Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer.

INTRODUCTION: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2-) MBC and recurrent ovarian cancer (ROC). METHODS: Cohorts of 3-6 patients with HER2- MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. PRIMARY ENDPOINT: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. RESULTS: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2- MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. CONCLUSION: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

Discrepancies in estradiol levels in a premenopausal woman receiving abemaciclib despite ovarian function suppression and bilateral salpingo-oophorectomy.

Abemaciclib is approved for use in the adjuvant setting in combination with endocrine therapy for patients with high-risk, hormone receptor-positive, HER2-negative early-stage breast cancer based on the monarchE trial. Options for endocrine therapy for premenopausal women include an aromatase inhibitor with ovarian function suppression or tamoxifen with or without ovarian suppression. We describe a unique case of a premenopausal woman with early-stage breast cancer receiving adjuvant abemaciclib and an aromatase inhibitor with elevated estradiol levels as measured by the Abbott Alinity chemiluminescent immunoassay despite chemical and surgical ovarian function suppression. Given low estradiol levels using liquid chromatography-mass spectrometry testing following a bilateral salpingo-oopherectomy, our case report suggests an interference of abemaciclib with the Abbott Alinity immunoassay. This possible interference has significant impacts on clinical care as false elevations in estradiol levels measured by immunoassays can lead to unnecessary treatment changes, including surgery.

Optimism and coping: do they influence health outcomes in women with breast cancer? A systemic review and meta-analysis.

BACKGROUND: Optimism, coping, and resilience may be independent predictors of anxiety, distress, depression, or health-related quality of life (HRQOL) in women with breast cancer. METHODS: Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) searches of PubMed, PsycINFO, and Google Scholar databases from January 1, 1990, to April 30, 2018, for articles (i.e., studies) determining the impact of optimism, coping, or resilience on anxiety, distress, depression, or HRQOL in women with breast cancer. Articles included only those that measured optimism by the life orientation test (LOT) or LOT-revised (R), coping by the COPE, brief (B)-COPE, or religious (R)-COPE, and resilience by the CD-Resilience Scale (CD-RIS). RESULTS: Forty-one out of 52 (79%) studies showed that optimism is a statistically significant predictor of study-specific aspects of anxiety, distress, depression, or HRQOL. In a meta-analysis focused on depression, optimism was a statistically significant predictor of depression. Coping style is a statistically significant predictor for study-specific aspects of anxiety, distress, depression, or HRQOL in 41/43 (95%) studies. The coping studies were too heterogeneous in their outcome variables to perform meta-analyses. There were too few studies (n = 6) on resilience to draw any conclusions. CONCLUSIONS: Despite many limitations of this literature, including the heterogeneity of study designs, differing sample sizes, across different countries, cultures, ethnicities, and races, most studies support that optimism and coping are predictors of anxiety, distress, depression, or HRQOL. Awareness of these psychological constructs and their potential impact on anxiety, depression, and HRQOL are a high priority.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

A phase II open-label study of ganetespib, a novel heat shock protein 90 inhibitor for patients with metastatic breast cancer.

BACKGROUND: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. PATIENTS AND METHODS: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). CONCLUSION: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.

Phase II Evaluation of Liposomal Doxorubicin with Docetaxel in Patients with Metastatic Breast Cancer.

BACKGROUND: Taxanes are effective in treating metastatic breast cancer. Liposomal doxorubicin (LD) is as effective as doxorubicin but less toxic. PATIENTS AND METHODS: This phase II trial assessed the combination of LD and docetaxel (D). Between 12/2002 and 9/2005, 12 women received monthly LD (30 mg/m(2)) and weekly D (30 mg/m(2)). Cycles were continued until progression or toxicity. Primary outcome was time to progression. Secondary endpoints included response rate, time to treatment failure, duration of response, survival, and toxicity. RESULTS: Median age was 49 (31-60) years. 9 (75%) patients had estrogen receptor-positive or progesterone receptor-positive tumors. 5 (41.7%) women had her-2/neu-positive tumors. 4 women stopped participation due to toxicity, and 7 due to progression. 8 (67%) participants (95% confidence interval (CI) 51.6-94.5%) had a partial response, and 2 (16.7%) had stable disease. Median time to progression was 9.6 months (95% CI 4.7-12.2). Median time to treatment failure was 6.5 months (95% CI 4.4-10.5). Median survival was 22.1 months (95% CI 9.6-40.8). Median duration of partial response was 2.7 months (95% CI 2.4-10.5). 10 (83%) women experienced grade 3/4 toxicities: neutropenia 3 (25%), infection 3 (25%), stomatitis 5 (41.7%), nausea 2 (16.7%), vomiting 1 (8.3%), dyspnea 2 (16.7%), pericardial effusion 1 (8.3), and palmar-plantar erythrodysesthesia 1 (8.3%). CONCLUSIONS: LD and D resulted in an encouraging response and unacceptable toxicities.