Dual HER2 Inhibition Plus Aromatase Inhibitor in Metastatic Breast Cancer

Key Points

  • The combination of lapatinib, trastuzumab, and an aromatase inhibitor was associated with improved progression-free survival vs trastuzumab plus an aromatase inhibitor.
  • The objective response rate was higher in the triple-combination group. 

The phase III ALTERNATIVE trial has shown progression-free survival benefit with the addition of lapatinib (Tykerb) to trastuzumab (Herceptin) and an aromatase inhibitor among postmenopausal women with HER2-positive, hormone receptor–positive metastatic breast cancer. These findings were reported in the Journal of Clinical Oncology by Johnston et al.

Study Details

In the open-label trial, 355 patients were enrolled from 112 sites in 29 countries by the data cutoff (March 2016) defined by the required number of progression-free survival events. Patients had received prior endocrine therapy and prior neoadjuvant or first-line trastuzumab plus chemotherapy. Patients were randomized 1:1:1 to receive lapatinib plus trastuzumab (n = 120), trastuzumab (n = 120), or lapatinib (n = 118), each with the investigator’s choice of aromatase inhibitor. Randomization was stratified by the aromatase inhibitor used (steroidal or nonsteroidal) and prior use of trastuzumab.

Lapatinib was given at 1,000 mg/d in the lapatinib-plus-trastuzumab group and at 1,500 mg/d in the lapatinib group. Trastuzumab was given at a loading dose of 8 mg/kg followed by maintenance at 6 mg/kg every 3 weeks in both the combination and trastuzumab groups. Investigator’s choice of aromatase inhibitor included letrozole at 2.5 mg/d, anastrozole at 1 mg/d, or exemestane at 25 mg/d.  The primary endpoint was investigator-assessed progression-free survival for the combination vs trastuzumab group in the intent-to-treat population; the analysis was performed when 137 events had occurred in the combination and trastuzumab groups.

Progression-Free Survival

Median progression-free survival was 11.0 months in the combination group vs 5.7 months in the trastuzumab group (hazard ratio [HR] = 0.62, P = .0064). A consistent benefit of combination treatment was observed across predefined subgroups. Median progression-free survival in the lapatinib group was 8.3 months (HR vs trastuzumab group = 0.71, P = .0361).

Overall response rates in the combination, trastuzumab, and lapatinib groups were 31.7%, 13.7%, and 18.6%, with median durations of response of 13.9, 8.3, and 11.1 months, respectively. Overall survival data were immature at the time of analysis; median overall survival was 46.0, 40.0, and 45.1 months in the 3 groups.

Adverse Events

The most common adverse events of any grade were diarrhea (69% in the combination group, 9% in the trastuzumab group, and 51% in the lapatinib group); rash (36%, 2%, and 28%); nausea (22%, 9%, and 22%); and paronychia (30%, 0%, and 15%). Grade 3 or 4 adverse events occurred in 34%, 22%, and 32% of patients; individual adverse events occurring in > 5% of patients were grade 3 diarrhea in 13% of the combination group and 6% of the lapatinib group. Serious adverse events occurred in 14%, 10%, and 17% of the respective groups. Adverse events led to study drug discontinuation in 3%, 6%, and 9%.

The investigators concluded, “Dual HER2 blockade with [lapatinib, trastuzumab, and aromatase inhibitor] showed superior [progression-free survival] benefit vs [trastuzumab and aromatase inhibitor] in patients with HER2-positive/[hormone receptor]–positive [metastatic breast cancer]. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.”

Original funding for the ALTERNATIVE study was provided by GlaxoSmithKline; as of March 2015, lapatinib is an asset of Novartis Pharmaceutical Corporation, the current sponsor of the study.

Stephen R.D. Johnston, PhD, of The Royal Marsden NHS Foundation Trust, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.