Trastuzumab Superior to Lapatinib in Frontline HER2-Positive Metastatic Breast Cancer

Treatment with lapatinib plus a taxane was associated with a shorter duration of progression-free survival compared with trastuzumab plus a taxane as a frontline therapy for patients with HER2-positive metastatic breast cancer.

Karen A. Gelmon, MD

Treatment with lapatinib plus a taxane was associated with a shorter duration of progression-free survival (PFS) compared with trastuzumab plus a taxane as a frontline therapy for patients with HER2-positive metastatic breast cancer, according to the final analysis of the MA.31 trial published in theJournal of Clinical Oncology.

The phase III open-label study examined lapatinib or trastuzumab with either paclitaxel or docetaxel. Patients with central nervous system (CNS) metastases at 4 weeks prior to randomization were excluded from the investigation. The primary endpoint was PFS, with secondary outcomes focused on overall survival (OS) and overall response rate (ORR).

"The NCIC CTG MA.31 trial was the first head-to-head comparison to our knowledge of trastuzumab and lapatinib in locally determined metastatic HER2-positive breast cancer, with separate analysis for centrally determined HER2-positive disease," the authors of the study wrote. "The combination of lapatinib and taxane was inferior for PFS, with OS results in the centrally confirmed HER2-positive population directionally similar to PFS results."

Efficacy and Safety Findings Favor Trastuzumab

In the study, 652 patients tested HER2-positive by local assessment, with 537 positive by central review. At a median follow-up of 21.5 months, the PFS was 9.0 months with lapatinib versus 11.3 months with trastuzumab (HR = 1.37; 95% CI, 1.13-1.65;P= .001). In patients with HER2-positive tumors by central review, the median PFS was 9.1 months with lapatinib compared with 13.6 months with trastuzumab (HR = 1.48; 95% CI, 1.20-1.83;P< .001).

In the full population, more deaths were observed in the lapatinib arm compared with trastuzumab; although a median OS was not reached. In those with centrally confirmed HER2 status, patients receiving lapatinib had a worse OS than with trastuzumab (HR = 1.47; 95% CI, 1.03-2.09;P= .03).

The ORR in the full population was 54% and 55%, for the lapatinib and trastuzumab, respectively. By central review, the ORR was 75.8% with lapatinib versus 75.9% for trastuzumab.

Grade 3/4 diarrhea and rash were more commonly observed in the lapatinib arm than with trastuzumab (P<.001). Additionally, per quality of life (QOL) scoring (EORTC QLQ-C30) those treated with trastuzumab had a lower mean score at 12 weeks compared with lapatinib (0.30 vs 2.45;P= .57).

CNS Findings Intriguing

"There was increased frequency of diarrhea and rash in the lapatinib arm, both expected toxicities. Decreases of ≥ 20% in LVEF, although infrequent, were seen only in the trastuzumab arm," the authors explained. "EORTC QLQ C-30 global QOL was not significantly different between arms at 12 weeks, although patients receiving lapatinib had significantly worse toxicity for some instrument scales, with increased diarrhea, appetite loss, social functioning, and skin rash."In the full population of the study, 18% of patients in the lapatinib arm and 24% of patients in the trastuzumab arm progressed with CNS metastases. The incidence of CNS metastases was 20% with lapatinib versus 28% with trastuzumab. The HR for CNS metastases as the first site of progression disease for lapatinib versus trastuzumab was 1.13 (95% CI, 0.74-1.73;P= .58).

"The frequency of CNS metastases was 6% to 8% lower with lapatinib; however, this difference was nonsignificant, possibly because of the low rate of CNS scans at progressive disease despite being mandated by the protocol, low frequency of CNS events, size of the study, or progressive disease in other sites," the authors wrote. "Other studies may provide further information about the activity of lapatinib in this setting."

Gelmon KA, Boyle FM, Kaufman B, et al. Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2—positive advanced breast cancer: final results of NCIC CTG MA.31.J Clin Oncol. 2015;33(14):1574-1583.