Monoclonal antibodies in gastrointestinal cancers

Introduction: Among gastrointestinal cancers, colorectal and gastric neoplasms are the most frequent. The development of new targeted drugs improved the efficacy of systemic therapy in advanced stages of those malignancies.

Areas covered: This review highlights the main biological processes implicated in gastrointestinal cancer development and progression, such as angiogenesis and epidermal growth factor receptor (EGFR) signaling pathway. On these bases, anti-EGFR and anti-vascular endothelial growth factor (VEGF) monoclonal antibodies in colorectal and gastric cancer are discussed. Data about further monoclonal antibodies in development are also reported.

Expert opinion: The use of monoclonal antibodies in colorectal and gastric cancers showed the best outcomes when combined with chemotherapy, even though single agent anti-EGFR antibodies seem active in particular setting of metastatic colorectal cancer (CRC) patients. It is not well defined whether the addition of anti-VEGF and anti-EGFR to chemotherapy could improve outcome in those patients susceptible to CRC-related metastases resection. Little and conflicting data are available about the role of these drugs in adjuvant setting. Tests are available to select patients with higher probability to get benefit from these treatments. Further biomarkers need to be evaluated to improve this selection and achieve “tailorization” of systemic therapy.     

The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors

Introduction: Use of both the vascular endothelial growth factor (VEGF) inhibitor bevacizumab and the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab as potential first-line therapies for patients with RAS-wild-type metastatic colorectal cancer presents clinicians with an important decision. We review clinical data evaluating first-line treatment with EGFR inhibitors. Additionally, by undertaking an integrated ‘bench-to-bedside’ approach, we provide potential models, testable hypotheses and biological rationales that might account for these clinical observations.

Areas covered: A literature search encompassing PubMed and the ASCO/ESMO websites was undertaken in October 2014. Search terms included ‘colorectal cancer’, ‘cetuximab’, ‘panitumumab’ and ‘bevacizumab’.

Expert opinion: A number of clinical studies indicate a survival benefit for patients receiving EGFR inhibitors in combination with chemotherapy in the first-line setting, relative to both chemotherapy alone and VEGF inhibitors plus chemotherapy. Existing preclinical and clinical data suggest that a biological basis exists for providing RAS-wild-type patients with first-line EGFR inhibitors, followed by second-line VEGF inhibitors. More specifically, first-line treatment with EGFR inhibitors may elicit unique biological changes that sensitize tumors to subsequent lines of therapy; conversely, first-line treatment with VEGF inhibitors may elicit biological changes that desensitize tumors to subsequent lines of therapy.     

Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance

Introduction: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms.

Areas covered: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation.

Expert opinion: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.     

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.     

Lung cancer]

Since the late 1980s, lung cancer incidence in men has declined in Germany whereas in women there is still a rise. There is no approved screening program for lung cancer up to now and results from randomized trials like the National Lung Screening Trial are eagerly awaited. In stage II and IIIA non-small cell lung cancer (NSCLC), several positive trials have demonstrated the advantage of adjuvant chemotherapy which is now an established modality to improve cure rates. Epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, has been approved for relapsed advanced-stage NSCLC. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a primary mediator of angiogenesis that is commonly overexpressed in solid tumors including lung cancer. Bevacizumab, in combination with chemotherapy, has demonstrated improved outcomes in advanced NSCLC and is now approved for selected patients with advanced-stage NSCLC. Patient selection for therapeutic use of bevacizumab is crucial to optimize safety. Ongoing trials explore multitargeted agents such as sorafenib, sunitinib, and vandetanib.     

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.     

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.     

Best practices in the management of toxicities related to anti-EGFR agents for metastatic colorectal cancer

PurposeTo provide oncology nurses with an overview of the toxicity management associated with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.MethodsMonoclonal antibodies such as cetuximab and panitumumab that target EGFR have provided patients with metastatic colorectal cancer with effective treatment options. Both antibodies can be used as monotherapy; cetuximab is also approved for use in combination with chemotherapy. We reviewed the literature regarding the signs and symptoms, assessment of severity, and strategies available to prevent and manage adverse events associated with these agents.Key resultsThis class of therapeutics is associated with an overall acceptable adverse event profile that is distinctly different from conventional chemotherapeutics. In contrast to cytotoxic chemotherapy, which causes myelosuppression, mucositis, and nausea and vomiting, common toxicities reported for anti-EGFR therapy include the more frequent cutaneous toxicities, electrolyte imbalances, and diarrhoea, as well as the less frequent ocular toxicities. Infusion reactions are also observed with the chimerical monoclonal antibody cetuximab.ConclusionsOncology nurses play a key role in the administration of multi-agent treatment regimens, especially with respect to the identification and management of toxicities, patient education, and patient support. By reducing the incidence and severity of the adverse events associated with anti-EGFR therapy, oncology nurses have the potential to sustain patient adherence to completion of treatment, identify signs and symptoms early, proactively manage adverse events, and provide appropriate treatment interventions, thereby improving patient quality of life.     

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.     

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.     

Recent developments in colorectal cancer treatment by monoclonal antibodies

A growing understanding of the molecular mechanisms involved in cancer biology and continuous refinement of available technologies for drug discovery have prompted the development of new therapeutic tools targeting specific cancer-associated molecular pathways. Among these so-called biological therapies, monoclonal antibodies have now reached the time of clinical application. Besides initial development of the murine antibody edrecolomab, the impact of monoclonal antibodies on cancer therapy has recently been clearly demonstrated in colorectal cancer by targeting two major pathways critical to tumourigenesis: the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signalling pathways. These antibodies showed significant clinical activity in advanced colorectal cancer, especially when combined with chemotherapy. This paper reviews the status of the monoclonal chimeric antibody cetuximab (Erbitux^®) and other anti-EGFR antibodies, and of bevacizumab (Avastin^®; an anti-VEGF humanised monoclonal antibody), in colorectal cancer treatment.     

Monoclonal antibodies and antibody fragments: state of the art and future perspectives in the treatment of non-haematological tumors

Introduction: The use of monoclonal antibodies is one of the strategies for targeting the specific key points of the main pathways of cancer growth and survival, but only a few antibodies have offered a clear clinical benefit in the treatment of non-haematological malignancies.

Areas covered: This review summarizes the general properties of monoclonal antibodies, including structure, nomenclature and production techniques. The antibodies approved for use in clinical practice for the treatment of non-haematological tumors and those antibodies still being developed in this setting are briefly described. The types of antibody fragments are also reported.

Expert opinion: Monoclonal antibodies were initially developed in order to avoid the cytotoxic effects of chemotherapy on healthy tissues. However antibodies have not yet replaced chemotherapy agents, since the combination of both kinds of drugs have usually appeared to achieve higher benefit compared with chemotherapy alone. The research for the development of new monoclonal antibodies aims to identify further targets and to provide innovative antibody constructs.     

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.     

Monoclonal antibodies for treating gastric cancer: promises and pitfalls

ABSTRACT

Introduction: Gastric cancer (GC) presents dismal prognosis when diagnosed at advanced stages, standard chemotherapy having shown little efficacy. Introduction of biotherapies interfering with novel targets and signaling pathways is currently an emerging strategy.

Areas covered: Only two monoclonal antibodies (trastuzumab and ramucirumab) have been approved, mostly in association with cytotoxics. Conversely, testing other promising biotherapies (panitumumab, cetuximab, bevacizumab, rilotumumab) have yielded conflicting results, since encouraging early clinical trials have failed to be confirmed in larger phase-III studies. Empirical and underpowered strategies when designing combinational studies, lack of comprehensive knowledge of pharmacokinetics/pharmacodynamics (PK/PD) relationships, and underestimation of the large inter-patient variability in drug exposure levels with monoclonal antibodies, could explain the failures in developing biotherapies in gastric cancer.

This review covers the achievements and limits of monoclonal antibodies in gastric cancer and proposes clues to overcome current failures.

Expert opinion: Trastuzumab efficacy could be improved thanks to its combination with triplet chemotherapy or with another anti-HER2 agents or in continuation during second-line chemotherapy. Concerning ramucirumab, further studies are necessary to prove its interest in first line treatment of advanced GC, to use the optimal dose in each patient-given the large inter-patients variability, and to find predictive biomarkers of efficacy.     

Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody

Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had coexpression of total and phosphorylated IGF-1R and EGFR at high levels compared with paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.     

Selection of chemotherapy for patients with advanced non-small cell lung cancer

Chemotherapy remains the first-line treatment for most patients with stage IV non-small cell lung cancer (NSCLC), but optimal regimens are now defined by histology. Platinum-based regimens with pemetrexed, bevacizumab, or both are reasonable first-line options for patients with nonsquamous NSCLC. The standard treatment for squamous NSCLC remains a platinum doublet with a drug other than pemetrexed. Maintenance therapy is emerging as a treatment strategy for patients who do not progress after four cycles of first-line chemotherapy. In the maintenance setting, pemetrexed and erlotinib significantly prolong overall survival compared with placebo after the completion of first-line chemotherapy.     

Cost-effectiveness Analysis of Monoclonal Antibodies in the First-line Treatment of RAS Wild-type Metastatic Colorectal Cancer: A Systematic Review

PurposeFirst-line treatment with monoclonal antibodies (bevacizumab, cetuximab, and panitumumab) for RAS wild-type metastatic colorectal cancer (mCRC) has advanced. The costs of drugs targeted to mCRC are high. This systematic review aimed to summarize the cost-effectiveness of monoclonal antibodies in the first-line treatment of RAS wild-type mCRC.MethodsWe searched 5 databases to find original-research cost-effectiveness analyses of monoclonal antibodies used in the first-line treatment of patients with RAS wild-type mCRC. Three reviewers independently evaluated all of the records to be screened.FindingsA total of 15 articles, 12 cost-effectiveness analyses, and 3 cost-utility analyses were identified. The reporting of identified articles was assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. They were assigned to 1 of 6 categories based on the combination of the intervention and control groups, the most common of which was cetuximab + chemotherapy versus bevacizumab + chemotherapy. The results of the cost-effectiveness analyses may have varied because of the differences in settings, such as country, study population, RAS mutation status, efficacy data, and model structure, in which each study was conducted.ImplicationsAlthough treatment with monoclonal antibodies has demonstrated efficacy in terms of life-years gained and progression-free survival, the most cost-effective treatment among monoclonal antibodies remains controversial; however, most of the studies that compared a monoclonal antibody + chemotherapy versus chemotherapy alone reported that chemotherapy alone was a cost-effective strategy. Future studies are needed to evaluate the cost-effectiveness of treating patients with mCRC using biomarker-driven precision medicine.     

The role of epidermal growth factor receptor in advanced non‐small cell lung carcinoma

Chemotherapy is the standard of care for patients with advanced non‐small cell lung cancer (NSCLC). Over the past 20 years, advances in chemotherapy have shown minimal incremental improvement in the survival outcomes of patients with advanced NSCLC. With the identification of molecular and genetic alterations in lung cancer, several new potential rationally designed therapeutic targets have emerged. One of these is the epidermal growth factor receptor (EGFR) and member of the ErbB family of receptor tyrosine kinases. Several inhibitors, both antibodies directed at the extra‐cellular portion of the receptor, and small molecule inhibitors directed at the tyrosine kinase domain of EGFR are in clinical development in lung cancer. This article will review the pre‐clinical rationale and the clinical studies of EGFR inhibitors alone and/or in combination with chemotherapy that have been performed to date in advanced NSCLC.