Introduction: Despite the success of anti-HER2 therapy, acquired resistance usually develops in the metastatic setting. CDK4/6 pathway activity has been identified as a mediator of this resistance, and in preclinical studies the combination of CDK4/6 and HER2 blockade can be more effective than either therapy alone. We conducted a single-arm phase 1b/2 study of the CDK4/6 inhibitor ribociclib given with trastuzumab or T-DM1 to subjects with advanced, treatment-refractory HER2-positive breast cancer. The results of the trastuzumab cohort are presented below. The primary objective was to determine the clinical benefit rate (CBR) at 24 weeks, and secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and adverse events. Methods: Individuals with locally advanced or metastatic, measurable HER2-positive breast cancer were eligible. All subjects must have previously received trastuzumab, pertuzumab, and T-DM1 as (neo)adjuvant or metastatic therapy. There was no limit on the number of prior lines of treatment. Patients with previous CDK4/6 inhibitor exposure, QTcF > 450msec on EKG, or without stable brain metastases were excluded. An initial safety run-in phase (with dose-limiting toxicity (DLT) monitoring) included six subjects who received trastuzumab (8mg/kg loading then 6mg/kg IV three-weekly) and ribociclib 400mg PO daily on a continuous schedule (cycle length 21 days). The study had a two-stage design. The first stage required 20 patients, at least 6 of whom must have demonstrated clinical benefit (CR+PR+ SD>24 weeks) in order to recruit 15 more patients to the second stage. All patients with accessible disease underwent metastatic tumor biopsies at baseline and C2D1. Results: 13 patients were enrolled (6 in the safety run-in and 7 in the expansion cohort). One patient was found to have HER2-negative disease and did not receive treatment. Patient characteristics are shown in Table 1 No DLTs were observed during the safety run-in phase, and ribociclib was thus used at 400mg po daily for the expansion cohort. Grade 3/4 toxicities were observed in 5 patients (41.7%) and included neutropenia (n=2), and fatigue, pain, and muscle weakness (all n=1). No patient demonstrated QTc prolongation >480 msec, or grade 3/4 LFTs. 1/12 patients ((8.3%); 95% CI 0.2%-38.5%) achieved stable disease>24 weeks; no objective responses were observed, and median PFS was 41.5 days. The trastuzumab portion of study was closed early due to limited clinical activity observed (the T-DM1 with ribociclib cohort remains open). Table 1Age (median, range)50.5 (42 - 71)Number of prior lines of systemic therapy for metastatic disease (median, range)5.5 (0-14)Number with Hormone receptor-positive disease (%)8 (67 %)Number of metastatic sites (median, range)2.5 (2 - 5) Conclusions: The combination of trastuzumab and ribociclib (400mg daily continuous schedule) is safe, with no new safety signals observed. The limited activity seen in this heavily pretreated population suggests that future efforts to incorporate CDK4/6 inhibition should be limited to a less extensively treat population. Citation Format: Goel S, Spring L, Rees R, Andrews C, Tahara RK, Mayer EL, Bardia A, Winer EP, Tolaney SM. A phase 1b/2 study of ribociclib plus trastuzumab for the treatment of advanced, treatment-refractory HER2-positive breast cancer [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 P6-18-10.

Background Radium-223 dichloride (Ra-223) is a therapeutic alpha particle-emitting radiopharmaceutical compound which have antitumor effect targeted on bone metastases. Alpha particles induces double strand DNA breaks and localized cytotoxic effect to cancer cells with limiting harm on normal tissues. We are conducting a phase II clinical trial of combination of Ra-223, hormonal therapy, and denosumab treatment in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer (NCT02366130). In this preliminary analysis of the study, we aimed to evaluate the feasibility and safety of this combination therapy. Methods This single-center phase II study seeks to determine the efficacy and safety of Ra-223 in combination with hormonal therapy and denosumab. Major eligibility criteria include HR-positive breast cancer with bone and/or marrow predominant metastases. Patients with two or more visceral metastases were not eligible. There was no limit in the number of prior hormonal therapies in the metastatic setting. Patients received Ra-223 injection (55 kBq/kg intravenously) on day 1 of the study and then every 4 weeks thereafter for 6 cycles. Patients were also administered a single hormonal agent (i.e., tamoxifen, aromatase inhibitor, or fulvestrant at standard doses) daily and denosumab (120 mg subcutaneously) every 4 weeks. For this analysis, adverse events (AEs) were summarized using descriptive statistics. Results A total of 25 patients were enrolled and 22 were evaluable between March 2015 and December 2016. Median age was 58.5 years (range 31-79), and 59% of patients were postmenopausal. ECOG performance status was 0 in 16 patients (73%), and 1 in six patients (27%). HER2/neu was positive in only one patient. Four patients (18%) were de novo metastasis, no patients had visceral metastasis, and multiple bone metastases in 20 patients (91%) vs. focal metastasis in 2 (9%). Median time from diagnosis of bone metastasis was 4.8 months (range 0.5-96.6). Prior therapy for metastatic disease consisted of hormonal therapy in 50% of the patients (eight patients with one line and three patients with two lines), chemotherapy (9%), palbociclib (14%), radiation to bone metastasis (50%), and bone-supportive therapy (27% with zoledronic acid, 27% with denosumab). The median number of cycles of Ra-223 administered was 6 (range 4-6). The median follow-up time was 4 months (range 2-8). There were no grade 3 or 4 AEs. Major non-hematological grade 1 and 2 AEs were bone pain (77%), fatigue (45%), nausea (36%), diarrhea (32%), AST/ALT elevation (23%), hot flashes (23%), and headache (18%). The most common hematological AEs were grade 1 or 2 neutropenia (23%), anemia (14%), and thrombocytopenia (18%). There was no treatment delay or discontinuation due to AEs. Conclusion Our results suggest that the addition of Ra-223 to hormonal therapy and denosumab is a feasible and safe combination therapy in patients with HR-positive breast cancer with bone-dominant metastasis. We continue to enroll patients in the phase II trial to evaluate the efficacy of the treatment. Citation Format: Tahara RK, Fujii T, Saigal B, Ibrahim NK, Damodaran S, Barcenas CH, Murray JL, Chasen BA, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Ueno NT. Phase II study of the feasibility and safety of radium-223 dichloride in combination with hormonal therapy and denosumab for the treatment of patients with hormone receptor-positive breast cancer with bone-dominant metastasis [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 P1-16-02.

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Background: Radium-223 dichloride (Ra-223) is a targeted alpha particle-based radiotherapeutic that has a localized cytotoxic effect on bone metastases. We sought to determine whether the circulating tumor cell (CTC) count and the presence of CTCs in epithelial-mesenchymal transition (EMT-CTCs) along with the standardized uptake value (SUV) on positron emission tomography-computed tomography (PET/CT) scans predict the efficacy of combined Ra-223 and hormonal therapy in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer. Patients and Methods: In this single-center phase 2 study (NCT02366130), 36 patients received Ra-223 (55 kBq/kg intravenously) on day 1 and then every 4 weeks for six cycles. Patients also received a standard care endocrine monotherapy. One non-bone metastatic site was allowed. The number of prior endocrine therapies was not limited and one prior chemotherapy was allowed for metastasis. Response was evaluated using the PET Response Criteria in Solid Tumors (PERCIST) with PET/CT at baseline, 6 and 9 months (mo) later. The CTC count (CellSearch) and the presence of EMT-CTCs (AdnaTest) was determined at baseline, 6 and 9 mo later. Progression-free survival (PFS) time was calculated to evaluate efficacy. Results: Seven patients (20%) had a non-bone metastatic site. The median number of prior therapies for metastasis was 1 (range, 0-4). Six patients (17%) received chemotherapy. The median CTC count at baseline was 4 (range, 0-306). Only four patients (11%) were positive for EMT-CTCs at baseline. The median follow-up time was 14.7 mo (95% confidence interval [CI], 13.2 mo-not reached [NR]). The disease control rate at 9 mo was 46% in 33 patients who reached 9 mo or progressed up to 9 mo. The tumor response rate at 6 mo was 52% (complete/partialresponse rate; 22/30 %) in 27 patients whose disease was evaluable using PERCIST. The SUV on PET/CT decreased significantly at 6 and 9 mo after baseline (average decreases of 1.5 (p=0.0004) and 2.5 (p=0.0054), respectively). The median PFS duration was 7.4 mo (95% CI, 4.8 mo-NR). The median bone PFS was 16 mo (95% CI, 7.3 mo-NR). Patients with bone-only metastasis (N=28, 80%) had a significantly longer median PFS duration than did patients with non-bone metastases at baseline (N=7, 20%) (13.8 mo versus 4.5 mo; p=0.017). Patients without prior treatment (N=12, 34%) tended to have longer median PFS durations than did those who underwent prior treatment (N=23, 66%) (16.8 mo versus 4.8 mo; p=0.1865). Also, patients with <5 CTCs at baseline (N=19, 54%) tended to have longer median PFS durations than did those with ≥5 CTCs (N=16, 46%) (13.8 mo versus 4.8 mo; p=0.1277). EMT-CTCs status did not predict efficacy. Conclusions: Bone-only metastatic breast cancer and SUV suppression by Ra-223 are predictive of efficacy. Patients with baseline <5 CTC count tended to have better outcomes than did those with ≥5 CTCs. Combined treatment with Ra-223 and a hormonal agent is especially effective at controlling bone metastasis in patients with HR-positive breast cancer. Bone-only metastatic disease and CTC count should be factored in future clinical trial designs. Citation Format: Ueno NT, Tahara RK, Reuben JM, Gao H, Saigal B, Fujii T, Lucci A, Ibrahim NK, Damodaran S, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Lim B, Chasen BA. CTCs and SUV to predict the efficacy of the bone-specific radiopharmaceutical agent radium-223 dichloride combined with hormonal therapy for hormone receptor-positive bone-dominant breast cancer metastasis [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 P1-18-04.