Dual HER2 Blockade Plus AI Improves Outcomes in HER2+/HR+ Breast Cancer

Dual HER2 blockade using lapatinib and trastuzumab along with aromatase inhibitor (AI) therapy was more effective than trastuzumab and an AI alone in a phase III trial of patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer.

Dual HER2 blockade has been shown to improve outcomes along with chemotherapy in the first-line setting of HER2-positive metastatic breast cancer. “However, not all patients with HER2-positive/HR-positive metastatic breast cancer may need or tolerate chemotherapy, and these patients could be candidates for anti-HER2 therapies plus endocrine therapy,” wrote study authors led by Stephen R. D. Johnston, MBBS, PhD, of the Royal Marsden NHS Foundation Trust in London.

The ALTERNATIVE study was designed to test whether dual HER2 blockade along with an AI, and without chemotherapy, could improve outcomes over trastuzumab plus an AI alone. It included 355 patients who had experienced progression after prior therapy with trastuzumab plus chemotherapy. The results were published in the Journal of Clinical Oncology.

Patients were randomized to one of three groups: 120 patients received lapatinib and trastuzumab plus an AI; 117 received trastuzumab plus an AI; and 118 received lapatinib plus an AI. Baseline characteristics were well balanced, with a median age ranging from 54 to 57 years; approximately 70% of patients were white.

The trial met its primary endpoint of progression-free survival (PFS). The median PFS with the dual HER2 blockade was 11 months, compared with 5.7 months with trastuzumab plus AI therapy, for a hazard ratio of 0.62 (95% CI, 0.45–0.88; P = .0064).

The lapatinib plus AI therapy group also fared better, with a median PFS of 8.3 months, for a hazard ratio compared with the trastuzumab plus AI group of 0.71 (95% CI, 0.51–0.98; P = .0361). The PFS benefits were seen across predefined subgroups, including those with measurable disease, those receiving prior trastuzumab in a neoadjuvant or metastatic setting, and others.

The overall response rate was 31.7% with the dual blockade, compared with 13.7% with trastuzumab plus AI therapy and 18.6% with lapatinib plus AI therapy. Clinical benefit rates in these three groups were 41%, 31%, and 33%, respectively.

Most adverse events were grade 1 or 2. Diarrhea was most common with dual blockade compared with the other groups (69%, 9%, and 51%, respectively), followed by rash (36%, 2%, and 28%, respectively). Serious adverse events were seen in 14% of dual blockade patients, compared with 10% of trastuzumab plus AI patients and 17% of lapatinib plus AI patients. Treatment-related serious adverse events in the three groups were seen in 5%, 2%, and 4%, respectively.

“The PFS benefit obtained with lapatinib + trastuzumab + AI in patients with HER2-positive, HR-positive metastatic breast cancer who had been previously treated with trastuzumab and endocrine therapy is clinically meaningful and robust,” the authors concluded. “This combination can potentially offer an effective and well-tolerated, chemotherapy-sparing alternative treatment regimen for patients for whom chemotherapy is not intended.”