Since the discovery of the HER2/neu gene in the late 1970s, aberrations in the HER2 signaling pathway have been implicated in a wide variety of human cancers.
Click to enlarge.
The figure illustrates the HER family protein receptors at the cell surface and the various ways they initiate and influence cell signaling pathways.
Amp indicates amphiregulin; β-cel, β-cellulin; EGF, epidermal growth factor; Epi, epinephrine; HB-GF, heparin-binding growth factor; NRG, neuregulin; TGF%u0251, transforming growth factor %u0251; VEGF, vascular endothelial growth factor. Akt, MAPK, MEK, PI3K, RAF, RAS, and SOS denote signaling pathways.
Source: Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti—HER-2 therapy and personalized medicine. The Oncologist. 2009;14:320-368. Reprinted with permission.
Since the discovery of the HER2/neu gene in the late 1970s, aberrations in the HER2 signaling pathway have been implicated in a wide variety of human cancers, most significantly in breast cancer. Substantial interest in this signaling pathway led to the development of the HER2-targeted drug trastuzumab (Herceptin, Genentech), which has become one of the most common therapeutic agents used in the treatment of breast cancer since its 1998 FDA approval.
Despite its successes, trastuzumab did not prove to be the “magic bullet” for cancer that many hoped it would be, and there are significant problems associated with resistance to therapy and cancer relapse. Recently, results presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) highlighted the exciting potential of an emerging therapeutic strategy involving a dual blockade of HER2 signaling with trastuzumab and a second HER2-targeted agent, pertuzumab. A new standard of care may be on the horizon for patients with HER2-positive breast cancer.
HER2 is a member of the human epidermal growth factor receptor family, along with 3 other proteins: HER1 or EGFR, HER3, and HER4, all of which are receptor tyrosine kinases that feed into a complex biological signaling network controlling numerous cellular processes, including proliferation, survival, differentiation, angiogenesis, invasion, and metastasis.
Receptor dimerization, a process through which 2 receptors such as HER2 receptors join, is an essential requirement for HER function and for the signaling activity of all HER receptors. Dimerization can occur between 2 different HER receptors (heterodimerization) or between 2 molecules of the same receptor (homodimerization).
Not all HER dimers have equivalent signaling potency. For example, homodimers are generally weaker than heterodimers. Heterodimers of HER2 and HER3 molecules have been shown to be particularly potent and are critical for the activation of the phosphatidylinositol-3-kinase (PI3K)/Aktmammalian target of rapamycin (mTOR) pathway, an important downstream signaling pathway that drives angiogenesis, cell survival, migration, apoptosis, and proliferation.
HER receptors normally exist as inactive monomers, with the molecules folded in a way that prevents dimerization, and only become active upon binding of their respective ligands. HER2, on the other hand, has no known ligand and remains in a constitutively active formation. HER2 activation is achieved through either homodimerization with other HER2 molecules (ligand-independent activation) or through heterodimerization with other ligand-activated HER receptors (ligand-dependent activation).
In many types of human cancer, the HER2 gene is amplified and/or HER2 is overexpressed at the mRNA or protein level. This occurs in about 20% of patients with early-stage breast cancer and in a number of other tumor types including gastric, thyroid, and head and neck cancers. Clinically, HER2-overexpressing breast tumors have historically been associated with a more aggressive phenotype and poorer outcomes.
In 1989, researchers at Genentech identified the first HER2- targeted therapy, a monoclonal antibody that specifically binds to the extracellular domain of the HER2 receptor and inhibits the growth of HER2-overexpressing breast cancer cells.
The antibody was developed into the renowned drug Herceptin, and in phase III trials, trastuzumab given after primary therapy (including surgery and chemotherapy) was shown to reduce recurrence rates by approximately 50% in patients with HER2-positive breast cancer.
The FDA has subsequently approved trastuzumab for the treatment of HER2-positive early-stage breast cancer and metastatic breast cancer, either as monotherapy or in combination with the chemotherapy drug paclitaxel. It is also approved for the treatment of metastatic HER2-positive stomach or gastroesophageal cancer in combination with a chemotherapy regimen (cisplatin and either capecitabine or 5-fluorouracil).
The use of trastuzumab led to significant, practice-changing improvements in survival in patients with HER2-positive breast cancer. In spite of this, and the development of other HER2-targeted therapies, such as the tyrosine kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), a significant proportion of patients with HER2-positive breast cancer still die each year in the United States, and resistance to these therapies is a major barrier to successful treatment.
Tumor formation is rarely dependent on a single aberrant signaling pathway, and there is much crosstalk between pathways. As a result, the concept of combining agents from the current armamentarium of targeted cancer drugs is becoming increasingly popular.
The oral drug, which the FDA approved in 2007, was paired with trastuzumab (Herceptin) for patients with HER2-positive, early breast cancer in one arm of the phase III NeoALTTO trial. Lapatinib is a tyrosine kinase inhibitor that targets HER2 with a different but seemingly complementary mechanism of action to trastuzumab, a monoclonal antibody.
The pathological complete response in the NeoALTTO trial for those participants whose regimen included the combination of the 2 drugs was 51.3% (78 of 152 patients), raising the possibility that this strategy may prove beneficial to patients in the neoadjuvant setting (Lancet; published online ahead of print January 16, 2012). Tykerb is a GlaxoSmithKline drug.
T-DM1 (trastuzumab emtansine)
This novel therapeutic is an antibody drug conjugate that combines trastuzumab with a cytotoxic agent and a linker designed to stabilize the combination so that it can reach its HER2 targets. Genentech is studying T-DM1 in various settings, including in combination with pertuzumab.
This investigational oral agent is a multitargeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), HER2, and HER4 kinases. A phase I study pairing neratinib with trastuzumab and paclitaxel in breast cancer was launched in August. Puma Biotechnology, Inc is investigating the drug in breast, brain, and gastric cancers under a licensing agreement with Pfizer Inc.
The oral tyrosine kinase inhibitor targets EGFR/HER1 and HER2. It was evaluated in a phase I trial in combination with trastuzumab that is now closed. Boehringer Ingelheim Pharmaceuticals is conducting phase III trials of afatinib in breast and non-small cell lung cancers. In one lung cancer study, afatinib is being paired with cetuximab (Erbitux), which inhibits EGFR.
This agent is a bispecific antibody able to bind to 2 distinct proteins. A study currently recruiting participants will combine the drug with targeted therapies in 3 arms: with trastuzumab plus cisplatin and capcitabine; with lapatinib and trastuzumab; and with paclitaxel and trastuzumab. Merrimack Pharmaceuticals Inc is developing the drug.
A monoclonal antibody that targets HER3, MM-121 is under clinical development in a variety of settings, including in combination with cetuximab and irinotecan in colorectal, head and neck, non-small cell lung, and triple-negative breast cancers. Merrimack is developing the agent in partnership with Sanofi.
In addition to pertuzumab, several agents that target members of the HER family protein receptors are being investigated in dual anti-HER settings. Key therapeutics under study include:
Numerous potential mechanisms of resistance to trastuzumab have been proposed. Importantly, it has been suggested that resistance may occur as a result of incomplete blockade of the HER2 pathway.
Although trastuzumab is effective against ligand-independent HER2 dimerization, it does not block ligand-dependent dimerization. HER2-containing heterodimers, particularly HER2-HER3 dimers, are the most prevalent and active of all the receptor pair combinations. Therefore, trastuzumab is ineffective against an important part of the potential driving force behind HER2-positive breast cancers.
Among the strategies developed to help address this issue is a new class of drugs called HER2 dimerization inhibitors. As the name suggests, these drugs are designed to block HER2 receptor dimerization.
The first agent to be developed in this class is the monoclonal antibody pertuzumab (Genentech/Roche), which binds to a different region of the HER2 extracellular domain and is able to block ligand-dependent HER2 dimerization. Pertuzumab is currently being studied in patients with early and advanced HER2- positive breast cancer and advanced HER2-positive gastric cancer.
As a single agent, success with pertuzumab has been limited, and it demonstrates only modest antitumor activity. However, preclinical testing indicated that there may be a synergistic effect in combining pertuzumab with trastuzumab. This effect was confirmed in phase II trials, which showed that a combination of these 2 agents produces responses in patients who previously experienced disease progression when receiving trastuzumab-based therapy.
The Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NEOSPHERE) showed a markedly higher pathologic complete response (pCR) rate with triple therapy (the chemotherapeutic docetaxel combined with both pertuzumab and trastuzumab) in patients with newly diagnosed HER2-positive breast cancer, as compared to the dual combinations of docetaxel with either agent alone. Interestingly, the combination of pertuzumab and trastuzumab without chemotherapy also produced a higher pCR rate than either of the other dual combinations, suggesting that if we were able to predict which patients would respond to this combination, it may be possible to treat them with an effective, nonchemotherapy approach.
The most exciting development in clinical research assessing this combination to date was presented at 2011’s SABCS. The results of the first, randomized phase III study, CLEOPATRA (Clinical Evaluation of Pertuzumb and Trastuzumab), were presented. Triple therapy with pertuzumab plus trastuzumab and docetaxel was compared to a combination of placebo plus trastuzumab and docetaxel in 808 patients with previously untreated HER2-positive metastatic breast cancer.
The initial findings from the CLEOPATRA trial showed that over a median followup period of 19.3 months, triple therapy increased progression-free survival by greater than 6 months compared with treatment with docetaxel and trastuzumab alone (18.5 mo vs 12.4 mo, respectively; hazard ratio = 0.62; P <.0001).The objective response rate (where objective response was tumor shrinkage ≥30%) was also significantly higher in the triple-therapy group (80.2% vs 69.3%).
Although this is only an interim analysis of the CLEOPATRA trial, a strong trend toward an overall survival benefit is also emerging, and no increase in cardiac toxicity has been observed, which can be an issue with trastuzumab treatment.
In the wake of these results, Genentech has submitted a biologics license application for this agent to the FDA, while its parent company Roche has submitted a marketing authorization application to the European Medicines Agency, for patients with previously untreated, HER2-positive, metastatic breast cancer. In February, the FDA granted priority review status to pertuzumab, which resulted in an approval on June 8.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.