utility in directing choice of further endocrine therapy. Citation Format: Ben O’Leary, Charlotte Fribbens, Lucy Kilburn, Sarah Hrebein, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith Bliss, Stephen Johnston, Nicholas Turner. ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-069.

Clinical Implications of the Progression-Free Survival Endpoint for Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

: Hormonal therapy for advanced breast cancer (ABC) has evolved significantly since the introduction of tamoxifen more than 40 years ago. The availability of selective antiestrogen therapies has further improved treatment options for women with hormone receptor-positive (HR+) ABC. However, with the development of resistance to hormonal therapies, a new treatment paradigm has emerged based on our understanding of biological pathways involved in HR+ breast cancer and mechanisms of resistance to hormonal therapy. Recent drug development efforts have focused on combining hormonal treatment with agents that target mammalian target of rapamycin serine-threonine kinases and cyclin-dependent kinases. In parallel with the evolution of hormonal and targeted therapies, our understanding of the utility of clinical endpoints has deepened. Progression-free survival (PFS) is a primary endpoint well-understood by clinicians and is increasingly accepted as a surrogate for overall survival (OS) by the U.S. Food and Drug Administration. Yet the perceived clinical benefit of PFS to patients is less well understood. Patients may not grasp the implications of prolonged PFS, highlighting the reality that patient preference in treatment selection encompasses factors that extend beyond drug activity. This presents an opportunity for clinicians to discuss PFS with patients in the context of their treatment plans, clinical outcomes, and quality-of-life measures. The objective of this review is to explore the clinical validity of the PFS and OS endpoints and the clinical relevance of PFS and OS to patients, especially in light of drivers that led to a range of treatment options for patients with HR+ ABC. Advances in drug development during the past two decades have provided numerous options for treatment of advanced breast cancer that include monotherapy with endocrine modulating agents and dual therapy that combines endocrine therapy with an inhibitor targeting the mammalian target of rapamycin serine-threonine kinase or cyclin-dependent kinase pathways known to be involved with resistance. Clinical trial endpoints for breast cancer have evolved as well. Communication of progression-free survival, overall survival, and other outcomes with patients should incorporate the context of the individual's treatment plan and include discussion of response rate, side effects, and quality of life.

PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC).

507Background: Hormonal therapy (HT) is the mainstay for patients (pts) with ER+ BC. P, a cyclin-dependent kinase 4/6 inhibitor, blocks growth of ER+/HER2– BC preclinical models. In PALOMA-1, an open-label Ph 2 trial, addition of P to L improved median PFS vs L alone (20.2 months [mo] vs 10.2 mo) in pts with first-line ER+/HER2– ABC with acceptable safety, leading to accelerated FDA approval. PALOMA-2 is a randomized double-blind Ph 3 trial designed to confirm these results. Methods: 666 postmenopausal pts with no prior systemic therapy for ABC were randomized 2:1 to receive P (oral 125 mg/d; 3 wks on/1 wk off) + L (2.5 mg/d continuously) or PLB + L every 28 days until disease progression, consent withdrawal or death. Pts were stratified by disease site, disease-free interval from end of (neo)adjuvant therapy, and prior HT (yes/no). Primary endpoint: investigator-assessed PFS; key secondary endpoints: overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR=CR + PR + SD ≥24 wks), p...

Efficacy and Safety of Nedaplatin in Advanced Breast Cancer Therapy

ABSTRACTPurpose: To compare the time-to-treatment failure (TTF), overall survival (OS), overall response rate (ORR), and adverse effects of regimens including nedaplatin- or cisplatin-based chemotherapy for advanced breast cancer (ABC). Methods: A total of 171 patients with ABC (admission between July 2008 and July 2013) were retrospectively analyzed. Patients received either nedaplatin 75 mg/m2 (arm N; n = 85) or cisplatin 75 mg/m2 (arm C; n = 86) in combination with other second-generation chemotherapeutic drugs, such as paclitaxel 175 mg/m2, docetaxel 75 mg/m2, gemcitabine 1.25 g/m2, and navelbine 25 mg/m2 every 21 days (nedaplatin, cisplatin, paclitaxel, docetaxel on day 1; gemcitabine, navelbine on days 1 and 8). The primary endpoint was TTF in each arm; secondary endpoints were OS, ORR, and toxicity. Results: In the assessable patient population, in arm N, median TTF and OS was 13.87 months (95% CI: 11.55–16.19) and 31.53 months (95% CI: 28.42–34.64), respectively, with an ORR of 48.2%. In arm C, median TTF and OS was 8.7 months (95% CI: 5.82–11.59) and 24.87 months (95% CI: 18.98–30.75), respectively, with an ORR of 37.2%. The occurrence of grades 3 and 4 hematologic toxicity was more frequent (45.9% vs. 25.6%, p = 0.003) in arm N than in arm C. However, grade ≥2 nonhematologic toxicity was less frequent in arm N than in arm C (12.9% vs. 46.5%, p = 2.05 × 10−7). Conclusions: Nedaplatin-based chemotherapy regimen was well tolerated and efficiently improved patients' quality of life characterized by prolonged TTF and OS, with a marginal ORR.

Palbociclib: efficacious but predictive biomarkers still needed

Several therapeutic options are available for management of premenopausal patients with metastatic hormone-receptor-positive breast cancer, including single-agent endocrine therapy or combination regimens. Single agent treatment with an aromatase inhibitor or tamoxifen has resulted in major improvements in the adjuvant setting but has shown little clinical benefit in metastatic disease. 1 Bonneterre J Thürlimann B Robertson JF et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000; 18: 3748-3757 Crossref PubMed Scopus (792) Google Scholar , 2 Mauri D Pavlidis N Polyzos NP Ioannidis JP Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst. 2006; 98: 1285-1291 Crossref PubMed Scopus (228) Google Scholar Endocrine therapy is the standard of care for hormone-receptor-positive luminal, HER2-negative metastatic breast cancer. However, resistance to endocrine treatment remains a major clinical problem, especially for patients with metastatic disease. Therefore management of resistance to endocrine therapy is an active area of research. 3 Johnston SR New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res. 2010; 16: 1979-1987 Crossref PubMed Scopus (171) Google Scholar Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trialFulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Full-Text PDF

Abstract OT1-03-10: A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA-1 or -2 mutated Her2 negative advanced breast cancer as first line treatment (REVIVAL study)

Abstract Background Preclinical studies revealed that the combination of platinum compounds and olaparib is additive and possibly even synergistic in cell models with BRCA1 or -2 mutations. Early clinical trials suggested high benefit of olaparib with induction carboplatin in BRCA1 and -2 mutation carrier enriched populations. However, there is no evidence yet that carboplatin-olaparib has a superior benefit-risk compared to current standard therapy in advanced breast cancer in BRCA1 and -2 mutation carriers. Trial design We initiated a phase-I/II study due to an olaparib formulation change from capsule to tablet. During phase-I a traditional 3+3 dose escalation study is performed. Carboplatin will be dose escalated in 1 step from AUC 3 to AUC 4 with a constant olaparib dose of 25 mg BID. Olaparib is then dose escalated in 3 steps to 50, 75 and 100 mg BID until &amp;gt; 1/6 patients develop a DLT, the previous safe dose-level will be determined the MTD. After the MTD is established a randomised phase-II trial will be initiated where patients are randomised between standard capecitabine 1250 mg/m2 BID day 1-14, q day 22 or 2 cycles carboplatin-olaparib followed by olaparib monotherapy 300mg BID. After progression, patients in the experimental arm receive capecitabine, all other patients receive physicians choice of paclitaxel, vinorelbine or eribulin at standard dose. A compassionate use program with olaparib is available for patients in the standard arm after progression on second line treatment. Eligibility criteria In phase-II patients with histological or cytological proof of advanced BRCA1 or -2 mutated HER2 negative breast cancer are eligible if they are ≥18 years, have measureable disease according to RECIST 1.1 criteria, a WHO performance status of 0–2, a life expectancy ≥ 3 months and a negative pregnancy test. Pretreatment should contain an anthracycline and/or taxane in the (neo)adjuvant setting, unless not indicated. In the advanced setting only hormonal pre-treatment is allowed. Minimal laboratory values ANC ≥ 1.5 x 109 /L, Hb ≥ 6.2 mM (no transfusions in the last 28 days), platelet count ≥ 100 x 109 /L, serum bilirubin &amp;lt; 1.5 x ULN, ASAT and ALAT &amp;lt; 2.5 x ULN and a serum creatinine &amp;lt; 1.5 x ULN or creatinine clearance ≥ 50 mL/min. Aims In phase-1 we establish the MTD for treatment in phase-II where we study progression free survival on first line treatment(PFS1) compared with standard of care capecitabine. Statistical methods Toxicity analysis in phase-I can take place after all patients completed their 28 day DLT period. A total of 104 events in 110 patients on first line treatment need to be observed in phase-II to detect a clinical meaningful improvement in median PFS1 in the experimental arm from 4 to 7 months, assuming an accrual of 2 years and a follow-up of ≥6 months, providing a power of 80% (two-sided significance level of 5%). An interim analysis for futility and efficacy will be performed when 52 events have been observed. Accrual It is expected that 15-20 patients are needed in phase-I, inclusion is due around November 2015. Phase-II will be multicentre and is expected to start accrual December 2015. Citation Format: Dackus GMHE, Schouten PC, Geenen JJ, Marchetti S, Sonke GS, Linn SC, Schellens JHM. A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA-1 or -2 mutated Her2 negative advanced breast cancer as first line treatment (REVIVAL study). [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 OT1-03-10.

Abstract OT3-02-04: Randomised phase II study evaluating, as first-line chemotherapy, single-agent oral vinorelbine administered with two different schedules in patients with hormone receptor positive, HER2-negative advanced breast cancer (TempoBreast-1 trial)

Abstract Background: Single-agent chemotherapy (CT) is the standard treatment option for patients (pts) with hormone receptor (HR) positive disease progressing after previous hormone therapy (HT). Oral CT offers significant advantages over intravenous CT because of its greater convenience, its ease of administration and reduced need for hospitalisation. Metronomic CT could be considered as a multi-targeted therapy for advanced breast cancer, combining effects not only on tumour cells but also on their microenvironment by inhibiting angiogenesis and stimulating anticancer immune response. Metronomic oral vinorelbine (OV) has been evaluated in phase I and II trials setting 50 mg total dose three times per week as the reference dosing. This schedule provides promising efficacy results, combined with a potentially improved safety by reducing the risk of neutropenia. Weekly administration of oral vinorelbine is one of the standard chemotherapy options in the management of advanced breast cancer. This study will provide key clinical data regarding the optimal management of this pt population: HR positive and HER2-negative disease previously treated by a HT. Trial design: In this open-label study, pts are randomised to receive (1 cycle = 3 weeks): OV 50 mg total dose three times weekly on Mondays, Wednesdays and Fridays (metronomic schedule) or OV 60 mg/m2/week (day 1, 8, 15) for the first cycle, then increased to 80 mg/m2/week from the second cycle in the absence of grade 3 or 4 toxicity (weekly schedule). Treatments are continued until disease progression, unacceptable toxicity or pt.'s refusal. Main eligibility criteria include: age ≥18 years, documented locally recurrent or metastatic disease previously untreated by CT, HR positive disease previously treated by at least one HT, HER2-negative disease, Karnofsky PS ≥70. Primary objective: disease-control rate. Secondary objectives: other efficacy parameters, evaluation of safety profiles of both arms and quality of life assessment. Statistical methods: the one-sample multiple testing procedure for phase II clinical trials described by Fleming is used. This procedure employs the standard single stage test procedure at the last one of 2 pre-specified testings, while both allowing for early termination (should extreme results be seen) and essentially preserving the size and power of the single stage procedure. 160 patients will be enrolled in this randomised phase II study (80 per treatment arm). Randomisation is stratified according to centre, prior taxane, prior everolimus and presence of visceral metastases. Study accrual is planned to start Q3 2015 with a duration of 24 months. Citation Format: De la Haba J, Cazzaniga M, Freyer G, Costa L, Petru E, Bartsch R, Staroslawska E, de Almeida C, Villanova G, Cardoso F. Randomised phase II study evaluating, as first-line chemotherapy, single-agent oral vinorelbine administered with two different schedules in patients with hormone receptor positive, HER2-negative advanced breast cancer (TempoBreast-1 trial). [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 OT3-02-04.