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Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Keenan, TE, Guerriero, JL, Barroso-Sousa, R, Li, T, O'Meara, T, Giobbie-Hurder, A, Tayob, N, Hu, J, Severgnini, M, Agudo, J, et al
Nature communications. 2021;(1):5563
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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First-line bevacizumab and eribulin combination therapy for HER2-negative metastatic breast cancer: Efficacy and safety in the GINECO phase II ESMERALDA study.
Hardy-Bessard, AC, Brocard, F, Clatot, F, Lortholary, A, You, B, Grenier, J, Martin-Babau, J, Lucas, B, Meunier, J, Ferrero, JM, et al
Breast (Edinburgh, Scotland). 2020;:256-263
Abstract
PURPOSE Combining bevacizumab with paclitaxel significantly improves progression-free survival (PFS) versus paclitaxel alone in HER2-negative metastatic breast cancer (MBC). Eribulin is active and tolerable in pretreated MBC. To assess whether eribulin may offer a more tolerable yet effective combination partner for bevacizumab, we evaluated a bevacizumab/eribulin combination regimen as first-line therapy for MBC. METHODS In this single-arm phase II study, patients with histologically confirmed HER2-negative MBC and no prior chemotherapy for MBC received eribulin 1.23 mg/m2 on days 1 and 8 every 3 weeks for ≥6 cycles plus bevacizumab 15 mg/kg on day 1 every 3 weeks until disease progression. The primary endpoint was non-progression rate at 1 year. Secondary endpoints included objective response rate (ORR), PFS, and safety. RESULTS The median age of the 61 treated female patients was 59 years, 16% had triple-negative MBC, 30% had ≥3 metastatic sites, and 71% had received prior (neo)adjuvant chemotherapy. Patients received a median of six eribulin and nine bevacizumab cycles. The non-progression rate at 1 year was 32% (95% confidence interval [CI]: 20-43%), ORR was 47% (95% CI: 34-60%), and median PFS was 8.3 months (95% CI: 7.0-9.6 months). The only grade ≥3 clinical adverse events in >5% of patients were hypertension (39%), neutropenia (26%), thrombosis (10%), and paresthesia/dysesthesia (7%). CONCLUSION First-line eribulin/bevacizumab combination therapy showed interesting activity in MBC with an acceptable safety profile, including a particularly low incidence of high-grade neuropathy.
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High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician's choice-in the EMBRACE study.
Miyoshi, Y, Yoshimura, Y, Saito, K, Muramoto, K, Sugawara, M, Alexis, K, Nomoto, K, Nakamura, S, Saeki, T, Watanabe, J, et al
Breast cancer (Tokyo, Japan). 2020;(4):706-715
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BACKGROUND Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). METHODS The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician's choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. RESULTS Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437-0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800-1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. DISCUSSION This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures. TRIAL REGISTRATION www.ClinicalTrials.gov code: NCT00388726.
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Health-related quality of life in patients receiving first-line eribulin mesylate with or without trastuzumab for locally recurrent or metastatic breast cancer.
Schwartzberg, L, McIntyre, K, Wilks, S, Puhalla, S, O'Shaughnessy, J, Berrak, E, He, Y, Vahdat, L
BMC cancer. 2019;(1):578
Abstract
BACKGROUND Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.2%, respectively. Median progression-free survival was 6.8 and 11.6 months, respectively. Tolerability profiles were similar to those from previous studies. This secondary analysis was conducted to assess health-related quality of life (HRQoL) in both phase 2 trials. METHODS Patients received eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of each 21-day cycle. Patients in Study 208 also received intravenous trastuzumab on day 1 of each cycle (8 mg/kg in cycle 1, then 6 mg/kg). HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life (QLQ-C30) assessment tool and the Quality-of-Life Questionnaire for Breast Cancer (QLQ-BR23) at baseline and cycles 2, 4, and 6. Results for clinically meaningful changes were based on previously published minimum important differences. RESULTS Of the 108 patients (56 in Study 206 and 52 in Study 208) treated, 57 and 87%, respectively, completed 6 cycles. Completion rates for both questionnaires were 94 and 98%, respectively, at cycle 6. Most patients had stable/improved HRQoL scores with some exceptions; for example, more patients experienced a worsening in cognitive functioning and systemic therapy side effects than experienced improvement. Mean QLQ-C30 symptom scores correlated with corresponding adverse event rates for nausea/vomiting, dyspnea, appetite loss, constipation, and diarrhea in Study 206 and for fatigue, nausea/vomiting, pain, dyspnea, insomnia, constipation, and diarrhea in Study 208. CONCLUSIONS First-line eribulin ± trastuzumab therapy did not lead to deterioration of overall HRQoL in most patients, with more than 60% of patients having stable/improved global health status/quality-of-life scores. Eribulin has been demonstrated to be comparable with other chemotherapy agents with an acceptable safety profile. Therefore, further evaluation is warranted to determine whether eribulin ± trastuzumab therapy may be a potential option for first-line treatment in some patients with metastatic breast cancer who were recently treated in the neoadjuvant setting. TRIAL REGISTRATION NCT01268150 (December 29, 2010), NCT01269346 (January 4, 2011).
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Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
Yuan, P, Hu, X, Sun, T, Li, W, Zhang, Q, Cui, S, Cheng, Y, Ouyang, Q, Wang, X, Chen, Z, et al
European journal of cancer (Oxford, England : 1990). 2019;:57-65
Abstract
INTRODUCTION The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC). METHODS This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2-5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m2, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m2, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS). RESULTS Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65-0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80-1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%-36.6%) with eribulin and 16.9% (95% CI: 12.6%-22.0%) with vinorelbine (P < 0.001). Treatment-emergent adverse events leading to treatment discontinuation were less frequent with eribulin (7.2%) than with vinorelbine (14.0%). CONCLUSIONS Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed. TRIAL REGISTRATION National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1.
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Clinical and radiological results comparison of allograft and polyetheretherketone cage for one to two-level anterior cervical discectomy and fusion: A CONSORT-compliant article.
Yang, S, Yu, Y, Liu, X, Zhang, Z, Hou, T, Xu, J, Wu, W, Luo, F
Medicine. 2019;(45):e17935
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BACKGROUND Recently, many kinds of cages for cervical fusion have been developed to avoid the related complications caused by tricortical iliac crest graft. The existing literature has reported the excellent clinical efficacy and superior fusion rate. However, various types of cages have their own disadvantages. Which bone graft material is the best choice for cage with the fewest complications? At present, there is still no conclusion. METHODS By reviewing patients with 1 to 2-level cervical degenerative disease in our hospital with a novel cage made of allograft or polyetheretherketone (PEEK), we evaluated the efficacy and reliability of the new cage in anterior cervical discectomy and fusion (ACDF). From 2015 to 2016, a prospective review of 58 and 49 consecutive cases with spondylotic radiculopathy or myelopathy undergoing ACDF using allograft (group A) and PEEK (group B) cage were performed. The follow-up ranged from 12 to 40 months. Intraoperative index, clinical outcome and complications were recorded. Radiographs evaluated segmental and overall cervical lordosis, the height of the intervertebral space, interbody height ratio (IHR), cage positioning, and fusion state. RESULTS A total of 134 cages were implanted. Compared to preoperatively, the visual analog scale (VAS) and neck disability index (NDI) were reduced postoperatively without any change during the subsequent follow-up in both groups. There was no migration or extrusion of the cages at the latest follow-up. There were 2 and 4 patients suffering dysphagia respectively. In both groups, the intervertebral height, IHR, segmental and overall cervical lordosis were significantly greater than pre-operation (P < .05) and were maintained at the last follow-up, but were not statistically significant (P > .05). The allograft group achieved a fusion rate of 100% (58/58) according to CT scans at 3 months post-operation, while PEEK group was 91.8% (45/49), which reached 95.9% (47/49) at 6 months and 100% at 12 months. In addition, the fusion state was maintained in all patients at the last follow-up. CONCLUSION Our data showed that the new allograft cage is superior to the PEEK cage in providing a high fusion rate and fewer complications after 1-level and 2-level ACDF procedures. It may represent an excellent alternative to other cages.
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A phase II study of eribulin in recurrent or refractory osteosarcoma: A report from the Children's Oncology Group.
Isakoff, MS, Goldsby, R, Villaluna, D, Krailo, MD, Hingorani, P, Collier, A, Morris, CD, Kolb, EA, Doski, JJ, Womer, RB, et al
Pediatric blood & cancer. 2019;(2):e27524
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BACKGROUND Patients with recurrent or refractory osteosarcoma have a poor prognosis with less than 30% surviving two years. Eribulin is a synthetic analog of halichondrin B, has a novel mechanism of action when compared with other microtubule inhibitors, and may have antitumor activity in osteosarcoma. METHODS A prospective study was designed to assess the disease control success at four months and objective response rates in patients with recurrent or refractory osteosarcoma treated with eribulin. Eligible patients were between 12 and 50 years of age, had measurable tumor, and met standard organ function requirements. Patients were given eribulin 1.4 mg/m2 /dose on days 1 and 8 of each 3-week cycle for up to 24 months if there was no progressive disease. Response to therapy was assessed using RECIST 1.1 criteria after cycles 2 and 5 and every fourth cycle thereafter. RESULTS Nineteen patients enrolled on the AOST1322 study. The median age of enrollment was 16 years (range, 12-25 years). Twelve patients were male and seven female. Eribulin was well tolerated, with neutropenia identified as the most common toxicity. The median progression-free survival was 38 days and no patients reached the four-month time point without progression. No objective responses were seen in any patient. CONCLUSION This study rapidly assessed the clinical activity of a novel agent in this patient population. Eribulin was well tolerated, but there were no patients who demonstrated objective response, and all patients had progression prior to four months.
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Phase II Trial of Eribulin in Patients With Metastatic Hormone Refractory Prostate Cancer: A Trial of the ECOG-ACRIN Cancer Research Group (E5805).
Stein, MN, Chen, YH, Carducci, MA, Hudes, GR, Lerma, PM, Tan, WW, Dalune, R, Rowland, KM, Kuzel, TM, DiPaola, RS
American journal of clinical oncology. 2019;(4):375-381
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BACKGROUND Eribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels. METHODS In a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata. RESULTS In total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia. CONCLUSIONS In summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.
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Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study.
Di Cosimo, S, La Verde, N, Moretti, A, Cazzaniga, ME, Generali, D, Bianchi, GV, Mariani, L, Torri, V, Crippa, F, Paolini, B, et al
PloS one. 2019;(8):e0220644
Abstract
BACKGROUND Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. METHODS Patients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. RESULTS In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. CONCLUSIONS Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation. TRIAL REGISTRATION EU Clinical Trial Register, EudraCT number 2012-004956-12.
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Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine.
Pivot, X, Im, SA, Guo, M, Marmé, F
Breast cancer (Tokyo, Japan). 2018;(3):370-374
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This post hoc subgroup analysis of a large phase 3 study compared the efficacy and safety of eribulin versus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received second-line treatment. In the phase 3 study, women with advanced/metastatic breast cancer and ≤ 3 prior chemotherapies were randomized 1:1 to eribulin mesilate 1.4 mg/m2 intravenously on days 1 and 8, or twice-daily oral capecitabine 1.25 g/m2 on days 1-14 (21-day cycles). This analysis included 392 patients. Median overall survival was longer in patients receiving eribulin compared with capecitabine (16.1 vs 13.5 months, respectively; HR 0.77, P = 0.026). Median progression-free survival and response rates were similar between arms. Both treatments had manageable safety profiles.