Pertuzumab and trastuzumab: the rationale way to synergy

Abstract

It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthesizes preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action.

Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer

“…Several mechanisms have been proposed to explain the observed synergism of trastuzumab and pertuzumab in treating HER2-positive cancers, including breast cancer, ovarian cancer, non-small cell lung cancer, and gastric cancer [ 178 , 179 , 180 , 181 ]. These mechanisms include: (1) the synergism due to the different functions of these two antibodies in targeting HER2-positive cancer cells (reviewed in [ 182 ]); (2) synergism due to composition-independent inhibitory effects of the combination of the two antibodies in a wide range of HER2/HER3 composition [ 183 ]; and (3) synergism of trastuzumab and pertuzumab partly due to the enhanced binding affinity towards the HER2 molecule that originated from the cooperative interactions between the two antibodies [ 184 ]. While the first one is supported by some experimental data, the other two mechanisms are purely based on computational models.…”

“…Many different functions have been attributed to trastuzumab and pertuzumab, and all of them could be used to explain the synergism of the two antibodies. One favored theory is that trastuzumab inhibits the homodimerization of HER2 and the downstream signaling pathways activated by HER2 homodimer, whereas pertuzumab preferentially blocks the heterodimerization of HER2 with EGFR, HER3, and HER4, and the downstream signaling pathways activated by HER2 heterodimers ( Figure 3 A) [ 182 , 185 ]. This theory is supported by some research data.…”

Trastuzumab in the management of gastroesophageal cancer: patient selection and perspectives

“…The binding site on domain II is distinct from the trastuzumab binding site on domain IV, allowing the two antibodies to be effectively delivered together 47. The combination of pertuzumab with docetaxel and trastuzumab in the first-line treatment of HER2-positive advanced breast cancer improved median PFS by ~6 months, with little additional toxicity 48.…”

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial)

“…Among these, the combination of trastuzumab with the second HER2 monoclonal antibody pertuzumab has shown substantial effect in HER2 -amplifed breast cancer. [ 9 , 10 ] The HER2 pathway also plays a key role in pathogenesis of gastric cancer, in which 1.2% to 9% of patients are HER2-positive. [ 11 ] This second indication for trastuzumab has been approved in Japan for HER2-positive advanced or recurrent gastric cancer.…”