Outcomes With Immunotherapy in Hormone Receptor-Positive Breast Cancer: A Systematic Review and Meta-Analysis.

The phosphatidylinositol-3-kinase (PI3K) pathway is mutated and aberrantly activated in breast and other cancers and plays a key role in cancer cell proliferation and survival.1 2 The PI3K pathway is deregulated through a variety of mechanisms, including mutation or amplification of PI3K, loss or inactivation of the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ), as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.3 4 Activating mutations in PIK3CA , the gene encoding the alpha isoform (p110 α) catalytic subunit of PI3K, is present in up to 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers5 6 and represents a molecular target to personalise therapy of selected patients with breast cancer.2 Standard of care therapy for advanced HR-positive/HER2-negative breast cancers consists on endocrine therapy with or without the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.7 Therapy-resistance inevitably occurs in the majority of patients. The rationale of combining PI3K inhibitors and endocrine therapy is to synergistically inhibit both the PI3K and ER pathways.8 Initial trials of pan-PI3K inhibitors plus endocrine therapy for patients with advanced breast cancer showed modest benefit with high rates of toxicity limiting their clinical drug development.9–11 Selective isoform-specific PI3K inhibitors, such as an α-specific PI3K inhibitor, have subsequently revealed activity with less toxicity.12 13 The phase III SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) trial investigated the efficacy and safety of alpelisib, a α-specific class-I PI3Kinhibitor, plus fulvestrant versus placebo plus fulvestrant in patients with metastatic HR-positive/HER2-negative breast cancer who had received endocrine therapy beforehand.14 About 85.6% of patients …

Male breast cancer, comprising approximately 1% of all breast cancer cases, often leads to the exclusion of male patients as a criterion in clinical trials. While the efficacy of Cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors has been established in metastatic hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2 -) breast cancer in women, limited data exist on their effectiveness in male patients. We aimed to evaluate the efficacy and safety of palbociclib or ribociclib in male patients with breast cancer. This study is a multicenter, retrospective study. We included male patients with HR + and HER2-metastatic breast cancer who received palbociclib or ribociclib as first-line treatment. Our primary endpoints were progression-free survival (PFS), overall response rates (ORR), and drug-related adverse effects. A total of 46 male patients from 27 institutions were enrolled. The median age at initiation of CDK 4/6 inhibitors was 63.64 ± 13.69years, with a median follow-up of 21.33 (95% CI 14.92-27.74) months. The ORR were 84% for palbociclib and 76.2% for ribociclib. The mPFS for the entire cohort was 28.06months (95% CI 18.70-37.42). No significant difference in PFS was observed between palbociclib and ribociclib (mPFS: 24.46months (95% CI 11.51-37.42) vs 28.33months (95% CI 14.77-41.88), respectively, p = 0.211). No new adverse events were reported. This study demonstrates that palbociclib and ribociclib are effective and safe options for first-line treatment in male patients with HR + /HER2 - metastatic breast cancer. However, further prospective studies are warranted to establish their efficacy in this population.

To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) after neoadjuvant chemotherapy (NAC). A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2- BC who received NAC from 2011 to 2022. All patients received current "standard of care" following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status.

71P The efficacy of palbociclib and ribociclib in the first-line treatment of metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer in male patients: A Turkish Oncology Group (TOG) study

The addition of palbociclib (a cyclin-dependent kinase 4/6 inhibitor) to endocrine therapy (ET) has been shown to significantly improve progression-free survival (PFS) and overall survival (OS) among patients with hormone receptor-positive (HR+) advanced breast cancer. The current study presents the local experience of using palbociclib at two cancer centers in Saudi Arabia. Electronic data of patients with metastatic HR+ and human epidermal growth factor receptor 2-negative breast cancer who progressed after prior ET and received at least one cycle of palbociclib plus ET, were retrospectively reviewed. A total of 97 patients were identified, and their data were included in the analysis. The median age of the patients was 55 years. Patients were heavily pretreated in the metastatic setting (55% received systemic chemotherapy and 49% received two or more lines of prior ET). In total, 29 (30%) and 50 (52%) patients achieved an objective response and clinical benefit, respectively. The median follow-up time was 31.0 months [95% confidence interval (CI), 16.9-44.9] and the median PFS time was 16.3 months (95% CI, 11.4-21.2), with 58% of patients remaining progression-free at 12 months. Upon multivariate regression analysis, liver involvement was the only significant independent variable that predicted a greater risk of progression or death (hazard ratio, 2.32; 95% CI, 1.22-4.40; P=0.010). The median OS time was 19.6 months (95% CI, 18.1-20.9), with 12- and 24-month OS rates of 75 and 30%, respectively. Overall, real-world data showed that administration of palbociclib in combination with ET in patients with advanced HR+ breast cancer achieved a favorable outcome that was comparable to that reported in clinical trials.

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Background: Pertuzumab provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer patients (pts) in the CLEOPATRA (Clinical evaluation of docetaxel, pertuzumab and trastuzumab) study. However, few studies have described the efficacy of other drugs in combination with pertuzumab plus trastuzumab. Here, we present a pre-specified analysis of eribulin in combination with pertuzumab plus trastuzumab as first- and second-line therapy for advanced or metastatic breast cancer (AMBC) in a multicenter, open-label phase II study (UMIN000012232, JBCRG-M03). Methods: HER2-positive AMBC with no or single prior chemotherapy for AMBC were enrolled. All pts were administered trastuzumab and taxane as adjuvant or first-line chemotherapy. Treatment consisted of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) plus pertuzumab (840 mg/body loading dose, then 420 mg/ body) once every 3 weeks, all administered intravenously. The primary endpoint was PFS, and secondary endpoints included overall response rate (ORR) and safety. PFS was determined using Kaplan–Meier analysis. Tumor response was assessed according to RECIST ver. 1.1. Results: Fifty pts were enrolled from November 2013 to April 2016. Forty-nine pts were eligible for safety analysis and the full analysis set (FAS) included 46 pts. The median age was 56 years (23–70), and 8 (16%) and 41 (84%) pts were treated in first- and second-line settings, respectively. Eleven pts (23.9%) were de-novo Stage 4, and 35 pts (76.1%) had progressed in metastatic disease after completion of local therapy. Median PFS was 9.3 months (M) (95% confidence interval [CI]: 6.4–12.3). Table 1 shows the efficacy data for each treatment line and includes ORR, complete response rate (CR), partial response rate (PR), stable disease rate (SD), progressive disease rate (PD), not evaluable rate (NE) and PFS in the FAS. The median relative dose intensities of eribulin, trastuzumab, and pertuzumab were 93.3% (77.0%–100%), 100% (96.0%–100%), and 100% (89.7%–100%), respectively, in the FAS. The grade 3/4 adverse events (AE) were neutropenia in 5 pts (10.2%), including 2 pts (4.1%) with febrile neutropenia; hypertension in 3 pts (6.1%), and other AEs in only one patient. The average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusion: In pts with HER2-positive AMBC, first- and second-line therapy of eribulin in combination with pertuzumab plus trastuzumab demonstrated substantial antitumor activity with an acceptable safety profile. We are planning a phase III study comparing eribulin with taxanes in combination with pertuzumab plus trastuzumab for the treatment of HER2-positive AMBC. Efficacy data for each treatment lineTreatment LineTotal (n=46)First line (n=8)Second line (n=38)PFS (95% CI), months9.3 (6.4-12.3)20.8 (2.8-38.7)8.7 (7.2-10.2)ORR (%)28 (60.9)7 (87.5)21 (55.3)CR (%)8 (17.4)3 (37.5)5 (13.2)PR (%)20 (43.5)4 (50.0)16 (42.1)SD (%)11 (23.9)1 (12.5)10 (26.3)PD (%)5 (10.9)05 (13.2)NE (%)2 (4.3)02 (5.3) Citation Format: Kawaguchi H, Yamashita T, Masuda N, Kitada M, Narui K, Hattori M, Yoshinami T, Matsunami N, Yanagihara K, Kawasoe T, Nagashima T, Bando H, Yano H, Hasegawa Y, Nakamura R, Kashiwaba M, Morita S, Ohno S, Toi M. Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-07.

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Tucidinostat, which is a subtype-selective histone deacetylase inhibitor, has been approved in China for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, existing evidence mainly stemmed from randomized controlled trials, and might have limitations in representing the complexities of clinical practice and diverse patient populations. Therefore, there is a need to explore the efficacy and optimal therapeutic modality for tucidinostat in real-world clinical settings. The objective of this real-world study was to analyze the clinical data of 47 patients with HR+/HER2- ABC who received tucidinostat treatment at West China Hospital, Sichuan University, between August 2020 and May 2023. The primary outcomes were progression-free survival (PFS) and clinical benefit rate [CBR; defined as partial response (PR) and stable disease (SD) for ≥6 months on clinical evaluation]. A total of 47 patients were included, and the median follow-up time was 18.20 months. The median line of tucidinostat therapy was 3 (range, 1-9). In all, 52.17% patients were treated with tucidinostat plus fulvestrant, while 38.30% were treated with tucidinostat plus aromatase inhibitors. Notably, 10.64% of the patients with rapidly progressing visceral metastases received tucidinostat plus endocrine therapy as maintenance treatment after achieving disease control with chemotherapy. The median PFS was 4.43 months [95% confidence interval (CI), 2.77-10.53], and the median overall survival was 19.57 months (95% CI, 12.83-not reached). The 6-month CBR for the overall population was 41.86%. Patients undergoing maintenance therapy demonstrated a significantly longer PFS than did those who did not receive it as maintenance therapy (14.13 vs. 3.93 months; P=0.01). Univariate Cox regression analysis showed that use of tucidinostat in lines 1-2, use of tucidinostat plus fulvestrant, presence of one metastatic site, and lack of brain metastasis were favorable factors for PFS. Thrombocytopenia was the most frequently reported adverse event, with an incidence rate of 31.91% at all grades and 14.89% at grade ≥3. Four (8.51%) patients discontinued the treatment. For patients with HR+/HER2- ABC, tucidinostat combination therapy offers certain survival benefits with controllable safety. Furthermore, compared with non-maintenance therapy, maintenance therapy after chemotherapy may have promising efficacy.

Dysregulation of the cyclin D-CDK4/6-INK4-RB pathway, which leads to uncontrolled cell proliferation, is frequently observed in breast cancer. Recently, 3 CDK4/6 inhibitors have been FDA approved as first-line treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Despite promising clinical results, the metabolic response to treatment with these new drugs has not been elaborately demonstrated yet. Herein, we presented a patient with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who demonstrated a complete metabolic response on 18F-FDG PET/CT to treatment with a CDK4/6 inhibitor (ribociclib).

The National Institute for Health and Care Excellence, as part of the institute’s single technology appraisal process, invited the manufacturer of ribociclib (Kisqali®, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer’s decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3–not reached) vs. 14.7 months (95% confidence interval 13.0–16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.

Conditional progression-free survival in patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with first-line ribociclib and endocrine therapy: real-world data from the RIBANNA study.

TPS3155 Background: B7-H4, a B7 immune checkpoint ligand, is expressed at low levels in normal tissue and negatively regulates T-cell function by inhibiting T-cell proliferation and cytokine production. B7-H4 expression is elevated in solid tumors, including breast, ovarian, and endometrial cancers. Targeting B7-H4–expressing tumor cells may relieve B7-H4–mediated T-cell inhibition. SGN-B7H4V is a novel, investigational vedotin antibody–drug conjugate directed to B7-H4 with proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. SGN-B7H4V elicited antitumor activity in cell line-derived xenograft models of triple-negative breast cancer (TNBC) and patient-derived xenograft models of TNBC and ovarian cancer (Gray et al 2021), providing a rationale to evaluate SGN-B7H4V in patients (pts) with advanced solid tumors. Methods: SGNB7H4V-001 (NCT05194072) is a phase 1, first-in-human, multicenter, open-label trial evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B7H4V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed locally advanced unresectable or metastatic solid tumors including high-grade serous epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, human epidermal growth factor receptor 2-negative and hormone receptor-positive breast cancer, TNBC, endometrial carcinoma, squamous non-small cell lung cancer, cholangiocarcinoma, or gallbladder carcinoma, are eligible. Pts must have ECOG PS 0–1 and relapsed/refractory disease or be intolerant to standard-of-care therapies. Prior treatment with an MMAE-containing agent or a B7-H4–targeted agent is not permitted. Primary endpoints include the rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are objective response rate (ORR), complete response rate, duration of objective response (DOR), progression-free survival (PFS), overall survival (OS), PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamic (PD) analyses, PD and PK exposure measurements, B7-H4 characterization on malignant cells, and biomarker analyses. Safety and antitumor activity endpoints will be assessed using descriptive statistics. ORR will be analyzed by tumor type and dose. DOR, PFS, and OS will be estimated using the Kaplan–Meier method. Enrollment for Part A is ongoing in North America and is planned in Europe. Clinical trial information: NCT05194072.

Triple-negative breast cancer (TNBC) has higher loco-regional recurrence and visceral metastasis compared to other breast cancer subtypes; however, little is known about the molecular pathogenesis of TNBC. Therefore, we compared the mutation profiles of early TNBC with those of hormone receptor-positive (HR+) and/or human epidermal growth factor receptor 2-negative (HER2−) breast cancer using a customized next-generation sequencing capture panel. DNA was obtained from the primary tumor tissues of 34 patients diagnosed with pT2N0-1M0 HR+/HER2− breast cancer or TNBC. Using SureSelectXT kit (Agilent), next-generation sequencing for 48 breast cancer-associated genes was performed on HiSeq platform (Illumina) with germline confirmation. Also, plasma was collected from 24 patients before surgery, cell-free nucleic acids were extracted, and performed therascreen PIK3CA RGQ PCR assay. Significant mutations were found in TP53, PIK3CA, AR, BRCA1, PTEN, BRCA2, BRIP2, KIT, MET, AKT1, ALK, BARD1, BRAF, CD274, ERBB2, FGFR1, IDH2, NOTCH1, RET, and STK11 (in descending order of occurrence). TP53 mutations were identified in the TNBC group more frequently than in the HR+/HER2− group (P = 0.003). The presence of TP53 mutations was associated with a higher tumor grade (P = 0.008), p53 positivity (P < 0.0001), and a higher Ki-67 index (P = 0.004). PIK3CA was the most frequently mutated gene in HR+/HER2− breast cancer (8/22, 36.4%), but not in TNBC (1/12, 8.3%). The TP53 mutation is associated with higher tumor grade and Ki-67 expression in both groups, and with larger tumor size in TNBC, but not in HR+/HER2– breast cancer. In the foundation of TP53 mutation, concomitant mutation numbers are proportional to tumor size, reflecting clonal progression.

BackgroundThis was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).MethodsEligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety.ResultsIn Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380–1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390–1.463).ConclusionsResults of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population.Clinical trial registrationNCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703.