Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival.

BACKGROUND: A randomized phase II study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel. Final survival analyses and updated safety results are reported. PATIENTS AND METHODS: Three hundred two patients with no previous chemotherapy for MBC were randomized to receive nab-paclitaxel 300 mg/m(2) q3w, nab-paclitaxel 100 mg/m(2) or 150 mg/m(2) the first 3 of 4 weeks (qw 3/4), or docetaxel 100 mg/m(2) q3w. The trial was powered for analyses of antitumor activity and safety. RESULTS: Treatment with nab-paclitaxel 150 mg/m(2) qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m(2) qw 3/4, nab-paclitaxel 300 mg/m(2) q3w, and docetaxel, respectively (overall P = .047). Patients receiving 150 mg/m(2)nab-paclitaxel had prolonged median OS compared with those in the 100 mg/m(2)nab-paclitaxel arm (hazard ratio, 0.575; P = .008). A trend toward a longer OS was noted in the 150 mg/m(2)nab-paclitaxel arm versus docetaxel arm (hazard ratio, 0.688). Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with docetaxel. CONCLUSIONS: Consistent with previously published efficacy results, these data suggest that 150 mg/m(2) qw 3/4 may represent the most clinically efficacious nab-paclitaxel dosing regimen for patients with no previous chemotherapy for MBC. A phase III trial confirming these results would be necessary and prudent before widespread adoption of the 150 mg/m(2) dose in clinical practice.

First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study.

PURPOSE: To investigate whether sunitinib plus docetaxel improves clinical outcomes for patients with human epidermal growth factor receptor 2 (HER2)/neu-negative advanced breast cancer (ABC) versus docetaxel alone. PATIENTS AND METHODS: In this phase III study, patients were randomly assigned to open-label combination therapy (sunitinib 37.5 mg/d, days 2 to 15 every 3 weeks; and docetaxel 75 mg/m(2), day 1 every 3 weeks) or monotherapy (docetaxel 100 mg/m(2) every 3 weeks). Progression-free survival (PFS) was the primary end point. RESULTS: Two hundred ninety-six patients were randomly assigned to combination therapy, and 297 patients were assigned to monotherapy. Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy, respectively (hazard ratio, 0.92; one-sided P = .265). The objective response rate (ORR) was significantly higher with the combination (55%) than with monotherapy (42%; one-sided P = .001). Duration of response was similar in both arms (7.5 months with the combination v 7.2 months with monotherapy). Median overall survival (OS) times were 24.8 and 25.5 months with combination therapy and monotherapy, respectively (one-sided P = .904). There were 107 deaths with the combination and 91 deaths with monotherapy. The frequency of common adverse events (AEs) was higher with the combination, as were treatment discontinuations caused by AEs. CONCLUSION: The combination of sunitinib plus docetaxel improved ORR but did not prolong either PFS or OS compared with docetaxel alone when given to an unselected HER2/neu-negative cohort as first-line treatment for ABC. Sunitinib combination therapy may also have resulted in AEs that yield an unfavorable risk-benefit ratio. The sunitinib-docetaxel regimen evaluated in this study is not recommended for further use in ABC.

A dose finding study of weekly and every-3-week nab-Paclitaxel followed by carboplatin as first-line therapy in patients with advanced non-small cell lung cancer.

INTRODUCTION: This nonrandomized study aimed to identify the optimal dose of every-3-week (q3w) and weekly nab-paclitaxel plus q3w carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) for a phase 3 trial. METHODS: Previously untreated patients with advanced NSCLC enrolled sequentially into seven cohorts (25 patients/cohort, N = 175). Cohorts 1 to 4 and 5 to 7 received nab-paclitaxel q3w and weekly, respectively. Patients were evaluated for efficacy and safety. RESULTS: The most common treatment-related > or = grade 3 adverse events were neutropenia (60%), neuropathy (19%), fatigue (9%), and thrombocytopenia (29%) (no grade 4 neuropathy or fatigue). A 100 mg/m(2) weekly nab-paclitaxel produced less serious adverse events than other doses/schedules. Response rate (RR) was greater in the weekly versus q3w cohorts (47% vs. 30%). Median progression-free survival (PFS) ranged from 4.8 to 6.9 months, and overall survival (OS) ranged from 8.3 to 15.0 months (all cohorts). Patients receiving 100 mg/m(2) weekly nab-paclitaxel achieved 48% RR with 6.2 and 11.3 months of PFS and OS, respectively. In a retrospective analysis, patients with nonsquamous cell carcinoma receiving weekly nab-paclitaxel had significantly improved RR (59.4% vs. 23.5%, respectively, p = 0.003), and >2 months longer PFS and OS compared with q3w schedule. In patients with squamous cell carcinoma, the q3w schedule significantly increased PFS by 3 months (p = 0.014) and OS by >2 months (no difference in RR) compared with the weekly schedule. CONCLUSION: nab-Paclitaxel plus carboplatin is an effective therapy for advanced NSCLC. Based on favorable efficacy and safety profiles, a phase 3, randomized, multicenter study comparing 100 mg/m(2) weekly nab-paclitaxel plus q3w carboplatin to solvent-based paclitaxel plus carboplatin has enrolled patients.

Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer.

PURPOSE: The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment. RESULTS: Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone. CONCLUSION: When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer.

PURPOSE: In patients with metastatic breast cancer (MBC), nab-paclitaxel produced significantly higher antitumor activity compared with patients who received solvent-based paclitaxel. This phase II study examined the antitumor activity and safety of weekly and every 3 week (q3w) nab-paclitaxel compared with docetaxel as first-line treatment in patients with MBC. PATIENTS AND METHODS: In this randomized, multicenter study, patients (N = 302) with previously untreated MBC received nab-paclitaxel 300 mg/m(2) q3w, 100 mg/m(2) weekly, or 150 mg/m(2) weekly or docetaxel 100 mg/m(2) q3w. RESULTS: nab-Paclitaxel 150 mg/m(2) weekly demonstrated significantly longer progression-free survival (PFS) than docetaxel by both independent radiologist assessment (12.9 v 7.5 months, respectively; P = .0065) and investigator assessment (14.6 v 7.8 months, respectively; P = .012). On the basis of independent radiologist review, both 150 mg/m(2) (49%) and 100 mg/m(2) (45%) weekly of nab-paclitaxel demonstrated a higher overall response rate (ORR) than docetaxel (35%), but this did not reach statistical significance. This trend was supported by statistically significant investigator ORR for both weekly nab-paclitaxel doses versus docetaxel. nab-Paclitaxel q3w versus docetaxel was not different for PFS or ORR. On the basis of both the independent radiologist and investigator review, disease control rate was significantly higher for patients receiving either dose of weekly nab-paclitaxel compared with docetaxel. Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms. The frequency and grade of peripheral neuropathy were similar in all arms. CONCLUSION: This randomized study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel, with a statistically and clinically significant prolongation of PFS (> 5 months) in patients receiving nab-paclitaxel 150 mg/m(2) weekly compared with docetaxel 100 mg/m(2) q3w.

Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study.

PURPOSE: To determine whether the combination of pegylated liposomal doxorubicin (PLD) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy. PATIENTS AND METHODS: This international, phase III study randomly assigned 751 patients to receive either docetaxel 75 mg/m(2) (n = 373) or PLD 30 mg/m(2) followed by docetaxel 60 mg/m(2) every 21 days (n = 378) and continued until disease progression or prohibitive toxicity. The primary end point was time to progression (TTP). Secondary end points were overall survival (OS), objective response rate (ORR), cardiac toxicity, and safety. RESULTS: Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months (hazard ratio [HR] = 0.65; 95% CI, 0.55 to 0.77; P = .000001) and the ORR from 26% to 35% (P = .0085). OS was similar between the two groups (HR = 1.02; 95% CI, 0.86 to 1.22). The incidence of grade 3 or 4 adverse events were similar (78% v 72%), although a higher incidence of hand-foot syndrome (24% v 0%) and mucositis/stomatitis (12% v 1%) were observed in the PLD-docetaxel combination. Protocol-defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5% and 1% in both treatment arms, respectively. CONCLUSION: The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity, although mucocutaneous toxicity was more common.