Dual HER2 Blockade Superior to Single Blockade for HER2+/HR+ Breast Cancer

Dual blockade of HER2 with lapatinib plus trastuzumab and an aromatase inhibitor (AI) was superior to single blockade with trastuzumab plus an AI in postmenopausal women with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer, according to the results of the phase III ALTERNATIVE study (abstract 1004) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

“Dual HER2 blockade with this triplet of lapatinib/trastuzumab and an AI can offer an effective and well-tolerated chemotherapy-sparing option for patients who are not intended or appropriate for chemotherapy,” said researcher William J. Gradishar, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, who presented the results.

According to Gradishar, it is well recognized that most patients with HER2-positive disease irrespective of estrogen receptor (ER) status are generally treated with HER2-targeted therapy and chemotherapy. Previous research has explored targeting of the HER2 pathway and the ER pathway simultaneously and shown that dual targeting resulted in an improvement in progression-free survival. In addition, dual HER2 blockade has been shown to have clinical benefit in both the neoadjuvant and metastatic settings compared with single blockade.

The ALTERNATIVE study evaluated a chemotherapy-sparing regimen and compared dual HER2 blockade with ER targeting vs single HER2 blockade with ER targeting. The study randomly assigned 355 postmenopausal women 1:1:1 to trastuzumab plus lapatinib plus an AI or to either trastuzumab or lapatinib plus an AI. All patients had progressed during or after treatment with trastuzumab plus chemotherapy.

Gradishar noted that the study was originally designed to evaluate overall survival between lapatinib/trastuzumab/AI compared with trastuzumab/AI, but the availability of newer treatment options results in a substantial prolongation of overall survival outcomes, making the initial protocol assumptions obsolete. The primary endpoint was progression-free survival with dual blockade with trastuzumab plus lapatinib compared with trastuzumab alone.

Patients assigned to dual blockade had a 48% reduction in risk for progression compared with trastuzumab plus an AI (hazard ratio [HR], 0.62; 95% CI, 0.45–0.88; P = .0064). The median progression-free survival was 11 months for the triplet compared with 5.7 months for trastuzumab plus an AI.

“Interestingly, lapatinib and an AI showed better progression-free survival than trastuzumab plus an AI,” Gradishar noted.

A secondary endpoint included comparison with lapatinib plus an AI; these patients had a median progression-free survival of 8.3 months.

There was no statistically significant difference in overall survival between the treatment arms.

Response rates also favored dual HER2 blockade. Patients assigned to the triplet combination had an overall response rate of 31.7% compared with 13.7% for trastuzumab plus an AI (odds ratio, 2.83; 95% CI, 1.43–5.89).

Adverse events were more common in patients receiving lapatinib. Gradishar noted that there were no significant cardiac signals in this trial. Diarrhea, rash, paronychia, and nausea were more common in patients receiving lapatinib either as part of the dual blockade arm or in combination with an AI compared with trastuzumab plus an AI.