To Evaluate Efficacy And Safety Of Lapatinib In Combination With Paclitaxel In Subjects With HER-2 Amplified Metastatic Breast Cancer

Objective:HER-2 overexpression is associated with resistance to hormo- therapy or chemotherapy and increase the risk of recurrence and death. Now target therapy is becoming a key point for breast cancer with HER-2 over- expression. Lapatinib is a novel dual tyrosine kinase inhibitor (TKI) of HER-1 and HER-2. This article is to evaluate and compare efficacy and safety of Lapatinib (GW572016) in Combination with Paclitaxel versus Paclitaxel plus placebo in Subjects with HER-2 amplified metastatic breast cancer. Also to evaluate efficacy and safety of monotherapy Lapatinib for subjects who are on paclitaxel .Method: The clinical data of 32 subjects enrolled from Feb.2006 to Mar.2009 that collected from the international multicenture clinical trial of EGF104535 are prospectively reviewed, to evaluate and compare efficacy and safety of Lapatinib (GW572016) in Combination with Paclitaxel (combination-therapy) versus Paclitaxel plus placebo (control) in Subjects with HER-2 amplified metastatic breast cancer. These subjects are collected from first Affiliated Hospital of Dalian Medical University, the second Affiliated Hospital of Dalian Medical University and Shandong Tumor Hospital. Cohort combination-therapy enrolled 15,cohort control enrolled 17. 32 subjects are randomized, double-mind to receive paclitaxel 80 mg/m2 IV weekly for three weeks, then have a rest for a week and oral Lapatinib 1500 mg once daily, or placebo once daily. All of the subjects accept paclitaxel no more than 6 cycles. The subjects of control includes an open extension with Lapatinib 1500mg once daily, 8 weeks as a cycle. The efficacy is evaluated according to RECIST (response evaluation criteria in solid tumor) every 8 weeks and safety according to NCI-CTCAEv3.0(common terminology criteria of adverse events v3.0)every 8 weeks.Result: 1.Based on The Intent-to-Treat (ITT) population and RECIST, there are 15 subjects in combination-therapy: Complete Response (CR) 2, Partial Response (PR) 7, Stable Disease (SD≥24 weeks)1, Progressive Disease (PD) 5. Response Rate (RR) 60%, Disease Control Rate(DCR)66.6%; Cohort control: CR 0, PR 4, SD 1, PD 12, RR 23.5%, DCR 29.4%. Statistical test show that RR and DCR of combination-therapy are higher than Cohort control, also have statistical significance. 2. Median TTP of combination- therapy is longer than cohort control, 37.4 weeks vs 24 weeks (P=0.021), have statistical significance.3. Most common adverse events of two cohorts are neutropenia (73%vs82%), alopecia (46%vs47%), rash (46%vs23%, P=0.04), diarrhea ( 53%vs11%,P=0.015) , and so on. Rash and diarrhea occurred more often in cohort combination-therapy, have statistical significance, subjects can tolerate them. 4.17 subjects accepted Lapatinib after paclitaxel failed, CR 1, PR 2, SD 2, PD 12, RR 17.6%. DCR 29.4%, TTP 21.8 weeks. The common adverse events of Lapatinib are rash(41%), diarrhea (35%), and so on, all are well tolerated.Conclusion:1. The efficacy of combination-therapy is better than cohort control, RR 60%,DCR 66.6%, Median TTP37.4 weeks,all of them are higher than cohort control obviously.2. Most common adverse events of combination-therapy are neutropenia (73%), alopecia (46 cohort control %), rash (46%), diarrhea (53%), and so on, the safety is comparable to cohort control.3. Subjects can receive a good efficacy with Lapatinib after paclitaxel failed: RR 17.6%. DCR 29.4%, TTP 21.8 weeks.4. The chief adverse events of Lapatinib are rash(41%), diarrhea (35%), and so on, most of them are gradeⅠ/Ⅱ.