HER3 mRNA as a predictive biomarker in anticancer therapy

Importance of the field: Heterodimerization of human EGF receptor (HER) 2 and HER3, a co-receptor of HER2, plays an important and dominant role in the functionality and transformation of HER-mediated pathways. Understanding the role of HER3 in oncogenesis as well as its place as a target for anticancer therapy is an ongoing area of research. Determination of biomarkers for clinical benefit from agents targeting HER3 is an essential component of translating basic science into real-world effective anticancer therapies, with the aim of ensuring the patients most likely to benefit from such treatments can be identified.

Areas covered in this review: This review focuses on the targeting of HER2 and HER3 by monoclonal antibodies and the potential for HER3 mRNA levels to predict treatment outcome in ovarian cancer.

What the reader will gain: An understanding of the value of biomarkers for clinical benefit to anticancer therapy and the current status of HER3 mRNA as a biomarker for clinical benefit of the HER2–HER3 dimerization inhibitor pertuzumab.

Take home message: HER3 mRNA levels may be a biomarker for active ligand-induced HER2–HER3 signaling, with low HER3 mRNA levels correlated with clinical benefit from the HER2–HER3 dimerization inhibitor pertuzumab.     

Use of Pertuzumab for the Treatment of HER2-Positive Metastatic Breast Cancer

Introduction

Targeting the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 (HER2)-positive breast cancer. Since resistance to trastuzumab occurs relatively frequently, particularly in the metastatic setting, novel anti-HER2 targeted therapies with complementary and/or synergistic mechanisms of action have been under development. Pertuzumab, a HER2-targeted monoclonal antibody that prevents HER2 dimerisation, is the first of a class of promising targeted agents for the treatment of HER2-positive breast cancer.

Methods

A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed. ClinicalTrials.gov was searched for appropriate clinical trials. The search terms used included breast neoplasm, pertuzumab, dimerisation, and HER2-positive. Abstracts of studies presented at the ASCO and ESMO Annual Meetings, and San Antonio Breast Cancer Symposium were also included.

Results

Pertuzumab represents a novel anti-HER2 targeted therapy for HER2-positive breast cancers. In this article, we describe the mechanism of action of pertuzumab, as well as its drug development process and preclinical testing results. Based on the results of ancillary studies, dual inhibition using pertuzumab and trastuzumab was shown to be effective for the management of HER2-positive metastatic breast cancers pre-treated with trastuzumab-based therapy. For the first-line setting, the combination of both pertuzumab and trastuzumab with docetaxel (CLEOPATRA trial; clinical evaluation of pertuzumab and trastuzumab) has changed the paradigm of patient management.

Conclusion

Pertuzumab provided a more comprehensive inhibition of HER2-driven signalling pathways. When administered together with trastuzumab, pertuzumab represent a significant advancement for the treatment of HER2-positive metastatic breast cancer patients.     

Adding Pertuzumab to Trastuzumab and Taxanes in HER2 positive breast cancer

Introduction: The monoclonal antibody trastuzumab has improved the median disease free and overall survival of patients with early stage breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). Despite this advance, some patients experience cancer relapse and novel approaches are always needed. One such advance is the monoclonal antibody pertuzumab, which prevents dimerisation between members of the HER family of transmembrane glycoprotein receptors.

Areas covered: In this review, the authors analyse recent research which has focused on the development of new HER2 targeting agents for HER2-positive breast cancer, particularly pertuzumab, and its addition to trastuzumab and taxanes.

Expert opinion: Pertuzumab has significantly improved disease control in patients with advanced HER2 positive breast cancer when added to chemotherapy and trastuzumab. Although pertuzumab has also increased response rates in the preoperative setting, this has not yet translated into increased overall survival. The authors believe that future research should focus on improvements in novel biomarkers to select patients for new treatments.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.

Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.

Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin beta1 (HRGbeta1) or transforming growth factor-alpha, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGbeta1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-alpha-stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGbeta1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGbeta1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGbeta1-enhanced phosphorylation of HER2 (Tyr(877)) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease.     

Pertuzumab and breast cancer: another piece in the anti-HER2 puzzle

Introduction: The mechanism of action of pertuzumab, a recombinant anti-HER2 humanized monoclonal antibody, is complementary to trastuzumab’s. On 8 June 2012, the Food and Drug Administration approved the combination of pertuzumab with trastuzumab and docetaxel as first-line treatment of HER2-positive metastatic breast cancer. Furthermore, pertuzumab is the first drug to be approved in the neoadjuvant setting using a pathological complete response as an endpoint.

Areas covered: The review provides insights into the main mechanisms of action of pertuzumab. In addition, it gives complete coverage of the landmark clinical and translational trials for this agent.

Expert opinion: The new therapeutic algorithm in the treatment of HER2-positive advanced disease and the awaited results of the Aphinity trial are expected to impact the sequence of anti-HER2 treatment. Accordingly, the value of pertuzumab beyond progression needs to be properly studied. Furthermore, to improve the toxicity profile and efficacy of future treatment, new pertuzumab-based regimens are being investigated.     

Mechanism of action of the trastuzumab biosimilar CT-P6

ABSTRACT

Objectives: Therapeutic monoclonal antibody biosimilars are expected to help reduce the sizeable economic burden of targeted treatments. Trastuzumab (Herceptin®), a recombinant humanized monoclonal antibody that binds to the extracellular domain of HER2, is approved for use in HER2-overexpressing breast cancer (in both the adjuvant and metastatic settings) and HER2-positive gastric cancer. CT-P6 (Herzuma®) is a biosimilar of trastuzumab, designed to bind with high affinity and specificity to the same HER2 epitope as the reference product. We investigated whether CT-P6 exerts its effects through the same mechanism of action as trastuzumab.

Methods: The mechanism of action of CT-P6 and trastuzumab, both as monotherapy and in combination with paclitaxel or pertuzumab, was compared in HER2-overexpressing breast cancer and gastric cancer cell models.

Results: We confirmed that CT-P6 functions in a manner similar to trastuzumab by binding to the HER2 receptor, which is central to the effects of trastuzumab in all indications.

Conclusions: Collectively, the results of this study show that the mechanisms of action of CT-P6 and trastuzumab are similar in HER2-positive breast cancer and gastric cancer models and, therefore, CT-P6 can be expected to perform similarly in the clinical setting.     

HER2 as a target for breast cancer therapy

Importance of the field: Differential levels of HER2 expression in normal versus HER2-overexpressing breast carcinomas, together with the demonstration of a key role for HER2 in tumor progression, make HER2 an ideal target for specific therapeutic approaches.

Areas covered in this review: This review considers the clinical value of trastuzumab and lapatinib, the two HER2-targeted therapies approved for clinical practice. References were chosen by searching the PubMed and MEDLINE datasets using as search term: ‘HER2’, in association with ‘prognosis’, ‘response’, ‘trastuzumab’, ‘lapatinib’ and ‘resistance’.

What the reader will gain: This review deals with HER2 as a target for breast carcinoma treatment, focusing on anti-HER2 therapies used in clinical practice, their merits and shortcomings.

Take home message: The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance.     

Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents

Introduction: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types.

Areas covered: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach.

Expert opinion: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.     

Farletuzumab in epithelial ovarian carcinoma

Importance of the field: Ovarian cancer is the leading cause of death from a gynecologic malignancy. Recurrence is both common and lethal, necessitating the development of novel targeted therapies. Farletuzumab (MORAb-003) is a humanized mAb with high affinity for folate receptor α (FRα), a 38 kDa GPI-anchored protein that is overexpressed in 90% of epithelial ovarian cancers.

Areas covered in this review: Preclinical and clinical trials, published or presented at national meetings from 2006 to the present, are presented in this review.

What the reader will gain: Preclinical studies have demonstrated robust antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, inhibition of tumor growth in ovarian tumor xenografts and a safe toxicology profile in non-human primates. Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal drug-specific toxicity. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive (recently launched) and platinum-resistant (planned) recurrent disease.

Take home message: FRα is overexpressed in ovarian cancers but largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab is a novel inhibitor of FRα and has shown clinical efficacy in early phase trials.     

AE37: a novel T-cell-eliciting vaccine for breast cancer

Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8⁺ T-cell-eliciting vaccines. AE37 is a promising primarily CD4⁺ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials.

Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine.

Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.     

Prognostic and therapeutic molecular markers in the clinical management of esophageal cancer

ABSTRACT

Introduction: Esophageal cancer is a deadly disease with high mortality. Treatment with chemotherapy, radiation, and surgery continues to leave many patients with disease progression and recurrence. Novel treatments are needed for this patient population. The development of molecular markers are important for identifying therapeutic targets, as well as prognosis.

Areas covered: This review evaluates three molecular markers in esophageal cancer: HER2, PD-L1, and MSI. The fundamentals of these markers, diagnosis, and rates of occurrence in esophageal cancer are explored. The prognostic potential of these markers is based on existing literature as well as application in clinical trials. Key trial findings pertaining to the therapeutic targets for HER2 and PD-1 as well as the role of MSI are discussed.

Expert commentary: Molecular markers are changing the practice for esophageal cancer. Therapeutic targeting for HER2 and PD-L1 have shown positive results in recent clinical trials. Trials evaluating immunotherapy as first-line agents are currently underway.     

Trastuzumab emtansine in breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)–targeted antibody–drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing.

Areas covered: Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1.

Expert opinion: T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner.     

Technology evaluation: pertuzumab, Roche/Genentech/Chugai

Genentech, Roche and Chugai are developing pertuzumab, a next-generation trastuzumab-like molecule (an anti-HER/neu monoclonal antibody), for the potential treatment of cancer. Pertuzumab is currently undergoing phase II clinical trials.     

The prospect of patritumab for treating non-small cell lung cancer

ABSTRACT

Introduction: The mutation or expression of HER family members serves as a therapeutic target for tyrosine kinase inhibitors or monoclonal antibodies in diverse cancers, such as non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, colorectal cancer, pancreatic cancer and glioblastoma. HER3, which heterodimerizes with HER1 and HER2, has received much attention as a potential target for anti-EGFR treatment. Patritumab is a novel, fully human monoclonal antibody directed against HER3.

Areas covered: In this review article, an overview of the market, chemistry, pharmacodynamics, pharmacokinetics, efficacy, and safety of patritumab is provided based on data from phase I studies, a combination phase I trial, and a randomized phase II trial comparing two doses of patritumab.

Expert opinion: The combination of patritumab plus erlotinib has shown a promising efficacy and safety in early-phase clinical trials. In a randomized phase II trial, higher mRNA expression of heregulin (a ligand of HER3) was associated with better progression-free survival and a tendency toward improved overall survival. In the era of precise treatment based on an appropriate target with a predictive biomarker, further studies with patritumab are needed to realize its potential in cancer treatment.     

Oncolytic vaccinia virus for the treatment of cancer

Introduction: Gene therapy offers promising approaches for the development of anticancer agents with new modes of action. Among gene therapy vectors, vaccinia virus has emerged as an attractive agent especially when used as an oncolytic virus.

Areas covered: This review describes the use of vaccinia virus in cancer therapy as a gene therapy vector, as an oncolytic virus and in the generation of oncolysates. The main achievements of each field are summarized with a special emphasis on vaccinia as an oncolytic vector and its combination therapies. The virus that has advanced furthest in clinical trials, GM-CSF expressing JX-594, is described in detail and its preclinical and clinical data are reviewed.

Expert opinion: Vaccinia virus has great potential in cancer gene therapy, especially when used as an oncolytic virus. In particular, JX-594 has shown promising preclinical and clinical data, and a multi-continental randomized Phase III trial in hepatocellular carcinoma is expected to start soon.     

VB-111 for cancer

Introduction: Antibody, small molecule and protein inhibitors of angiogenesis are used in the management of several cancers. These do not specifically target tumor vascularity, and resistance can be problematic. VB-111 is a vascular-targeting agent consisting of a non-replicating adenovirus vector with a pre-proendothelin-1 promoter that encodes an apoptotic receptor.

Areas covered: The rationale and design of VB-111, its mechanism of action, and preclinical studies examining antitumor activity, toxicology and pharmacodynamics are reviewed. Phase I and Phase II clinical trials are also reviewed.

Expert opinion: VB-111 is a vascular-targeting gene therapeutic that is both tissue- and condition-specific, with effects limited to endothelial cells undergoing angiogenesis. Systemic administration produces selective destruction of tumor vascularity. Synergistic antitumor activity can be observed when combined with chemotherapy. VB-111 has been found to be safe and well tolerated in a Phase I clinical trial in patients with advanced solid tumors. Phase II clinical trials are in progress. VB-111 is novel agent for cancer that may have application as monotherapy and in combination with other therapies.     

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer

Introduction: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies.

Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016–2017 ASCO and ESMO conference proceedings for ‘ABP 980’ or ‘trastuzumab biosimilar’. ‘ABP 980 and breast cancer’ or ‘trastuzumab biosimilar and breast cancer’ were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included.

Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.