Dual HER2 Blockade Plus AI Offers ALTERNATIVE Strategy For Metastatic Breast Cancer

Combining lapatinib and trastuzumab with an aromatase inhibitor may improve progression-free survival for women with HER2-positive, hormone receptor-positive metastatic breast cancer

medwireNews: Phase III trial findings point to a strategy of dual human epidermal growth factor receptor 2 (HER2) blockade plus aromatase inhibitor (AI) therapy for patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer who are unsuitable for chemotherapy.

The study recruited a group of patients who had previously received endocrine therapy, as well as (neo)adjuvant and/or first-line trastuzumab and chemotherapy for metastatic disease, explain Stephen Johnston, from The Royal Marsden NHS Foundation Trust in London, UK, and co-workers.

“The ALTERNATIVE trial showed relevant clinical benefit with a relatively good tolerability, supporting that patients with HER2-positive/HR-positive MBC who are not candidates for chemotherapy can be adequately treated with dual HER2 blockade ([lapatinib ]+ [trastuzumab]) plus an AI”, they write in the Journal of Clinical Oncology

“This combination can potentially offer an effective and well-tolerated, chemotherapy-sparing alternative treatment regimen for patients for whom chemotherapy is not intended.” 

Progression-free survival (PFS) was a median of 11.0 months for the 120 women who were randomly assigned to receive lapatinib 1000 mg/day plus trastuzumab at a 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose every 3 weeks, alongside an investigator’s choice of letrozole 2.5 mg/day, anastrozole 1 mg/day or exemestane 25 mg/day.

This was significantly longer than the median PFS of 5.7 months achieved by the 117 patients who were given trastuzumab on the same schedule, plus an AI, giving a hazard ratio (HR) of 0.62 demonstrating superiority of the dual HER2 blockade regimen.

And the dual-blockade strategy PFS was also significantly longer than the median 8.3 months achieved by the 118 patients who were randomly assigned to receive lapatinib 1500 mg/day plus an investigator’s choice of AI, with a HR of 0.71

Patients given lapatinib plus trastuzumab and AI also had a higher overall response rate than those given trastuzumab or lapatinib plus AI (31.7 vs 13.7 and 18.6%, respectively) and a longer duration of response (13.9 vs 8.3 and 11.1 months, respectively).

And although overall survival (OS) data have not yet matured, the researchers report a trend towards improved outcomes with the dual HER2 blockade plus AI strategy compared with trastuzumab plus AI, at a median of 46.0 and 40.0 months, respectively. The median OS for lapatinib plus AI was 45.1 months.

The most common any-grade adverse events in the dual HER2 blockade, trastuzumab plus AI, and lapatinib plus AI groups, were diarrhoea (69, 9 and 51%, respectively), rash (36, 2 and 28%), nausea (22, 9 and 22%) and paronychia (30, 0, 15%).

Most adverse events were grade 1 or 2, with grade 3 or 4 side effects occurring in less than 5% of patients except for grade 3 diarrhoea in the dual HER2 blockade and lapatinib plus AI arms (13 and 6%, respectively).

There was a low rate of adverse events leading to discontinuation in the three arms but trastuzumab was interrupted in 19% of the dual HER2 blockade and 9% of trastuzumab plus AI groups, while lapatinib therapy was interrupted in 38% of the dual HER2 blockade-treated patients and 35% of those using lapatinib plus AI.

Discussing their findings further, the researchers note that the “meaningful clinical benefit” seen with dual HER2 blockade plus AI in the ALTERNATIVE trial and other metastatic breast cancer studies is in contrast to findings in the early-stage breast cancer adjuvant setting, such as in the ALTTO and APHINITY trials.

“This discrepancy may be the result, at least in part, of the excellent outcome with adjuvant single HER2 blockade with [trastuzumab], making the demonstration of additional benefit with dual blockade harder”, suggest Stephen Johnston et al.

 “Dual HER2 blockade may benefit only a small subset of high-risk patients.” 


Johnston SRD, Hegg R, Im S-A, et al. Phase III, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: ALTERNATIVE. J Clin Oncol; Advance online publication 15 December 2017. DOI: 10.1200/JCO.2017.74.7824

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