Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

INTRODUCTION: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity. AREAS COVERED: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing. EXPERT OPINION: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.     

Necitumumab for non-small cell lung cancer

Introduction: Targeting the EGFR pathway is a rational approach to treat patients with advanced NSCLC. Necitumumab, a second-generation recombinant fully human immunoglobulin G1 monoclonal antibody directed against EGFR, has recently been assessed in combination with first-line cisplatin-based chemotherapy.

Areas covered: This article reviews literature on necitumumab development, from preclinical data to results of Phase III clinical trials, either published or presented in international scientific conferences. Ongoing clinical trials were searched with the clinical-trials.gov website.

Expert opinion: During the last decade, advances in treatment of metastatic NSCLC have been exclusively achieved in patients with non-squamous histology. In this context, any treatment improvement, even modest, was eagerly awaited for patients with squamous NSCLC. In this patient’s population, the SQUIRE Phase III study demonstrated a relatively small, but statistically significant survival benefit in patients treated with necitumumab in combination with standard chemotherapy (cisplatin and gemcitabin) compared with those treated with chemotherapy alone. However, the identification of predictive biomarker for treatment outcome is still needed to select the patients who will experience a large benefit from the targeted treatment.     

Is there still room for large registrative trials in unselected cancer patients? The case of anti-epidermal growth factor receptor antibodies in advanced non-small-cell lung cancer

Necitumumab, a monoclonal antibody directed against EGFR, is currently under development as a treatment for advanced NSCLC. Two Phase III randomized trials are ongoing, testing the addition of necitumumab to first-line platinum-based chemotherapy. In the same setting, cetuximab produced a statistically significant but clinically modest benefit in the whole study population, and no solid data have been produced about predictive factors of efficacy. Will the difference in structure between the two antibodies be enough to obtain a clinically relevant advantage, making real progress in the treatment of advanced NSCLC? Large Phase III trials in unselected patients risk demonstrating statistically significant results with debatable clinical relevance in the whole population, and the study of predictive factors is often left to subgroup analysis performed after the conduction of the trial. We do not need further 'me-too' drugs, or drugs that produce a small benefit in the unselected population. On the contrary, the oncologic community needs drugs to be used with a proper selection of patients, to obtain larger, relevant benefits in molecularly characterized subgroups. Final results of randomized trials with necitumumab in advanced NSCLC are expected in a couple of years.     

Is there still room for large registrative trials in unselected cancer patients? The case of anti-epidermal growth factor receptor antibodies in advanced non-small-cell lung cancer

Necitumumab, a monoclonal antibody directed against EGFR, is currently under development as a treatment for advanced NSCLC. Two Phase III randomized trials are ongoing, testing the addition of necitumumab to first-line platinum-based chemotherapy. In the same setting, cetuximab produced a statistically significant but clinically modest benefit in the whole study population, and no solid data have been produced about predictive factors of efficacy. Will the difference in structure between the two antibodies be enough to obtain a clinically relevant advantage, making real progress in the treatment of advanced NSCLC? Large Phase III trials in unselected patients risk demonstrating statistically significant results with debatable clinical relevance in the whole population, and the study of predictive factors is often left to subgroup analysis performed after the conduction of the trial. We do not need further ‘me-too’ drugs, or drugs that produce a small benefit in the unselected population. On the contrary, the oncologic community needs drugs to be used with a proper selection of patients, to obtain larger, relevant benefits in molecularly characterized subgroups. Final results of randomized trials with necitumumab in advanced NSCLC are expected in a couple of years.     

Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return?

Introduction: Two humanized monoclonal antibodies, bapineuzumab and solanezumab, directed against the N terminus and mid-region of β-amyloid (Aβ), respectively, were recently tested in large, long-term Phase III trials in patients with mild-to-moderate Alzheimer’s disease (AD).

Areas covered: This review discusses current clinical data on solanezumab, bapineuzumab and their failure in Phase III trials to show significant clinical benefits, as well as other monoclonal antibodies under investigation for AD.

Expert opinion: Solanezumab showed some beneficial cognitive effects in mildly affected AD patients and this subgroup of AD patients is currently being tested in another Phase III trial to this subgroup of AD patients to confirm previous encouraging observations. Two other monoclonal antibodies, gantenerumab, which preferentially binds to fibrillar Aβ, and crenezumab, which preferentially binds to soluble, oligomeric and fibrillar Aβ deposits, are being tested in secondary prevention trials in presymptomatic subjects with autosomal dominant AD mutations. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive positron emission tomography scans for brain amyloid deposits. These ongoing secondary prevention trials will tell us if Aβ really plays a crucial role in the pathophysiology of AD.     

Anti-EGFR and antiangiogenic monoclonal antibodies in metastatic non-small-cell lung cancer

ABSTRACT

Introduction: In recent years, several clinical trials have evaluated the efficacy and safety of biological therapies in lung cancer. Epidermal growth factor receptor (EGFR) and the axis vascular endothelial growth factor receptor (VEGF/VEGFR) are targeted by small molecules and monoclonal antibodies (mAbs), especially in non-squamous non-small-cell lung cancer (NSCLC).

Areas covered: The current state of the art of anti-EGFR and antiangiogenic monoclonal antibodies in metastatic NSCLC is reviewed and discussed.

Expert opinion: Bevacizumab and cetuximab are the most studied mAbs in NSCLC, but only bevacizumab is in clinical practice in the first-line setting. Necitumumab is a new anti-EGFR monoclonal antibody that improves survival when combined to cisplatin/gemcitabine chemotherapy and has been approved in first-line advanced NSCLC. Ramucirumab, an antiangiogenic drug binding with high affinity to VEGFR-2, improves the results of chemotherapy alone when administered with docetaxel and has been approved in second-line setting. Moreover, the novel combination of bevacizumab and erlotinib is very promising for the treatment of patients with NSCLC harbouring EGFR mutations. The association of antiangiogenic mAbs and immunotherapy is under investigation too.     

Emepepimut-S for non-small cell lung cancer

Introduction: Immunotherapy as a possible therapeutic option for cancer has been of great importance due to the innovative development of vaccines. Various molecules have been tested and emepepimut-S (Biomira Liposomal Peptide 25 (BLP 25)) has emerged as an option, particularly in lung cancer.

Areas covered: A PubMed literature and ClinicalTrials.gov search was conducted using the terms: emepepimut, BLP25, NSCLC, cancer immunotherapy, cancer vaccine and MUC1. This review covers how emepepimut-S acts against the mucin 1 (MUC1) tumor-associated antigen producing a cellular immune response against the cells that express MUC1 and the most important clinical data available that led to the ongoing Phase III trial.

Expert opinion: The results obtained in the Phase I/II trials are promising, showing a favorable toxicity with a benefit in survival in NSCLC patients. As future trials develop, demonstration of the long-term survival benefit, understanding of the various mechanisms of immune response initiated by the drug and the selection of patients that will highly benefit from the immunotherapy will be elucidated. The safety and extension in survival makes emepepimut-S a very interesting drug and could, therefore, offer a possibility of treatment and maintenance, particularly for good performance status patients with locally advanced NSCLC.     

The role of talactoferrin alfa in the treatment of non-small cell lung cancer

Importance of the field: Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.

Areas covered in this review: Talactoferrin alfa is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.

What the reader will gain: Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alfa and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.

Take home message: The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.     

Solanezumab for Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a debilitating neurodegenerative illness affecting over 35 million people worldwide. Solanezumab is a monoclonal antibody that binds to β-amyloid (Aβ), a protein that plays a key role in the pathogenesis of AD. The drug is currently being investigated in Phase III trials as a disease-modifying treatment for AD.

Areas covered: This paper reviews literature on solanezumab that is available in PubMed from 2008 to 2010, other treatment trials in clinicaltrials.gov and published abstracts from conferences. The article also provides a discussion of the early trials of AN1792 and an overview of the immunotherapies currently in development. The authors provide the reader with a critical appraisal of the to-date clinical trial data on solanezumab and its implications for the broader field of immunotherapies for AD.

Expert opinion: Solanezumab can neutralize soluble Aβ peptides, which may represent the more neurotoxic of the Aβ species. Phase II findings support the compound's safety, which has been a concern for some Aβ immunotherapies. Cerebrospinal and plasma biomarker changes with solanezumab treatment are encouraging. Results of the ongoing Phase III trials will be instrumental in determining the drug's clinical significance.     

Cetuximab for treating non-small cell lung cancer

Introduction: Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders.

Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers.

Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches.     

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.     

Immunomodulation with heat shock protein DiaPep277 to preserve beta cell function in type 1 diabetes – an update

Importance of the field: Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review.

Areas covered in this review: A literature search of Pubmed listed publications covering 1990 – 2009 and a website search of the licensing company were performed.

What the reader will gain: DiaPep277 has been successfully employed in animal models and has been investigated in Phase I – III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes.

Take home message: Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.     

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.     

Role of MetMAb (OA-5D5) in c-MET active lung malignancies

Introduction: MetMAb (OA-5D5) is a one-armed monoclonal antibody developed to bind to and inhibit c-MET receptor tyrosine kinase. Though only in early clinical testing, this agent holds great promise in diseases thought to be driven by c-MET activation, as evidenced by the Phase II results in NSCLC where a benefit in overall survival was observed in patients with MET-diagnostic-positive disease. Thus far, both alone and in combination with other targeted agents, this drug has been well tolerated and no new significant safety signals have been identified.

Areas covered: This review summarizes the structure and function of the c-MET receptor and its ligand hepatic growth factor (HGF), provides an overview of select targeted monotherapies developed to interfere in the MET–HGF signaling pathway, discusses pre-clinical and clinical data surrounding MetMAb, and concludes with an expert opinion regarding this novel agent.

Expert opinion: MetMAb has been well tolerated and based on Phase II data testing it, in combination with erlotinib in advanced NSCLC, may have a role in improving survival in patients with disease driven by c-MET activation. However, Phase III validation is underway and the results of these studies will help elucidate which patients will benefit most from this novel agent.     

Bevacizumab for the treatment of high-grade glioma: an update after Phase III trials

Introduction: Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results.

Areas covered: This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGG with a focus on outcome results. A future perspective about the expected future role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab, as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of antiangiogenic therapy are also discussed.

Expert opinion: Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab might offer clinical benefits and is currently approved as a single agent for this indication. Although clinical trials demonstrate a prolonged progression-free survival (PFS) in bevacizumab-treated HGG, a benefit on overall survival has not been demonstrated. Research so far shows that bevacizumab appears to prolong PFS in newly diagnosed glioblastoma. Available data do not demonstrate a survival benefit in newly diagnosed patients. In the recurrent setting, there is no adequately powered randomized clinical trial to address whether there is a PFS or survival benefit with bevacizumab. Bevacizumab has also been introduced into other settings in neuro-oncology, including concurrent administration with re-irradiation for recurrent HGG.     

MEDI 4736 (durvalumab) in non-small cell lung cancer

Introduction: Immune checkpoint inhibitors (ICI) are now a therapeutic option for advanced non-small cell lung cancer (NSCLC) patients. ICI, such as the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab, have already been marketed for the treatment of pretreated patients with advanced NSCLC. Other notable PD-L1 inhibitors under development include avelumab and durvalumab.

Areas covered: This article reviews literature on durvalumab development, from the preclinical data to the results of phase III clinical trials, whether published or presented at international scientific conferences. Ongoing clinical trials were also reviewed.

Expert opinion: Early phase trials of durvalumab monotherapy (and in combination) have demonstrated activity in advanced NSCLC patients and it has demonstrated a good safety profile. The authors believe that durvalumab will likely play an important role in future treatment strategies for NSCLC. The PACIFIC trial assessing durvalumab after standard chemoradiotherapy for locally advanced NSCLC has already met its primary endpoint and the potential of durvalumab will be reinforced if phase III randomized studies of first-line (MYSTIC trial) and second or subsequent (ARCTIC trial) lines of therapy demonstrate superiority over the current standard of care.     

Current situation of zalutumumab

Background: Increased EGFR expression has been observed in many tumours. This overexpression usually correlates with a more advanced disease stage, a poorer prognosis and a worse chemotherapy response. EGFR inhibition has been considered an attractive approach in cancer treatment. Various strategies to intervene in EGFR signalling have been developed, mainly receptor inhibition of extracellular domain using anti-EGFR monoclonal antibodies and receptor inhibition on the intracytoplasmic domain using small-molecule tyrosine kinase inhibitors. Cetuximab and panitumumab are the most developed anti-EGFR monoclonal antibodies, and there is plenty of published information about their current status Objective/methods: In this review we focus on Zalutumumab, an IgG1 completely human anti-EGFR monoclonal antibody. Results/conclusions: Apart from EGFR inhibition, another anti-neoplastic effect of zalutumumab has also been postulated, mediated by immune mechanisms, specifically by antibody-dependent cell cytotoxicity. Zalutumumab is under clinical development, mainly for squamous cell cancer of head and neck and there are also ongoing trials in NSCLC and colorectal cancer.     

Pembrolizumab for the first-line treatment of non-small cell lung cancer

Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.

Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and ?189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.

Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.     

Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes

Importance of the field: Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections.

Areas covered in this review: Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing.

What the reader will gain: To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs.

Take home message: The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.