A Single-Arm Phase II Trial of First-Line Paclitaxel in Combination with Lapatinib in HER2-Overexpressing Metastatic Breast Cancer

Abstract

Introduction: Lapatinib, an orally active tyrosine kinase inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and ErbB2 (HER2), has activity as monotherapy and in combination with chemotherapy in HER2-overexpressing metastatic breast cancer (MBC). Methods: This phase II single-arm trial assessed the safety and efficacy of first-line lapatinib in combination with paclitaxel in previously untreated patients with HER2-overexpressing MBC. The primary endpoint was the overall response rate (ORR). Secondary endpoints were the duration of response (DoR), time to response, time to progression, progression-free survival (PFS), overall survival, and the incidence and severity of adverse events. All endpoints were investigator- and independent review committee (IRC)-assessed. Results: The IRC-assessed ORR was 51% (29/57 patients with complete or partial response) while the investigator-assessed ORR was 77% (44/57). As per the IRC, the median DoR was 39.7 weeks, and the median PFS was 47.9 weeks. The most common toxicities were diarrhea (56%), neutropenia (44%), rash (40%), fatigue (25%), and peripheral sensory neuropathy (25%). Conclusions: First-line lapatinib plus paclitaxel for HER2-overexpressing MBC produced an encouraging ORR with manageable toxicities. This combination may be useful in first-line treatment for patients with HER2-overexpressing MBC and supports the ongoing evaluation of this combination as first-line therapy in HER2-overexpressing MBC.

Mechanisms of lapatinib resistance in HER2-driven breast cancer

“…In the clinical setting, the combination of lapatinib and capecitabine is indicated for the treatment of patients with advanced HER2-postive (HER2+) breast cancer in progression after treatment with chemotherapy plus trastuzumab [9]. Combined with paclitaxel, lapatinib is active as first-line treatment [10]. Unfortunately, some patients are constitutively resistant to lapatinib treatment and, even in responders, the disease often progresses because of the selection of tumor cells that have acquired resistance to the drug [11].…”

Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

“…Lapatinib is an orally active dual TKI that has been used in combination with capecitabine or letrozole for the treatments of patients with advanced breast cancer (25). We previously reported that lapatinib inhibited the function of ABCB1, ABCG2 and MRP10 (26,27).…”

A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer

“…22 Several other studies have also reported a rash incidence in excess of 40% in patients receiving lapatinib plus a taxane. 5,23–26 Although rash is a commonly reported adverse event associated with lapatinib, it appears that the schedule of the coadministered taxane might have an influence on the incidence and severity of this toxicity. In our study, we observed a greater incidence of rash with lapatinib and paclitaxel given every 2 weeks (DD) compared with the reported incidence using the weekly paclitaxel schedule.…”