Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

PURPOSE: Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety. RESULTS: The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm. CONCLUSION: This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.

Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer: efficacy, safety, and biomarker results from Chinese patients.

Overexpression of human epidermal growth factor receptor-2 (HER2) in metastatic breast cancer (MBC) is associated with poor prognosis. This single-arm open-label trial (EGF109491; NCT00508274) was designed to confirm the efficacy and safety of lapatinib in combination with capecitabine in 52 heavily pretreated Chinese patients with HER2-positive MBC. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), time to response (TTR), duration of response (DoR), central nervous system (CNS) as first site of relapse, and safety. The results showed that there were 23 patients with partial responses and 7 patients with stable disease, resulting in a CBR of 57.7%. The median PFS was 6.34 months (95% confidence interval, 4.93-9.82 months). The median TTR and DoR were 4.07 months (range, 0.03-14.78 months) and 6.93 months (range, 1.45-9.72 months), respectively. Thirteen (25.0%) patients had new lesions as disease progression. Among them, 2 (3.8%) patients had CNS disease reported as the first relapse. The most common toxicities were palmar-plantar erythrodysesthesia (59.6%), diarrhea (48.1%), rash (48.1%), hyperbilirubinemia (34.6%), and fatigue (30.8%). Exploratory analyses of oncogenic mutations of PIK3CA suggested that of 38 patients providing a tumor sample, baseline PIK3CA mutation status was not associated with CBR (P = 0.639) or PFS (P = 0.989). These data confirm that the lapatinib plus capecitabine combination is an effective and well-tolerated treatment option for Chinese women with heavily pretreated MBC, irrespective of PIK3CA status.

Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial.

OBJECTIVES: A planned interim analysis of study EGF100151 prompted early termination of enrollment based on a longer time to progression with lapatinib and capecitabine than with capecitabine alone in patients with human epidermal growth factor receptor (HER)-2(+) previously treated advanced breast cancer or metastatic breast cancer (MBC). Here, we report final analyses of overall survival. PATIENTS AND METHODS: Women with HER-2(+) MBC who progressed after regimens that included, but were not limited to, anthracyclines, taxanes, and trastuzumab, were randomized to lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m(2)) or capecitabine monotherapy (2,500 mg/m(2)) on days 1-14 of a 21-day cycle. RESULTS: At enrollment termination, 399 patients were randomized, and nine were being screened and were offered combination treatment. In total, 207 and 201 patients were enrolled to combination therapy and monotherapy, respectively. Thirty-six patients receiving monotherapy crossed over to combination therapy following enrollment termination. The median overall survival times were 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.71-1.08; p = .210). A Cox regression analysis considering crossover as a time-dependent covariate suggested a 20% lower risk for death for patients treated with combination therapy (HR, 0.80; 95% CI, 0.64-0.99; p = .043). The low incidence of serious adverse events was consistent with previously reported rates. CONCLUSIONS: Although premature enrollment termination and subsequent crossover resulted in insufficient power to detect differences in overall survival, exploratory analyses demonstrate a trend toward a survival advantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2(+) MBC.

A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.

PURPOSE: Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed. RESULTS: 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. CONCLUSION: The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.

Pooled analysis of diarrhea events in patients with cancer treated with lapatinib.

PURPOSE: To characterize diarrhea events in patients with cancer treated with lapatinib as monotherapy or in combination with capecitabine or taxanes. PATIENTS AND METHODS: Eleven clinical trials (phase I, II, or III) in patients with metastatic cancer were analyzed. Lapatinib was administered at doses ranging from 1,000 to 1,500 mg/day as monotherapy (n = 926) or in combination with capecitabine (n = 198) or taxanes (n = 687). Diarrhea events were characterized based on severity, time to onset, duration, required interventions, and clinical outcomes. RESULTS: In the pooled analysis of nine studies, diarrhea occurred in 55% of lapatinib-treated patients and 24% of patients not receiving lapatinib. All grade diarrhea occurred in 51% of patients treated with lapatinib monotherapy and 65% treated with lapatinib plus capecitabine. In a separate analysis, 48% of patients treated with lapatinib plus a taxane experienced diarrhea. Overall, most diarrhea events were grade 1/2. Grade 3 events occurred in <10% of patients and grade 4 events were rare (

Lapatinib in combination with capecitabine in the management of ErbB2-positive (HER2-positive) advanced breast cancer.

Lapatinib is an oral, reversible, dual inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and human epidermal growth factor receptor type 2 ErbB2 (HER2). Results of a phase III study comparing lapatinib plus capecitabine with capecitabine alone in women with ErbB2-overexpressing advanced breast cancer previously treated with an anthracycline, a taxane, and trastuzumab were reported early based on superiority of the combination in prolonging time to tumor progression (TTP). An updated analysis in 399 women supports the earlier findings. In this updated analysis, TTP (hazard ratio [HR] 0.57) favored lapatinib plus capecitabine. Survival trended in favor of the combination. The incidence of cardiac events was numerically higher in the combination arm (5 cases in the combination arm, 2 cases in the monotherapy arm).