The pace of change in treating human epidermal growth factor-2 positive (HER2+) breast cancer over the past five years has upended established treatment paradigms and created challenges for physicians in determining the best therapy for individual patients.

New developments in the pipeline are likely to multiply the options available in the next few years, according to an article in Cancer Treatment Review.

HER2+ breast cancer affects 15% to 20% of all women with breast cancer. Treatment with HER2 targeting agents such as trastuzumab, lapatinib, pertuzumab and T-DM1 (trastuzumab emtansine) have doubled median overall survival, which now exceeds 50 months, and tripled the five year survival rate for this aggressive form of breast cancer.

Cancer drugs. Source

The review identifies immunotherapy 20 agents—some entirely new, some approved for other types of breast cancer or other malignancies—currently in trials for HER2+ breast cancer. They include designed ankyrin repeat proteins, cyclin-dependent kinase 4/6 inhibitors, anti-programmed death-1/anti-programmed death ligand-1 agents, new anti-HER antibodies, bi-specific antibodies, antibody drug conjugates, alpha-specific PI3K inhibitors and pan-HER2 tyrosine kinase inhibitors and combinations of agents in these classes.

Regimens that include palbociclib, pembrolizumab, margetuximab, the antibody drug conjugate SYD-0985 (trastuzumab conjugated with duocarmycin), neratinib and pyrotinib are currently in phase 3 trials.

Of particular note, the CDK 4/6 inhibitors abemaciclib and palbociclib are being combined with anti-HER2 agents to address “triple positive” breast cancer. Just emerging as a distinct subtype of HER2+ breast cancer, the triple positive variant’s tumors express both estrogen receptors (ER+) and progesterone receptors (PR+) as well as exhibit overexpression of HER2.

The use of CDK 4/6 inhibitors with estrogen therapy and an anti-HER agent in patients with HER2+/HR+ disease appears promising as “preclinical evidence suggests intense interconnection between the ER and HER2 signalling pathways.” The ER pathway also appears to provide a backdoor to promote resistance to anti-HER2 therapy.