Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer.

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Phase II Study of Eribulin Mesylate Administered Biweekly in Patients With Human Epidermal Growth Factor Receptor-2-negative Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor-2-negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity. PATIENTS AND METHODS: In this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2-negative MBC received intravenous eribulin 1.4 mg/m2 over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]). RESULTS: Among 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support. CONCLUSION: The efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study.

Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate Versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer.

PURPOSE AND METHODS: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m(2) on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m(2) on days 1-14 (21-day cycles). RESULTS: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. CONCLUSIONS: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies. TRIAL REGISTRATION PRIMARY STUDY: This study reports the subgroup analyses of eribulin versus capecitabine from a phase 3, open-label, randomized study (www.clinicaltrials.gov; ClinicalTrials.gov identifier: NCT00337103).

Pharmacokinetics of eribulin mesylate in cancer patients with normal and impaired renal function.

PURPOSE: To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors. METHODS: Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30-50 mL/min), severe impairment (CrCl 15-29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m(2) (except cycle 1 day 1, 1.4 mg/m(2)); severe, 0.7 mg/m(2); normal, 1.4 mg/m(2). RESULTS: Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration-time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI -0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m(2) in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m(2) in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events. CONCLUSIONS: Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m(2) in patients with moderate or severe renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT01418677.

Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. CONCLUSION: In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

"New" metastases are associated with a poorer prognosis than growth of pre-existing metastases in patients with metastatic breast cancer treated with chemotherapy.

INTRODUCTION: Progression-free survival (PFS) and overall survival (OS) endpoints often only weakly correlate. This analysis investigates how different progression events impact on OS, using data from two phase 3 studies with eribulin in women with advanced/metastatic breast cancer (MBC). METHODS: In Study 301, 1102 women with ≤2 prior chemotherapies for advanced/MBC were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or capecitabine (1.25 g/m(2) twice daily on days 1-14 every 21 days). Study 305/EMBRACE enrolled 762 patients following two to five prior chemotherapies for advanced/MBC, randomized to eribulin (as above) or treatment of physician's choice. We analyzed OS and PFS post hoc for patients whose disease progressed due to development of "new" metastases, growth of pre-existing lesions, and patients with no reported disease progression. RESULTS: In both clinical studies, development of new metastases was associated with an increased risk of death (p < 0.0001). The time to development of new metastasis or death was significantly longer with eribulin than the comparator in Study 305 (p = 0.0017), but not in Study 301 (p = 0.46). Significantly longer OS was observed in the eribulin compared with the comparator arm for the new metastases subgroup in Study 301 (p = 0.008), but not in Study 305 (p = 0.16), compared with other progression subgroups. CONCLUSIONS: Patients with MBC progressing with new metastases have a worse prognosis than those whose disease progresses due to growth of existing lesions or patients with no reported disease progression. These findings have potentially important implications for the interpretation of clinical study data and clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov registration IDs: Study 301: NCT00337103 ; Study 305: NCT00388726 .

Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies.

Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or treatment of physician's choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m(2) b.i.d. on days 1-14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio [HR] 0.85; 95% CI 0.77, 0.95; P = 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82; P = 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin.

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes.

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose-independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC.

NCIC CTG IND.190 phase I trial of dalotuzumab (MK-0646) in combination with cisplatin and etoposide in extensive-stage small-cell lung cancer.

The insulin-like growth factor receptor is a potential target in small-cell lung cancer. We conducted a phase I study of cisplatin, etoposide plus dalotuzumab. Two dose levels of dalotuzumab (DL1 5 mg/kg, DL2 10mg/kg IV weekly) were evaluated in combination with cisplatin (25 mg/m²) and etoposide (100 mg/m²) IV D1-3, every 21 days, for patients with chemotherapy-naive extensive-stage small-cell lung cancer. Primary outcome was determination of the recommended phase 2 dose. Secondary outcomes included response rate and toxicity. Twelve patients were treated (DL1, 3 and DL2, 9). The median age was 63 years (48-70), with six males and six females. The majority of patients were Eastern Cooperative Oncology Group 1 and had four or more sites of disease. No dose-limiting toxicities were observed in DL1 or DL2, although one patient died from neutropenic sepsis in an expanded cohort at DL2. The recommended phase 2 dose of dalotuzumab was 10 mg/kg/week. The confirmed objective response rate was 67% (partial response 8, stable disease 2, progressive disease 1, nonevaluable 1). Grade 3 or higher toxicities (any cycle) occurring in more than one patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in one of three (DL1) and five of nine (DL2) patients. Eight serious adverse events (thrombosis, febrile neutropenia, infection, syncope, fatigue [2], dyspnea, back pain) were observed in three patients. Dalotuzumab can be combined at full dose with standard doses of cisplatin and etoposide. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which seems to be dose dependent.

Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163.

PURPOSE: To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response. PATIENTS AND METHODS: Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response. RESULTS: The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer. CONCLUSION: Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.

Situación nutricional de niños en contextos de pobreza de Puerto Iguazú, Misiones, Argentina / Nutritional status of poor children from Puerto Iguazú, Misiones, Argentina

Introducción. A partir del año 2002, Argentina sufrióuna agudización de su crisis socioeconómica,con 73,5 por ciento de niños pobres y más de la mitad deellos, indigentes. Desde la gestación y hasta los tresaños, las deficiencias nutricionales ocasionan secuelasirreversibles en el crecimiento y desarrollocorporal y cognitivo. El objetivo del trabajo fuevalorar el estado nutricional de niños pobres de 0 a14 años de barrios aledaños a Puerto Iguazú.Población, materiales y métodos. Estudio transversaly descriptivo, empleando el método antropométrico,sobre niños convocados por un plan de asistenciaalimentaria y de salud, durante cinco días dediciembre de 2002. Se evaluó edad, sexo, peso, talla,pliegue cutáneo tricipital, perímetro muscular ycefálico, peso al nacer y edad gestacional. Los datosse expresaron a través de variables cualitativas, informadas como proporciones. Para contrastar la diferencia de proporciones se utilizó la prueba de X2para muestras independientes.Resultados. Se valoraron 243 niños; se encontrabanpor debajo del percentilo 10 para peso/edad: 32,92 por ciento, para peso/talla: 21,5 por ciento; para talla/edad: 34,15 por ciento. El 32,61 por ciento de los niños menores de 4 años presentó perímetro cefálico disminuido. El 30,93 por ciento tenía unpeso al nacer bajo o insuficiente.Conclusiones. El porcentaje de retraso crónico delcrecimiento según la relación talla/edad supera ala deficiencia aguda de peso según peso/talla. Elbajo peso/edad predomina en los menores de 6años; la talla/edad muestra una tendencia semejante.La deficiencia aguda de peso según peso/talla es similar a partir del primer año de vida

Situación nutricional de niños en contextos de pobreza de Puerto Iguazú, Misiones, Argentina / Nutritional status of poor children from Puerto Iguazú, Misiones, Argentina

Introducción. A partir del año 2002, Argentina sufrióuna agudización de su crisis socioeconómica,con 73,5 por ciento de niños pobres y más de la mitad deellos, indigentes. Desde la gestación y hasta los tresaños, las deficiencias nutricionales ocasionan secuelasirreversibles en el crecimiento y desarrollocorporal y cognitivo. El objetivo del trabajo fuevalorar el estado nutricional de niños pobres de 0 a14 años de barrios aledaños a Puerto Iguazú.Población, materiales y métodos. Estudio transversaly descriptivo, empleando el método antropométrico,sobre niños convocados por un plan de asistenciaalimentaria y de salud, durante cinco días dediciembre de 2002. Se evaluó edad, sexo, peso, talla,pliegue cutáneo tricipital, perímetro muscular ycefálico, peso al nacer y edad gestacional. Los datosse expresaron a través de variables cualitativas, informadas como proporciones. Para contrastar la diferencia de proporciones se utilizó la prueba de X2para muestras independientes.Resultados. Se valoraron 243 niños; se encontrabanpor debajo del percentilo 10 para peso/edad: 32,92 por ciento, para peso/talla: 21,5 por ciento; para talla/edad: 34,15 por ciento. El 32,61 por ciento de los niños menores de 4 años presentó perímetro cefálico disminuido. El 30,93 por ciento tenía unpeso al nacer bajo o insuficiente.Conclusiones. El porcentaje de retraso crónico delcrecimiento según la relación talla/edad supera ala deficiencia aguda de peso según peso/talla. Elbajo peso/edad predomina en los menores de 6años; la talla/edad muestra una tendencia semejante.La deficiencia aguda de peso según peso/talla es similar a partir del primer año de vida(AU)

Situación nutricional de niños en contextos de pobreza de Puerto Iguazú, Misiones, Argentina / Nutritional status of poor children from Puerto Iguazú, Misiones, Argentina

Introducción. A partir del año 2002, Argentina sufrióuna agudización de su crisis socioeconómica,con 73,5 por ciento de niños pobres y más de la mitad deellos, indigentes. Desde la gestación y hasta los tresaños, las deficiencias nutricionales ocasionan secuelasirreversibles en el crecimiento y desarrollocorporal y cognitivo. El objetivo del trabajo fuevalorar el estado nutricional de niños pobres de 0 a14 años de barrios aledaños a Puerto Iguazú.Población, materiales y métodos. Estudio transversaly descriptivo, empleando el método antropométrico,sobre niños convocados por un plan de asistenciaalimentaria y de salud, durante cinco días dediciembre de 2002. Se evaluó edad, sexo, peso, talla,pliegue cutáneo tricipital, perímetro muscular ycefálico, peso al nacer y edad gestacional. Los datosse expresaron a través de variables cualitativas, informadas como proporciones. Para contrastar la diferencia de proporciones se utilizó la prueba de X2para muestras independientes.Resultados. Se valoraron 243 niños; se encontrabanpor debajo del percentilo 10 para peso/edad: 32,92 por ciento, para peso/talla: 21,5 por ciento; para talla/edad: 34,15 por ciento. El 32,61 por ciento de los niños menores de 4 años presentó perímetro cefálico disminuido. El 30,93 por ciento tenía unpeso al nacer bajo o insuficiente.Conclusiones. El porcentaje de retraso crónico delcrecimiento según la relación talla/edad supera ala deficiencia aguda de peso según peso/talla. Elbajo peso/edad predomina en los menores de 6años; la talla/edad muestra una tendencia semejante.La deficiencia aguda de peso según peso/talla es similar a partir del primer año de vida(AU)