Safety profile of Pertuzumab with Trastuzumab and Docetaxel in patients from Asia with human epidermal growth factor receptor 2-positive metastatic breast cancer: results from the phase III trial CLEOPATRA.

INTRODUCTION: We report detailed safety analyses by geographic region from the phase III study CLEOPATRA with pertuzumab, trastuzumab, and docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer. PATIENTS AND METHODS: Patients received pertuzumab/placebo at 840 mg in cycle 1 and 420 mg in subsequent cycles, and trastuzumab at 8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles; docetaxel was initiated at 75 mg/m(2). All study drugs were given intravenously, 3 times weekly. RESULTS: Docetaxel dose reductions below 75 mg/m(2) were more common in patients from Asia (47.0%) than other regions (13.4%); docetaxel dose escalations to 100 mg/m(2) were less frequent in Asia (2.4%) than other regions (18.7%). Rates of edema (26.1% and 5.4% for Asia and other regions, respectively), myalgia (42.3%, 14.7%), nail disorder (39.9%, 15.1%), febrile neutropenia (18.6%, 7.1%), upper respiratory tract infection (25.7%, 10.2%), decreased appetite (47.0%, 19.1%), and rash (44.3%, 22.0%) were at least twice as high in Asia as in other regions. Adverse events did not result in a reduction in the median number of study treatment cycles administered in patients from Asia. Efficacy analyses per region showed hazard ratios similar to those of the whole intention-to-treat (ITT) population for progression-free survival (ITT: 0.63; Asia: 0.68; other regions: 0.61) and overall survival (ITT: 0.66; Asia: 0.64; other regions: 0.66). CONCLUSION: Despite a higher proportion of docetaxel dose reductions in patients from Asia, survival benefits were comparable between regions. The benefit-risk profile of pertuzumab, trastuzumab, and docetaxel supports this regimen as the first-line therapy for patients with HER2-positive metastatic breast cancer from all geographic regions.

Epidermal growth factor receptor mutation analysis in previously unanalyzed histology samples and cytology samples from the phase III Iressa Pan-ASia Study (IPASS).

OBJECTIVES: Epidermal growth factor receptor (EGFR) mutation testing is standard practice after lung adenocarcinoma diagnosis, and provision of high-quality tumor tissue is ideal. However, there are knowledge gaps regarding the utility of cytology or low tumor content histology samples to establish EGFR mutation status, particularly with regard to the proportion of testing performed using these sample types, and the lack of an established link with efficacy of treatment. METHODS: The randomized phase III Iressa Pan-ASia Study (IPASS; ClinicalTrials.gov identifier NCT00322452) of first-line gefitinib versus chemotherapy analyzed samples meeting preplanned specifications (n=437 evaluable for EGFR mutation; n=261 mutation-positive). This supplementary analysis assessed tumor content and mutation status of histology (n=99) and cytology samples (n=116) which were previously unanalyzed due to sample quality, type, and tumor content (<100 cells). Objective response rate (ORR) and change in tumor size with gefitinib treatment were assessed. RESULTS: EGFR mutation testing was successful in 80% and 19% of previously unanalyzed histology and cytology samples, respectively. Mutations were detected in 54 tumors previously described as mutation-unknown (histology, n=45; cytology, n=9). ORRs in mutation-positive cytology (83%) and histology (74%) subgroups were consistent with previous analyses (71%). Tumor size decrease was consistent across previously analyzed and unanalyzed samples (all mutation subgroups), with less consistency across ORRs in mutation-negative cytology (16%) and histology (25%) subgroups versus the previous analysis (1%). CONCLUSIONS: Histology samples with low tumor content and cytology samples can be used for EGFR mutation testing; patients whose mutation status was confirmed using these sample types achieved a response to treatment consistent with those confirmed using high-quality histology samples. Better sample quantity/quality can potentially reduce false-negative results.

Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial.

PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments. RESULTS: There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed. CONCLUSION: This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.

Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes.

Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were randomized to ixabepilone (40 mg/m(2) intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m(2) on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a median survival of 12.9 months compared to 11.1 months for patients receiving capecitabine alone (HR = 0.9; 95%CI: 077-1.05; P = 0.19). This observed increase in median OS favored the combination; however, the difference was not statistically significant. Predefined subset analyses showed a clinically meaningful increase in OS in KPS 70-80 patients receiving ixabepilone plus capecitabine (HR = 0.75; 95% CI: 0.58-0.98). Ixabepilone plus capecitabine did not show a significant improvement in survival compared to capecitabine alone in patients with MBC resistant to anthracyclines and taxanes. The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup.

Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer.

Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.

Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment.

PURPOSE: Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. RESULTS: Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. CONCLUSION: Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.

Multicenter, randomized trial of ramosetron plus dexamethasone versus ramosetron alone in controlling cisplatin-induced emesis.

GOALS: To establish whether the combination of a corticosteroid (dexamethasone) and the newer serotonin-3 (5-HT(3)) receptor antagonist ramosetron is superior to ramosetron alone in controlling cisplatin-induced emesis. PATIENTS AND METHODS: A total of 283 patients aged 18-75 years with confirmed malignant disease who were scheduled to receive cisplatin > or =50 mg/m(2) with or without other antineoplastic agents were randomized to intravenous treatment with either ramosetron 300 microg plus dexamethasone 20 mg ( n=149) or ramosetron 300 microg alone ( n=134) given 30 min prior to cisplatin infusion. If vomiting occurred in the following 24 h, patients in both groups received an intravenous rescue dose of ramosetron 300 microg. Subsequently, on days 2 and 3, treatment was continued orally with either ramosetron 100 microg once daily plus dexamethasone 8 mg twice daily, or ramosetron 100 microg once daily. MAIN RESULTS: During the first 24 h after cisplatin infusion, significantly more patients receiving combination therapy had a complete response (no nausea or vomiting or requirement for rescue therapy) than those receiving ramosetron alone (68% vs 54%, respectively; P=0.034), and significantly fewer patients needed a rescue dose of ramosetron (22% vs 34%, respectively; P=0.032). In addition, the percentages of patients with no nausea and no vomiting were significantly greater in the ramosetron plus dexamethasone group than in the ramosetron-alone group at both 24 h and 72 h after cisplatin administration. CONCLUSIONS: The antiemetic efficacy of ramosetron in cancer patients receiving highly emetogenic cisplatin chemotherapy is significantly enhanced by its use in combination with dexamethasone.