Weighing the options for human epidermal growth factor receptor 2-directed therapy in metastatic breast cancer

Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control. Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial morbidity and mortality. The two articles that accompany this editorial directly address several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n 537; HR, 1.47; P .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30), was similar between arms, although expected differences were seen that favored trastuzumab for outcomes such as diarrhea and rash. Rates of therapy discontinuation for reasons other than progression or death were similar between arms. The CEREBEL trial, as reported by Pivot et al, also compared trastuzumab versus lapatinib, this time with a capecitabine backbone. In contrast with MA.31, patients could be enrolled either in the firstline setting or in a subsequent line of therapy. Just under half of patients who were included in CEREBEL had not received any previous therapy for metastatic breast cancer. As with MA.31, although objective response rates were similar between arms, patients who were randomly assigned to the trastuzumab-containing arm experienced longer PFS and OS compared with patients who were randomly assigned to the lapatinib-containing arm (median PFS, 6.6 v 8.1 months; HR, 1.30; 95% CI, 1.04 to 1.64; median OS, 22.7 v 27.3 months; HR, 1.34, 95% CI, 0.95 to 1.90). In placing these data into context, at least two issues come to mind: the patient populations enrolled, and data regarding other anti-HER2 agents that have been developed since these trials were initiated. The patient populations in both studies were notable: in MA.31, less than 20% of patients had received previous adjuvant or neoadjuvant trastuzumab, and 43% of patients presented with de novo metastatic disease. In CEREBEL, the patient population included 18% with de novo disease; only 28% of patients had received adjuvant trastuzumab, and only 35% had previously received trastuzumab for metastatic disease. Results of the studies are generally consistent with preoperative data from several studies, including CALGB (Cancer and Leukemia Group B) study 40601, in which lapatinibtaxane was inferior to trastuzumab-taxane with respect to the primary end point of pathologic complete response in newly diagnosed, trastuzumab-naive patients with clinical stage II to III, HER2positive breast cancer. To what extent MA.31 and CEREBEL can be generalized to a population of first-line patients with metastatic disease who have relapsed despite adjuvant trastuzumab is somewhat unclear. Indeed, in a hypothesis-generating subset analysis of CEREBEL, the benefit of trastuzumab-capecitabine compared with lapatinib-capecitabine was restricted to patients without previous exposure to trastuzumab or chemotherapy. PFS did not differ by arm among patients with previous trastuzumab exposure or those treated in the second-line setting or beyond. Since these trials were initiated, two new agents have gained regulatory approval for HER2-positive metastatic breast cancer: pertuzumab and T-DM1. Given the superiority of trastuzumab-taxane compared with lapatinib-taxane in MA.31, and the superiority of pertuzumab-trastuzumab-taxane compared with trastuzumab-taxane in CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1