Regimens For Metastatic Breast Cancer Research Articles

Genomic testing and uptake of alteration-targeted therapies among patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).

e13084 Background: There is no recognized standard of care treatment after progression on first-line endocrine therapy plus CDK4/6 inhibitor in HR+ / HER2 negative MBC. Alteration-targeted therapies (ATT) have the potential to delay initiation of chemotherapy with more favorable toxicity, and perhaps improved efficacy. Next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) can identify actionable mutations for targeted therapy. In this study, we sought to assess the results of genomic testing and uptake of ATT among patients with HR+ / HER2-negative MBC. Methods: We studied a retrospective cohort of patients with MBC who received treatment in the Koontz Center for Advanced Breast Cancer (KABCC) at St. Luke’s Cancer Institute, a community-based health system in the Kansas City metro area. The analytic cohort included 125 patients with HR+ / HER2-negative MBC who received treatment after progression on first-line therapy. Genomic testing was performed as a standard of care from ctDNA or tumor-tissue using commercially available NGS assays. Targetable alterations were defined as those with FDA-approved or routinely used off-label treatment regimens in MBC ( PIK3CA, PTEN, AKT, ESR1, ERBB2, BRCA1, BRCA2, PALB2 mutations; TMB >10 or PDL1+). We identified patients who received any ATT and compared them with those who did not. Overall survival (OS) and time to initiation of chemotherapy (TTC) were compared between the two groups using Kaplan-Meier analyses and the log-rank test. Results: Ninety-nine patients (79.2%) had genomic testing and 49 (39.2%) were tested prior to second-line therapy. Of those tested, 84% had at least one targetable alteration. ESR1 mutations were most common, detected in 36% of patients, followed by PIK3CA (31.2%), PTEN (12%), BRCA1/2 (7.2%) and ERBB2 (5.6%). A total of 35 patients received ATT, and around half of those (17 patients) received ATT in the second line. Alpelisib was the most common ATT (62.9%), followed by elacestrant (20%) and neratinib (14.3%). There was no significant difference in OS or TTC between the two groups. Conclusions: Approximately 80% of patients with HR+ / HER2-negative MBC in our cohort underwent genomic testing after progression on first-line therapy, and the vast majority had at least one targetable alteration identified. However, only 35 patients received ATT with most receiving alpelisib. We observed no significant improvement in OS or TTC among those who received ATT, although the numbers were small. There have been two new targeted therapies approved in the past year and many novel agents are currently under investigation in clinical trials. Newer therapies with distinct targets, improved tolerability and efficacy have the potential to improve the uptake and clinical benefit of targeted therapy in MBC.

A propensity score–weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

319P A propensity score weighted study comparing two versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of Pegylated Liposomal Doxorubicin (PLD) has been approved for the treatment of Metastatic Breast Cancer (MBC). Phase II trials have suggested interest for a 2-weekly regimen. The aim of this study was to compare efficacy and safety of these two modalities.

Docetaxel and bevacizumab with or without trastuzumab as first-line treatment for patients with metastatic breast cancer: a meta-analysis.

Although bevacizumab and trastuzumab have been widely added to the standard regimen for metastatic breast cancer, the clinical outcomes remain controversial. The purpose of this study was to conduct meta-analysis to verify the clinical efficacy and safety of docetaxel and bevacizumab with or without trastuzumab as first-line treatment for patients with metastatic breast cancer (MBC). All available literature of clinical trials about docetaxel, bevacizumab, trastuzumab and metastatic breast cancer was pooled from PubMed, Embase and Cochrane library database. The meta-analysis combined the progression free survival (PFS), overall response rate (ORR) and incidence of all grades adverse events in MBC patients. Seven clinical trials were included by two reviewers. Docetaxel and bevacizumab with trastuzumab show the pooled PFS was 16.53 months (95% CI: 13.95-19.11 months), the pooled ORR was 0.75 (95% CI: 0.69-0.80) in HER2-positive MBC patients. Docetaxel and bevacizumab show that the pooled PFS was 8.49 months (95% CI: 7.80-9.18 months), the pooled ORR was 0.51(95% CI: 0.47-0.55) in HER2-negative MBC patients. Both for patients with HER2-positive and negative metastatic breast cancer, docetaxel and bevacizumab with or without trastuzumab as first-line treatment resulted in long survival, especially in terms of progression-free survival. Although the overall response rates are also significantly improved, it is still controversial based on the current evidence.

Pharmacoeconomic aspects of oral vinorelbine application: a budget impact analysis considering the new registered price

Objective: comparative assessment of the economic effect of oral vinorelbine when used as indicated, taking into consideration the new registered price.Material and methods. A clinical-economic study was performed to compare active platinum-containing chemotherapy regimens of the first line for stage IV non-small-cell lung cancer with oral vinorelbine and pemetrexed as well as first-line chemotherapy regimens for metastatic breast cancer presented with oral vinorelbine and ixabepilone alone. A systematic search for information in medical databases was carried out, the cost estimate was made out in accordance with the recommendations of The Center for Healthcare Quality Assessment and Control of the Ministry of Health of the Russian Federation. The direct medical costs were estimated, formed on the basis of the dosage, frequency and dosage regimen of the compared drugs, based on the data of the State Register of maximum selling prices, clinical guidelines for the studied nosologies, and instructions for medical use. The comparison of the economic effect of the studied drugs was carried out in pairs using the cost minimization method with a sensitivity analysis. Further, the calculations of the amounts of reimbursement of medical care provided were made using each of the compared drugs. An economic assessment of the economic effect of oral vinorelbine was carried out taking into consideration the change in the price of the drug and a budget impact analysis with a sensitivity analysis.Results. It was determined that the use of oral vinorelbine provides financial savings for a medical organization at the amount of 246,042.34 rubles per 6 cycles of chemotherapy for each patient with stage IV non-small-cell lung cancer compared with the use of pemetrexed, and 558,659.32 rubles per year – for the treatment of each patient with metastatic breast cancer compared with ixabepilone. The results of the budget impact analysis showed that the indication of oral vinorelbine saved 3,287,470.56 rubles for the budget fund considering the change in the cost of 1 mg of the drug for a hypothetical population of patients with stage IV non-small-cell lung cancer in 1000 people. This would create the possibility of therapy for additional 15 patients with this diagnosis. The indication of oral vinorelbine in first-line chemotherapy of metastatic breast cancer for a similar target population would save 18,355,043.96 rubles for the budget fund, which makes it possible to treat 15 more patients with this diagnosis.Conclusion. The use of oral vinorelbine is associated with the saving of financial resources of a medical organization. In addition, the reimbursement for medical care provided from the compulsory medical insurance funds when using regimens with oral vinorelbine is primarily lower than for comparison drugs. Thus, the use of regimens with oral vinorelbine is more beneficial for the payer (the Federal Compulsory Health Insurance Fund) and for the medical organization. The change in the cost of the drug is associated with an increase in the availability of medical care for patients with stage IV non-small-cell lung cancer and patients with metastatic breast cancer.

Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer

BackgroundEribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting.MethodsSystematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician’s choice (TPC), and vinorelbine (VIN).ResultsThe network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66–0.99) or GEM+VIN (0.62; 0.42–0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64–0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17–1.67) and CAP+UTI (1.61; 1.23–2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54–0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer.ConclusionsThis network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.

Results from CONTESSA 2: A multinational, multicenter, phase 2 study of tesetaxel (T) plus a reduced dose of capecitabine (C) in patients (pts) with hormone receptor + (HR+), HER2- metastatic breast cancer (MBC) not previously treated with a taxane.

1061 Research Funding: Odonate Therapeutics, Inc. Background: T is a novel, oral taxane with unique properties, including: oral administration with a low pill burden, a long (8-day) half-life in humans, once-every-3-weeks dosing, no observed hypersensitivity reactions and significant activity against chemotherapy (CT)-resistant breast cancer cell lines. T had encouraging monotherapy activity in a phase 2 study in 38 pts with HR+, HER2- MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% (Seidman, 2018 ASCO Annual Meeting, Abstract 1042). In CONTESSA, a randomized phase 3 study in 685 pts with HR+, HER2- MBC previously treated with a taxane, T plus a reduced dose of C improved progression-free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC) vs. the approved dose of C alone: median of 9.8 months (mo) vs. 6.9 mo, an improvement of 2.9 mo (HR=0.716; p=0.003) (O'Shaughnessy, SABCS 2020, GS4-01). Methods: CONTESSA 2 is a multinational, multicenter, phase 2 study of T (27 mg/m2 on day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day for 14 days of a 21-day cycle) in pts with HR+, HER2- MBC previously treated with 0-1 prior CT regimens for MBC and not previously treated with a taxane. The primary endpoint is ORR as assessed by the IRC. The secondary efficacy endpoints are duration of response (DoR), PFS and disease control rate (DCR) as assessed by the IRC, and overall survival (OS). Results: 150 pts were enrolled and treated. 80% had visceral disease, 46% had de novo MBC, 52% were previously treated with a CDK 4/6 inhibitor and 33% were ≥65 years old. At the prespecified interim analysis approx 4 mo after the last patient enrolled, the confirmed ORR was 51% (95% CI: 42%-60%), and the unconfirmed ORR was 63% (95% CI: 54%-71%). The median DoR was 9.5 mo (95% CI: 5.4-11.5 mo), the median PFS was 12.9 mo (95% CI: 8.1 mo-NR) and the DCR was 71% (95% CI: 62%-79%). OS data are immature. Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) occurring in ≥5% of pts were: neutropenia (74.0%), leukopenia (10.7%), hypokalemia (7.3%), anemia (6.7%), hand-foot syndrome (6.0%) and diarrhea (5.3%). Gr 2 alopecia occurred in 11.3% of pts, febrile neutropenia occurred in 4.7% of pts and Gr ≥3 neuropathy occurred in 2.0% of pts. Discontinuation of T and C due to any adverse event occurred in 13.3% of pts. Conclusions: An all-oral regimen of T plus a reduced dose of C demonstrated a high level of antitumor activity in pts with HR+, HER2- MBC not previously treated with a taxane. The confirmed ORR was 51%, median DoR was 9.5 mo and median PFS was 12.9 mo. Neutropenia was the most frequent Gr ≥3 TEAE; the rate of febrile neutropenia was 4.7%. Rates of clinically significant alopecia and neuropathy were low. Clinical trial information: NCT03858972 . Clinical trial information: NCT03858972 .

Phase II study of sequential S-1 and cyclophosphamide therapy in patients with metastatic breast cancer

BackgroundS-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m2/day for S-1 and 100 mg/m2/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen.MethodsThis was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2×/day for 14 consecutive days, and then CPA was administered orally 2×/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety.ResultsThirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8–12.6 months). The median OS was 20.2 months (95%CI: 15.0–25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality.ConclusionThe combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy.Trial registrationJRCT, JRCTs031180296. Registered 2 December 2019 – Retrospectively registered.

Weekly and 3-Weekly Taxane Regimens in Metastatic Breast Cancer: Outcomes in Unselected Patients

Weekly and 3-Weekly Taxane Regimens in Metastatic Breast Cancer: Outcomes in Unselected Patients

Prognostic Value and Influence of Receptor Conversion on Treatment Regimen in Metastatic Breast Cancer at the First Time of Recurrence

Purpose: At the first time of metastatic breast cancer recurrence, conversion of the receptors status may occur between primary lesions and metastatic lesions, including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Whether the decision of the treatment regimen is based on the primary receptor status or that of metastatic lesions is still unclear. Methods: This study enrolled 411 female patients with a diagnosis of metastatic breast cancer at the first time of recurrence to explore the influence of receptor conversion on prognosis prediction and treatment regimen of patients with metastatic breast cancer. Results: ER and PR changes from negative to positive are both prognostic factors for patients with breast cancer. Patients receiving endocrine therapy showed a better survival after recurrence than those using chemotherapy alone in the ER or PR Prim– Met+ subgroup. Patients in the HER2 Prim– Met+ subgroup using HER2-targeted therapy in multilines showed a post-recurrence survival advantage. In the bone re-biopsy subgroup, the PR change from positive to negative appeared to be more frequent than at other re-biopsy sites. Conclusions: Patients with metastatic breast cancer should perform re-biopsy to clarify the receptor status of the first metastatic lesions, which may provide clinicians valuable evidence to conduct treatments with higher precision.

Abstract PD7-10: Randomized, multicenter phase II trial of weekly paclitaxel with or without the oral selective aurora kinase A (AURKA) inhibitor, Alisertib, in patients with ER+ HER2- metastatic breast cancer

Abstract Elevated expression of AURKA adversely affects prognosis in ER+ breast cancer and is associated with resistance to taxanes, endocrine therapy, and PI3K inhibitors. A recent randomized phase II trial of combined paclitaxel plus alisertib (P+A) in recurrent ovarian cancer patients (pts) showed improved progression-free survival (PFS) compared to paclitaxel (P) alone (Falchook G. JAMA Oncol 2019). We conducted a randomized phase II trial of P alone versus P+A in pts with ER+ HER2- metastatic breast cancer (MBC). Methods: The primary objective of the trial was PFS in the intent-to-treat (ITT) population with secondary endpoints of overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; CR+PR+SD>6 mos), safety and analysis of archival breast cancer for molecular predictors of benefit from alisertib. ER+ HER2- MBC pts who had had prior endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, > 12 mos treatment-free interval from neo/adjuvant taxane therapy, and who had measurable or evaluable lytic bone disease were randomized to receive P 90 mg/m2 IV D1, 8, 15 on a 28-day cycle or P 60mg/m2 D1, 8, 15 plus A 40 mg PO BID D1-3, 8-10, 15-17 on a 28-day cycle until disease progression or unacceptable toxicity. Pts were stratified by prior neo/adjuvant taxane (yes/no) and by whether they were receiving first (1L)- or second (2L)-therapy for MBC. Proportions of ORR and CBR were compared using Chi-square test between the two study arms. Kaplan-Meier estimator was applied to estimate OS and PFS and univariate Cox regression was used to assess the hazard ratio of study treatment. Results: 139 pts were randomized (69 to P+A; 70 to P) in the US Oncology Network between 2/2015 and 2/2018 and 136 pts received treatment on trial. At data cut-off, 76% of pts had had a documented PFS event and the median followup was 19.7 mos. The median age was 62 and 69% of pts received trial therapy as 1L treatment; 41% had had prior neo/adjuvant taxane therapy. Median PFS in the ITT population was 10.2 mos with P+A vs 7.1 mos with P alone, HR 0.56, 95% CI 0.37-0.84, p=0.005. Median OS was 29.8 mos with P+A vs 24.4 mos with P alone, HR 0.85, p=0.486. ORR and CBR in the response evaluable population were 31% and 67%, respectively, in the P+A arm vs 34% and 57%, respectively, in the P alone arm (p>0.05). Grade 3/4 adverse events (AEs) occurred in 83% of P+A pts vs 47% with P alone. The main grade 3/4 AEs with P+A vs P were neutropenia 59% vs 15%, anemia 10% vs 1%, febrile neutropenia 1.5% vs 0, diarrhea 11% vs 0, stomatitis 15% vs 0, peripheral neuropathy 1.5% vs 9%. 1 pt died of sepsis with P+A. Conclusions: Addition of oral A to weekly P significantly improved PFS, the primary endpoint, compared with P alone, and toxicity with P+A was manageable with A dose reduction. These data support further evaluation of alisertib in ER+ HER2- MBC pts. Citation Format: Joyce O'Shaughnessy, Kristi McIntyre, Sharon Wilks, Ling Ma, William Fintel, Margaret Block, David Andorsky, Michael Danso, Nicholas Koutrelakos, Tracy Locke, Amy Scales, Lauren Steckel, Yunfei Wang. Randomized, multicenter phase II trial of weekly paclitaxel with or without the oral selective aurora kinase A (AURKA) inhibitor, Alisertib, in patients with ER+ HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-10.

Abstract P6-12-09: My PROfile: A web-based tool to assess patient reported outcomes (PROs) in women with metastatic breast cancer (MBC): Preliminary results

Abstract Introduction: An emphasis on patient-centered care has led to a growing interest in collecting PROs in cancer care. Our prior work has demonstrated substantial variation in what types of PROs patients deem most important; although physical symptoms are common, a substantial minority of patients report concerns in non-physical symptom (non-PSx) domains, such as emotional or social health, practical or financial problems, and daily functional activity. Here we report initial findings from a pilot study of a secure web-based tool, called My PROfile, which addresses not only individual symptoms but also non-PSx domains. Methods: We enrolled women who had started a treatment regimen for MBC within the past 6 weeks at Smilow Cancer Hospital of Yale New Haven Hospital or an affiliated care center. Using My PROfile, participants responded to validated surveys and provided PROs addressing physical symptoms as well as non-PSx domains including practical problems, social well-being, emotional well-being, spiritual or religious concerns, alcohol and drug use, daily activities and any other areas of difficulties experienced within the past week. Patients also ranked their top 3 concerns at the time of My PROfile completion. Patients were followed prospectively for 6 months and asked to complete My PROfile as often as desired during that time frame, but at least once prior to each visit with their provider. This information was compiled into a report that was shared with their medical oncology provider prior to the clinic visit. For this analysis, we analyzed the frequency of reporting individual symptoms and domains by patient. Results: A total of 28 patients consented to participate. At the time of data analysis, 9 patients had completed all six months of the pilot. Across the different PRO domains, the majority of patients reported difficulties with physical symptoms (68%) or emotional well-being (50%). Overall, 21% of patients reported physical symptoms only, and 46% of patients reported difficulties with both physical symptoms and non-PSx domains; however, 32% of patients reported difficulties from non-PSx domains only. Approximately 29% of patients reported practical problems (including 21% who noted the impact of treatment on diet/activity and 14% who had concerns about monitoring diet and activity in general). Difficulties with daily activities were reported in 29% of patients (with 18% reporting housework and walking specifically). Difficulties in social well-being were reported by 18% of patients, including 11% who specifically reported concerns with family health. The PRO domain reported by the fewest number of patients (n=1) was alcohol and drug use. The three most common individual symptoms reported were fatigue (57% of patients), pain (54% of patients), and worry (36% of patients). Nearly half (47%) of our respondents (13 out of 28) used My PROfile at least 3 times during follow-up. Among these patients, all but 1 patient reported difficulties with physical symptoms at least twice. Additionally, 23% of these patients reported the non-PSx domains of practical concerns and daily activity concerns more than once during the follow-up period. Conclusion: Although physical and mental health symptoms are commonly reported among patients undergoing systemic treatment for metastatic breast cancer, a substantial minority of patients report non-physical symptom concerns including practical and daily activity-based challenges. Because the specific concerns of interest vary substantially across patients, tools to collect PROs should include additional domains that can significantly affect quality of life in women with MBC. Citation Format: Sarah Mougalian, Maureen Canavan, Renee Capasso, Jenerius Aminawung, Carolyn J. Presley, Cary P Gross. My PROfile: A web-based tool to assess patient reported outcomes (PROs) in women with metastatic breast cancer (MBC): Preliminary results [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-12-09.

Phase II trial of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab in patients with HER2-positive metastatic breast cancer.

e12508 Background: Metronomic chemotherapy is an emerging paradigm of cancer therapy in which low doses of chemotherapy are delivered at frequent intervals. Activity in patients with metastatic breast cancer (MBC) has been demonstrated in several phase II clinical trials. Methods: We proposed a regimen with metronomic chemotherapy and dual HER2 inhibition in HER2 positive patients with MBC. We hypothesized that this regimen will be highly active in MBC and have a favorable toxicity profile. Patients were treated on a 21-day cycle with capecitabine 1500mg PO daily, cyclophosphamide 50mg daily, lapatinib 1000mg PO daily and trastuzumab 6mg/kg IV once per 21-day cycle. This regimen was continued until disease progression or unacceptable toxicity. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety and tolerability of this regimen. Eligibility criteria were patients 18 years of age and older who had histologically confirmed HER2-positive metastatic breast cancer with prior trastuzumab use in the adjuvant or metastatic setting with no more than two prior regimens for MBC. Results: Ten patients were accrued from Jan 2014-Oct 2016. Median age was 52 (range 38 - 79) years. Median number of chemotherapy regimens for metastatic disease was 0.5 (range 0-2). Median PFS was 13.7 (95% CI: 2.6, 16.6) months. Median OS was 29.6 (95% CI: 11.8, 60.5+) months. ORR was 30%, and CBR was 70%. Grade 3 or 4 toxicities were identified in 6 patients. The most common toxicities of any grade were fatigue (100%), diarrhea (80%), anemia, neutropenia, ALT increase, nausea and hand-foot syndrome 50% each. One patient achieved CR for over 3 years and continues on treatment at time of this report. 8 patients progressed and 1 patient withdrew from study without response evaluation. The trial was closed due to lack of accrual. Conclusions: The proposed regimen of metronomic capecitabine and cyclophosphamide with lapatinib and trastuzumab appears to be active in patients with HER2 positive MBC but with significant toxicity. Clinical trial information: NCT01873833.

Abstract P5-14-06: Prioritization of patient reported outcomes by women with metastatic breast cancer

Abstract Introduction: An emphasis on patient-centered care has led to a growing interest in collecting patient-reported outcomes (PROs) in the setting of cancer care. Routine collection of actionable PROs has been shown to improve patient satisfaction with care and even prolong survival. However, completion rates of PROs outside of the research setting are low, which may be due to an incomplete understanding of the outcomes patients value most. Prior work has focused primarily on symptom burden, but patients are also affected by disease and treatment across multiple domains (e.g. physical, psychological, social, and financial). To address this knowledge gap, we conducted a qualitative study among women with metastatic breast cancer (MBC) to identify the optimal patient-centered approach to collecting PRO data. Methods: We conducted 1-on-1 interviews with patients who had started a treatment regimen for MBC within the past 6 weeks at the Breast Center at Smilow Cancer Hospital of Yale New Haven Hospital to determine which PROs were most personally relevant. We assessed heterogeneity across patients in their prioritization. Patients were asked which of a list of six PRO domains they would like their provider to have information about and then ranked the domains by order of importance (from most to least important). The following domains were created from the NCCN Distress Thermometer: physical well-being, emotional well-being, treatment burden, functional status, financial concerns, and social well-being. For each ranked domain, patients were asked to rank items within the domain using a card sorting exercise where the number of items ranged from 5 to 15. Patients were then asked where and how often they preferred to report PROs. Results: Ten women with MBC completed the card sorting exercise: mean age was 58 years (+/- 12), 7 were white, 2 African American and 1 Asian; 1 identified as Hispanic. After 10 interviews, it was apparent that no single set of domain rankings was common across patients. Patient prioritization of PRO domains was unique and varied. Selection and prioritization of PRO domains and items within each domain were unique and varied. Five women reported “physical well-being” as the most important domain; treatment burden and emotional well-being were also selected as most important or ranked as highly important. Participants preferred reporting MBC PROs while in the waiting room for all domains except emotional well-being (from home was the preference). However, participants were willing to complete PRO assessment in the waiting room for about ten minutes and at home for twenty minutes. Conclusion: Substantial variation exists in how women with MBC rate the importance of specific PRO domains and items within each domain. Importantly, “physical symptoms” was not the top concern for half of the interviewed patients. This is an important finding, given that previous published studies of patient-reported outcomes have focused on one domain, such as symptoms and side effects or the financial burden of treatment. Our findings support the development of multi-dimensional tools for the collection of PROs. Although toxicity and physical symptoms are of utmost concern, clinicians should not neglect other dimensions of quality of life in women with MBC. Citation Format: Mougalian SS, Aminawung JA, Presley C, Canavan ME, Holland ML, Hu X, Gross CP. Prioritization of patient reported outcomes by women with metastatic 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 P5-14-06.

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. Methods: A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. Results: A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months (P=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (P<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (P=.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively (P=.56). Conclusions: Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression.

Phase II, Multicenter, Single-arm Trial of Eribulin as First-line Therapy for Patients With Aggressive Taxane-pretreated HER2-Negative Metastatic Breast Cancer: The MERIBEL Study

BackgroundEribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors. Patients and MethodsEribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin. ResultsThe median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia. ConclusionEribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.

The role of circulating tumor cells in metastatic breast cancer: prognostic and predictive value.

The aim of the current study was to assess the prognostic value of circulating tumor cells (CTCs) and their related markers at different points of chemotherapy regimens in metastatic breast cancer (MBC) patients. The impact of CTCs on progression free survival (PFS) and overall survival (OS) rates were also assessed. Peripheral blood samples were obtained from 66 female patients with MBC at different time intervals for evaluation of CTCs by flow cytometry (FC). cytokeratin 19 (CK19), mammaglobin, prolactin inducible peptide (PIP), aldehyde dehydrogenase 1 (ALDH1) and human chorionic gonadotropin (hCG) were also assessed by qRT-PCR. Analysis of different CTC levels (at 4, 5, and 6 cells/7ml), showed statistically significant values at 4 cells/7ml blood. The presence of baseline CTCs < 4 cells/7ml, associated significantly with higher PFS (P value = 0.03). Patients showing a decrease in the CTCs level after treatment had significantly prolonged median PFS and OS rates compared to those whose CTCs level increased (P = 0.007 and P = 0.014; respectively). Mammaglobin, CK19, PIP, ALDH1 and hCG expression did not affect PFS or OS. However, patients with CTCs ≥ 4at diagnosis had higher rates of progression compared to those with CTCs < 4 (1.9 times, P = 0.07), and who metastasized before 4years showed a worse decrease outcomes (they were 2.4 time more progressed than those who metastasized after 4 years; P = 0.029). CTCs could be an independent prognostic and predictive biomarker for MBC patients' outcomes. Although none of the assessed genes (mammaglobin, CK19, PIP, ALDH1 and hCG) showed correlation with PFS or OS rates, further studies on a larger number of patients are required to validate the current results.

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Polyphor.

Abstract P3-10-03: Effects of guideline-concordant treatment on ED visits, hospitalizations, and cost in metastatic breast cancer

Abstract Purpose: The National Comprehensive Cancer Network (NCCN) developed treatment guidelines that have directed care of patients with cancer for over 20 years. Receipt of treatment according to these guidelines is increasingly recognized as a marker of high quality care. A knowledge gap exists regarding concordance of treatment regimens for metastatic breast cancer with NCCN guidelines, as well as the potential impact of this concordance (or lack thereof) on resource utilization and costs – an issue that assumes significance in the new era of value-based healthcare. Methods: From 2007-2013, women with de novo (n=988) or recurrent, treated metastatic breast cancer (n=5,651) were evaluated for concordance of first-line systemic therapy with NCCN guidelines within the SEER–Medicare linked database. Types of non-concordant treatments were reviewed and categorized. Outcomes include monthly rates of ED visits, monthly rates of hospital admissions, total overall and Medicare costs, and mortality. Specific (hospitalizations, antineoplastic agents, growth factor) and total costs to Medicare (excluding home health, hospice, skilled nursing facility) were calculated from initiation of treatment until death or available follow-up and examined by concordance status. Part D costs were excluded because costs are shared by Medicare, other payers, and patients. Cox regression was used to evaluate mortality risk. Student's t-tests, generalized linear models, and generalized mixed effects models were utilized to evaluate the relationship between concordance status and outcomes. Results: We previously reported the prevalence of non-concordant first-line systemic therapy for de novo metastatic breast cancer (19%) and recurrent metastatic breast cancer (18%). The adjusted risk of mortality was comparable by concordance status. In the current analysis, non-concordant treatments were associated with a 9% increased rate of ED visits and a 7% increased rate of hospitalizations (p&amp;lt;.01). Total Medicare cost for patients receiving concordant and non-concordant treatments was $79,372 and $109,471, respectively (p&amp;lt;.001). Significant cost differences were found when comparing patients receiving concordant and non-concordant treatments by antineoplastic agents ($14,256 vs $24,817, p&amp;lt;.001) and growth factor ($1,754 vs $3,414, p&amp;lt;.001). A trend toward lower cost attributed to hospitalizations was observed for patients receiving concordant treatment compared to those receiving non-concordant treatment ($28,113 vs $34,134, p=.06). Overall, hospitalizations, antineoplastic agents, and growth factor accounted for 56% of total Medicare costs. Average monthly Medicare costs were higher for non-concordant patients by $1,761 (p&amp;lt;.01). Conclusions: While not associated with increased overall mortality, non-concordant treatment is associated with higher health care utilization rates and cost. Increased costs attributed to non-concordant care were largely driven by antineoplastic agents and growth factor use. These findings may have policy implications for payment reform initiative, in particular pathway programs which aim to reduce variability in care and spending on medications. Citation Format: Rocque GB, Williams CP, Jackson BE, Halilova KL, Adewakun SA, Pisu M, Forero A, Bhatia S. Effects of guideline-concordant treatment on ED visits, hospitalizations, and cost in 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 P3-10-03.

Abstract OT2-07-10: ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC)

Abstract Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087 p=0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86] p&amp;lt;0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting) pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC) ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT] stereotactic RT or surgical resection as single-agent or combination) signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥ 7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR=0.67) 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment began early 2017. For enrollment information contact Dr. Alison Hannah, Dr. Mary Tagliaferri, or Minnie Kuo at StudyInquiry@nektar.com. NCT02915744 Citation Format: Tripathy D, Sara T, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves CJ, Diéras V, Müller V, Hannah A, Tagliaferri M, Cortés J. ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC) [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 OT2-07-10.