etirinotecan-pegol and Breast-Neoplasms

Advanced breast cancer is incurable for most patients with limited therapeutic options. As such, there is a critical need for new and novel agents that lack cross-resistance and mitigate overlapping toxicities.. This review examines etirinotecan pegol as a promising new agent for the treatment of refractory metastatic breast cancer. Etirinotecan pegol is the first topoisomerase I inhibitor with a novel design: a long-acting polymer conjugate of irinotecan molecularly engineered to concentrate in vascularized tumors and provide sustained circulation time of SN38 for prolonged tumor cell exposure. Etirinotecan pegol pharmacology is reviewed in this paper along with safety and efficacy data from preclinical and clinical trials. In the phase II advanced breast cancer setting, etirinotecan pegol provided promising activity, which was maintained in poor prognostic subgroups, with low rates of neutropenia and neuropathy - issues plaguing our currently available agents.. Etirinotecan pegol demonstrates anti-tumor activity and improved tolerability in patients with refractory metastatic breast cancer. As a novel topoisomerase I inhibitor in breast cancer, etirinotecan pegol holds great therapeutic potential, allowing the challenge of resistance in the advanced disease setting to be addressed.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Polyethylene Glycols; Topoisomerase I Inhibitors

Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician's choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM.. To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician's choice in a confirmatory trial.. This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019.. Patients were randomized to receive etirinotecan pegol, 145 mg/m2, every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel).. The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate.. A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non-central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable.. The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research.. ClinicalTrials.gov Identifier: NCT02915744.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Middle Aged; Polyethylene Glycols

The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744.

Topics: Adult; Aged; Brain Neoplasms; Breast Neoplasms; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Polyethylene Glycols; Progression-Free Survival; Topoisomerase I Inhibitors

Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.. HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m. Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of -9.4 and -10.8 points, respectively.. There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression.. NCT01492101.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Albumins; Anorexia; Antineoplastic Agents; Body Image; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cancer Pain; Deoxycytidine; Docetaxel; Dyspnea; Epothilones; Fatigue; Female; Furans; Gemcitabine; Health Status; Heterocyclic Compounds, 4 or More Rings; Humans; Ketones; Liver Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Paclitaxel; Polyethylene Glycols; Quality of Life; Reproductive Health; Sleep Initiation and Maintenance Disorders; Taxoids; Vinblastine; Vinorelbine; Vomiting

New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.. In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101.. Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock).. This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients.. Nektar Therapeutics.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Capecitabine; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Middle Aged; Neoplasm Staging; Physicians; Polyethylene Glycols; Taxoids

New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials.. In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug.. 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none).. On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Camptothecin; Drug Administration Schedule; Europe; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Intention to Treat Analysis; Irinotecan; Kaplan-Meier Estimate; Middle Aged; Polyethylene Glycols; Time Factors; Topoisomerase I Inhibitors; Treatment Outcome; United States

Topics: Brain Neoplasms; Breast Neoplasms; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Polyethylene Glycols

Topics: Brain Neoplasms; Breast Neoplasms; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Polyethylene Glycols

Topics: Breast Neoplasms; Camptothecin; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Irinotecan; Polyethylene Glycols; Topoisomerase I Inhibitors

Topics: Antineoplastic Agents; Breast; Breast Neoplasms; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Microtubules; Molecular Targeted Therapy; Neoplasm Metastasis; Polyethylene Glycols; Receptor, ErbB-2