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in Breast Cancer The following is an invited report based on abstracts presented at recent oncology meetings. Bevacizumab With Docetaxel or Docetaxel With Placebo as First-Line Therapy in Locally Recurrent or Metastatic Breast Cancer: The AVADO Study The AVADO study, a randomized, double-blind, placebo-controlled, phase III trial, evaluated the combination of bevacizumab plus docetaxel as first-line therapy in patients with locally recurrent or metastatic breast cancer. A previous study had demonstrated superior progression-free survival (PFS) for bevacizumab plus paclitaxel compared with paclitaxel alone. Patient eligibility criteria included HER2-negative, inoperable locally recurrent or metastatic breast cancer; no prior chemotherapy for advanced disease; ECOG PS 0-1; adequate left ventricular ejection fraction (LVEF), and no CNS metastases. From March 2006 to April 2007, researchers in 24 countries randomized 736 patients to docetaxel 100 mg/m2 plus placebo or docetaxel plus bevacizumab at either 7.5 mg/kg or 15 mg/kg. Docetaxel was administered every 3 weeks for up to 9 cycles. Bevacizumab or placebo was administered every 3 weeks until disease progression or unacceptable toxicity. PFS was the primary end point. With a median follow-up of approximately 11 months, both bevacizumab-containing arms demonstrated statistically significantly superior PFS compared with docetaxel alone (bevacizumab 7.5 mg/kg, P=0.0035; bevacizumab 15 mg/kg; P=0.0001). The overall response rate (CR + PR) was 44.4% in the docetaxel alone arm vs 55.2% (P=0.0295) and 63.1% (P=0.0001) in the bevacizumab 7.5 mg/kg and 15 mg/kg arms, respectively. Grade ≥3 adverse events for the docetaxel alone, bevacizumab 7.5 mg/kg, and bevacizumab 15 mg/kg arms were 67.0%, 74.8%, and 74.1%, respectively, and included GI perforation 0.9%, 0.4%, and 0.4% and febrile neutropenia 12.0%, 15.2%, and 16.6%, respectively. Overall survival rate data were immature at the time of the report. Results indicate that both doses of bevacizumab in combination with docetaxel significantly improved PFS and response rate when compared with docetaxel alone. Safety results were comparable in the two bevacizumab arms, and although toxicities were slightly increased relative to the control group, no new safety concerns emerged. Miles D, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA1011. By Beverly Moy, MD, MPHTrends 8 The American Journal of Hematology/Oncology A Phase III Study of Capecitabine vs Capecitabine Plus Trastuzumab in HER2+ Patients With Metastatic Breast Cancer That Progressed During Trastuzumab Treatment (GBG 26/BIG 3-05) Agreement is lacking on whether trastuzumab treatment should be continued beyond disease progression. The German Breast <strong>Group</strong> (GBG) and the Breast International <strong>Group</strong> (BIG) conducted a treatment beyond progression (TBP) phase III study, GBG 26/BIG 3-05, of trastuzumab therapy. Eligible patients had HER2+, locally advanced or metastatic breast cancer that progressed during trastuzumab treatment with or without adjuvant and/or first-line metastatic chemotherapy. Patients were prospectively randomized to receive either capecitabine (2500 mg/m 2 on days 1-14, every 21 days) or capecitabine plus continuation of trastuzumab (6 mg/kg, every 3 weeks). The primary end point was time to progression. The slowly accruing trial was closed prematurely after the registration of lapatinib. Between January 2004 and May 2007, a total of 156 patients were randomized. Of these, 78 received capecitabine, and 78 received capecitabine plus trastuzumab. Patients were stratified according to previous treatment: taxane/trastuzumab as first-line therapy (111 patients), taxanes/trastuzumab as adjuvant therapy (3 patients), trastuzumab alone or without taxanes as first-line treatment (42 patients). Of note, 75 patients (48.1%) had received anthracyclines. Visceral metastasis was observed in 119 patients (76.3%). At the time of the report, median follow-up was 11.8 months, and analysis had revealed a PFS of 5.6 months with 53 events in the capecitabine group and 8.5 months with 48 events in the capecitabine plus trastuzumab group (HR=0.71). In patients receiving capecitabine or capecitabine plus trastuzumab, respectively, brain metastases were seen in 4 patients vs 7 patients; overall survival was 19.9 months with 31 events vs 20.3 months with 26 events (HR=0.79); crude response rates were 24.6% vs 49.1%; and primary progressions were seen in 26.3% vs 16%. Reported grade 3/4 toxicities for capecitabine and capecitabine plus trastuzumab, respectively, included neutropenia, 3.3% vs 6.3%; febrile neutropenia, 0% vs 0%; vomiting, 6.0% vs 1.6%; diarrhea, 20.9% vs 14.8%;
hand-foot syndrome, 23.9% vs 31.1%; and cardiac, 2.9% vs 4.9%. There were no therapy-related deaths. The preliminary results of this TBP study suggest similar toxicity but higher efficacy for continuing trastuzumab beyond progression when second-line chemotherapy with capecitabine is initiated. The final efficacy analysis was scheduled to be released at a later date. Von Minckwitz G, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1025. Anastrozole Plus Gefitinib Compared With Anastrozole Plus Placebo in Postmenopausal Women With Hormone Receptor–Positive Metastatic Breast Cancer Preclinical data indicate the presence of crosstalk between growth factor receptor pathways and the estrogen receptor. Thus, a technique to overcome hormonal resistance might involve inhibition of both epidermal growth factor receptor and estrogen receptor signaling. This phase II multicenter, double-blind, randomized trial was designed to evaluate the efficacy and tolerability of anastrozole plus gefitinib vs anastrozole plus placebo in postmenopausal women with newly diagnosed hormone receptor–positive metastatic breast cancer. Ninety-four patients were randomized to receive anastrozole 1 mg/day plus either gefitinib 250 mg/day or placebo (50 women received anastrozole plus placebo; 43 received anastrozole plus gefitinib; one died prior to treatment). PFS was the primary end point. The secondary end points included objective response rate, clinical benefit rate (defined as objective response or stable disease ≥24 weeks), overall survival, safety, and tolerability. Enrollment was stopped early because of slow recruitment, and fewer statistical analyses were performed. However, a marked advantage in PFS was seen for anastrozole plus gefitinib over anastrozole plus placebo (median 14.5 vs 8.2 months). Complete response was noted in 1 patient in each group. A numerical advantage in clinical benefit rate was seen for anastrozole plus gefitinib (21 patients, 49%) vs anastrozole plus placebo (17 patients, 34%). There were no unexpected safety or tolerability findings. Treatment-related adverse events, mostly mild, were seen in 79% of patients in the anastrozole plus gefitinib arm vs 38% in the anastrozole plus placebo arm. Death occurred in 2 patients in the anastrozole plus gefitinib arm and 1 patient in the anastrozole plus placebo arm; none were considered related to treatment. The authors concluded that anastrozole plus gefitinib was well tolerated and showed a marked advantage in PFS when compared with anastrozole plus placebo in postmenopausal women with newly diagnosed hormone receptor–positive metastatic breast cancer. They also reported that the data suggest the need for further investigation of this combination. Cristofanilli M, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1012. Lapatinib Alone or in Combination With Trastuzumab in Heavily Pretreated HER2+ Metastatic Breast Cancer That Progressed on Trastuzumab Therapy Preclinical data indicate possible synergy between trastuzumab and lapatinib, an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab. In this randomized phase III study, researchers evaluated lapatinib alone and in combination with trastuzumab in women with HER2+ metastatic breast cancer who had experienced progressive disease while on trastuzumab therapy. Women with these characteristics were eligible for participation if they had also received prior anthracycline and taxane therapy and had measurable lesions or bone-only disease. Patients were first stratified according to hormone receptor status and the presence of visceral or nonvisceral disease, then randomized to receive either lapatinib (1500 mg qd) or lapatinib (1000 mg qd) plus trastuzumab (2 mg/kg weekly after a 4 mg/kg loading dose). The primary end point was PFS (determined by investigator assessment); secondary end points were clinical benefit rate at 24 weeks, response rate, and overall survival. Patients who progressed while taking lapatinib were allowed to cross over to the lapatinib plus trastuzumab arm. Of the 296 patients who were randomized, all had received prior trastuzumab therapy and a median of 6 prior chemotherapy regimens. The addition of trastuzumab to lapatinib significantly improved PFS (median 8.4 weeks for lapatinib vs 12.0 weeks for lapatinib plus trastuzumab; P=0.029) and clinical benefit rate (13.2% for lapatinib vs 25.2% for lapatinib plus trastuzumab; P=0.020). Response rate and overall survival were similar in the two arms. In general, both treatment arms were well tolerated. Grade 1/2 diarrhea was higher in the lapatinib plus trastuzumab arm (53% vs 41%); acneiform rash was more common in the lapatinib alone arm and was likely caused by the higher lapatinib dose. An asymptomatic decline in LVEF (>20%, and below LLN) occurred in 5% of the patients in the combination arm and in 2% of patients in the lapatinib alone arm. One patient in the lapatinib plus trastuzumab arm died; death was attributed to cardiac toxicity. This is the largest study of two targeted agents in HER2+ metastatic breast cancer and the first to demonstrate the synergy of lapatinib plus trastuzumab in a phase III trial. The authors concluded that the combination of lapatinib plus trastuzumab in patients progressing on trastuzumab-based therapy improved clinical outcome without major changes in the side effect profile. The authors also referred to the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study, in which the role of combined anti-HER2 therapy plus chemotherapy is being studied in less heavily pretreated patients with early-stage disease. O’Shaughnessy J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 1015. November 2008 • Vol 7 • Supplement 5 9
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