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.     

Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer

Angiogenesis is the process by which new blood vessels are created from pre-existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor-A (VEGF-A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab-related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.     

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.     

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.     

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.     

肺癌中EGFR、VEGF与NET-1的表达及与临床病理因素的关系

目的探讨表皮生长因子受体(EGFR)、血管内皮生长因子(VEGF)、NET-1在肺癌中的表达及其与临床病理因素的关系。方法采用免疫组织化学SP法,检测120例肺癌组织及10例正常肺组织(对照组)中EGFR、VEGF、NET-1的表达。结果 EGFR、VEGF、NET-1在肺癌中的阳性表达率(69.16%、55.83%、85.00%)明显高于正常肺组织(10.00%、0.00%、40.00%)。EGFR、VEGF、NET-1蛋白在肺癌中的表达差异与患者性别、年龄、病变部位无关(P均>0.05),但与肺癌组织的分化程度、临床分期、有无淋巴结转移相关(P<0.05)。结论 EGFR、VEGF、NET-1的阳性表达与肺癌的分化程度、临床分期、淋巴结转移有关,且在癌组织中表达强度显著高于正常组织,提示三者具有促进肿瘤细胞转化、增殖、迁移的作用,可作为临床判定肺癌恶性程度及评估预后的指标。     

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.     

Update of cetuximab for non-melanoma skin cancer

Introduction: Non-melanoma skin cancer (NMSC) has become the most common malignancy in humans. Targeted therapies are recent developments for these tumors. Monoclonal antibody cetuximab has proven its efficacy and has improved tolerability compared to classical chemotherapy protocols, and this prompted us to analyze new data on the use of cetuximab in cutaneous NMSC.

Areas covered: The monoclonal antibody cetuximab against epidermal growth factor receptor (EGFR) has been investigated for its use in NMSC during the years between 2011 and 2013. A PUBMED research 2011 – 2013 has been conducted using the following terms: ‘Non-melanoma skin cancer AND cetuximab’, ‘cutaneous squamous cell carcinoma AND cetuximab’, and ‘basal cell carcinoma AND cetuximab’ and ‘cetuximab AND skin toxicity’. Available data were analyzed – irrespective of their level of evidence, that is, case reports and case series were included.

Expert opinion: Current evidence of cetuximab's efficacy in NMSC was mainly obtained in cutaneous squamous cell carcinoma (SCC) and to a lesser extent in basal cell carcinoma (BCC). Response rates vary for neoadjuvant, adjuvant, monotherapy and combined therapy with cetuximab. Limitations are the low number of patients treated (33 patients with SCC, 4 patients with BCC) and the low quality of studies reported. Management of cutaneous toxicities of EGFR inhibitors is necessary, and guidelines are available. Proactive therapy might also prevent skin toxicity of higher grades, with EGFR inhibitor cetuximab as an option for recurrent or advanced NMSC of the skin. It seems to be justified particularly in very high risk epithelial tumors. There is an urgent need for Phase III trials. In the future, combined drug therapy with other monoclonal antibodies and/or radiotherapy may further improve efficacy and response rates for NMSC.     

Panitumumab in colon cancer: a review and summary of ongoing trials

Panitumumab is a fully human antibody developed against the human epidermal growth factor receptor receptor (EGFR/HER-1), which is overexpressed in ≥ 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and has the promise of decreased infusion reactions. Clinical studies have demonstrated that panitumumab has significant activity as a single agent and improves progression-free survival when compared with best supportive care. It can also be safely combined with standard cytotoxic chemotherapy. Ongoing studies are being performed to determine if the addition of panitumumab to first-line standard treatment for metastatic colorectal cancer will improve the progression-free and overall survival of these patients.     

Cetuximab in non-melanoma skin cancer

Human epidermal growth factor receptor 2 (HER2) was acknowledged as an important therapeutic target in breast cancer more than 25 years ago. Subsequently, significant basic science and translational discoveries have resulted in the approval of four HER2-targeted therapies over the past 15 years. This editorial discusses future challenges regarding selection and development of treatments for HER2-positive breast cancer, which can only be met by continuing to support research efforts into the basic mechanisms by which cancer cells escape targeted therapies. Identifying specific molecular mechanisms underlying the sensitivity or resistance to each HER2-targeted agent will ultimately allow individualized therapy for each patient.     

The developing trend of monoclonal antibodies in the treatment of colorectal cancer

Monoclonal antibodies (mAbs) against growth factors, receptors and tumor-specific/tumor-selective antigens represent a rapidly growing class of pharmaceutical agents which are poised to make a major impact on the treatment of colorectal cancer. mAbs targeting the epidermal growth factor receptor and the vascular endothelial growth factor have already been approved for the treatment of metastatic colorectal cancer. Other antibodies to the same and other molecular targets implicated in tumor growth and metastasis are undergoing intense preclinical and clinical evaluation. In both the neoadjuvant and adjuvant clinical settings, although mAbs are typically administered in combination with established cytotoxic chemotherapy regimens given their synergistic effect, several agents have demonstrated efficacy when given as monotherapy. At the same time, combination therapies with multiple targeted biological agents are actively being investigated. Existing clinical data and recent progress in preclinical and clinical studies of mAbs are reviewed.     

乳腺癌患者手术前后相关实验室数据的检测意义

目的探讨乳腺癌患者手术前后可溶性细胞膜糖蛋白(Endoglin)、血管内皮生长因子(VEGF)、表皮生长因子受体(EGFR)的水平变化,分析可溶性Endoglin、VEGF和EGFR水平检测在乳腺癌患者中的临床意义。方法选取2016年10月至2018年9月在该院进行手术的乳腺癌患者52例作为观察组,以同期健康体检者50例作为对照组,分别检测观察组手术前后和对照组可溶性Endoglin、VEGF和EGFR水平,并对数据进行比较分析。结果观察组患者手术前可溶性Endoglin、VEGF和EGFR表达水平均明显高于对照组,差异均有统计学意义(P<0.05);观察组患者手术前可溶性Endoglin、VEGF和EGFR表达水平均明显高于手术后,差异均有统计学意义(P<0.05);观察组患者手术后可溶性Endoglin、VEGF和EGFR表达水平与对照组比较,差异均无统计学意义(P>0.05)。结论在乳腺癌患者中,存在可溶性Endoglin、VEGF和EGFR表达水平异常,可溶性Endoglin、VEGF和EGFR水平检测对乳腺癌患者手术前后的病情观察及预后有一定临床应用价值。     

Cetuximab in the treatment of patients with colorectal cancer

Introduction: Cetuximab is a chimeric mAb with avidity for the EGFR higher than that of the natural ligands of the receptor. Preclinical studies showed that cetuximab demonstrated synergy with topoisomerase I inhibitors in the treatment of human colorectal cancer (CRC) cell lines in vivo. Subsequent clinical trials have shown that cetuximab can reverse resistance to topoisomerase I inhibitors in addition to having modest monotherapy activity. These studies led to accelerated provisional FDA approval of the drug for the treatment of patients with irinotecan-refractory metastatic CRC. Its clinical utility has been improved with the discovery of negative predictive biomarkers; these have shown that there is a lack of cetuximab benefit for patients whose tumors generally harbor a KRAS mutation, thus sparing these patients the toxicity of the agent which would not be of treatment benefit.

Areas covered: This review covers the last decade of clinical trials that have determined the toxicity and efficacy of cetuximab when given to patients with CRC, as well as some of the molecular subgroups tumors from patients with CRC who appear to not derive benefit from this mAb.

Expert opinion: Cetuximab has modest single-agent efficacy in the treatment of patients with metastatic CRC whose tumors do not harbor a KRAS mutation. In combination with irinotecan, it is associated with an overall survival (OS) and progression-free survival (PFS) advantage in first-line therapy in patients with KRAS non mutant metastatic CRC; it can be combined with irinotecan to overcome resistance in patients with KRAS non mutant CRC who have previously progressed on prior irinotecan chemotherapy. Future studies of putative biomarkers are likely to give additional information to clearly define which patients with metastatic CRC receive therapeutic benefit from cetuximab and other monoclonal anti-EGFR therapies.     

Bevacizumab in the treatment of colorectal cancer

Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, and has been shown to improve survival when given with chemotherapy to patients with metastatic colorectal cancer. In a pivotal Phase III clinical trial, 813 subjects were treated with irinotecan, 5-fluorouracil (5-FU) and leucovorin and randomised to receive placebo or bevacizumab. Median survival for the group receiving bevacizumab was increased by 30%, from 15.6 to 20.3 months (p ≤ 001). Other Phase II and III studies in colorectal cancer have demonstrated a benefit when bevacizumab is added to regimens of 5-FU and leucovorin, and 5-FU, leucovorin and oxaliplatin. The toxicity associated with bevacizumab is generally mild, consisting of manageable hypertension, clinically insignificant proteinuria and mild mucosal bleeding. Infrequent severe toxicities have been reported, consisting of arterial thrombosis and gastrointestinal perforations (1.5%). Bevacizumab represents the first angiogenesis modulator that has a proven benefit in cancer therapy.     

The role of cetuximab in the treatment of squamous cell cancer of the head and neck

The epidermal growth factor receptor (EGFR) is a member of the HER family of tyrosine kinase growth factor receptors. Binding to EGFR by its natural ligands, mainly epidermal growth factor (EGF) or transforming growth factor (TGF)-α, results in a conformational change in the receptor, which promotes homo- or heterodimerisation or oligomerisation with other EGFR molecules or other HER family members. Dimerisation results in the activation of intracellular tyrosine kinase, autophosphorylation and activation of signal transduction molecules, ultimately leading to cell cycle progression, reduced apoptotic capacity, angiogenesis and the metastatic phenotype. EGFR is expressed on normal human cells and also across a range of malignancies. Tumour EGFR expression correlates with poor prognosis and resistance to therapy. Cetuximab is a chimeric human:murine monoclonal antibody that binds competitively to the EGFR. Binding of the antibody to the EGFR prevents activation of the receptor by endogenous ligands; proliferation is reduced, apoptosis enhanced, and angiogenesis, invasiveness and metastasis reduced. Binding of cetuximab to the receptor also results in internalisation and degradation of the antibody–receptor complex, downregulating EGFR expression. EGFR has been recognised as an important therapeutic target in cancer. Other antibodies are also in development, and small molecular inhibitors of the tyrosine kinase domain are available. Cetuximab adds to the activity of radiotherapy in locoregional head and neck cancer, and when given with platinum-based chemotherapy is active in a proportion of patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck, as is cetuximab monotherapy. When cetuximab is added to cisplatin monotherapy in the first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck, the objective response rate is significantly improved and the hazard ratio for progression is 0.78. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that occurred in 70 – 80% of patients treated with cetuximab. Presence of the characteristic rash is significantly associated with response and/or survival. It is possible that development of acneiform rash may become an important clinical prognostic marker. Serious cetuximab-related toxicities include hypersensitivity reactions. Thus, cetuximab is biologically active across a range of clinical scenarios in squamous cell carcinoma of the head and neck. Ongoing studies will be important in establishing its role in the routine management of head and neck cancer.     

Bevacizumab: current indications and future development for management of solid tumors

Background: Angiogenesis is essential for cancer growth and metastasis. VEGF is a key modulator of angiogenesis and its overexpression is correlated with advanced disease and poor prognosis. Bevacizumab, a recombinant humanized anti-VEGF mAb, is the most clinically advanced anti-angiogenic agent. Although bevacizumab has received most attention for first-line treatment of advanced colorectal and non-small-cell lung cancer, there is a rapidly growing body of evidence for its efficacy in treatment of a number of other solid tumors. Objective/methods: We present the background, current status, and important ongoing trials involving the use of bevacizumab therapy. Results/conclusions: Bevacizumab has an established role in the treatment of metastatic colon, breast, and lung cancer. Yet many questions remain on its use in other disease types and demographic groups.     

miRNA-484预计胃癌小鼠中抗血管内皮生长因子靶向治疗的反应研究

目的:探讨人胃癌动物模型中抗血管内皮生长因子(vascular endothelial growth factors,VEGF)靶向治疗与miRNA表达的关系。方法:人胃癌MGC-803细胞系接种到BLBA/c裸鼠左后肢皮下。当肿瘤达5 mm左右后随机分为A组(抗VEGF+化疗)、B组(化疗)和c组(空白对照),每组8只,持续4w腹腔给药,每天测量肿瘤的最大径和最小径,以肿瘤体积大小为衡量药效的指标。采用PT-PCR检测mir484的表达。结果:A组对肿瘤生长的抑制作用明显优于B组,且mir484的表达明显下降。结论:Mir484与胃癌的抗血管治疗疗效明显相关,可成为新型的胃癌靶向治疗的生物标志。     

IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody,for treatment of head and neck cancer

Squamous cell carcinoma (SCC) of the head and neck (H&N) remains a clinical challenge due to its high rate of locoregional disease recurrence. The importance of the epidermal growth factor receptor (EGFR) in the development and progression of many solid tumours (including SCC of the H&N) is well understood; increased expression is associated with enhanced tumour invasion, resistance to chemotherapy and decreased patient survival. Several approaches have been developed to achieve EGFR blockade as an anticancer treatment strategy, including an anti-EGFR monoclonal antibody (mAb), IMC-C225, which competetively binds to the extracellular receptor site to prevent binding by natural EGFR ligands (EGF and TGF-α). Preclinical studies evaluating this chimeric mAb in human cancer cell lines in vitro and human tumour xenografts in vivo have demonstrated its potent antitumour activity. The clinical efficacy of IMC-C225 appears to involve multiple anticancer mechanisms, including inhibition of cell cycle progression, induction of apoptosis, anti-angiogenesis, inhibition of metastasis and its ability to enhance the response to chemotherapy and radiation therapy. Phase I studies of IMC-C225 combined with chemotherapy or radiation for SCC of the H&N demonstrate excellent response rates in patients with recurrent or refractory disease. Phase II and III trials examining the efficacy and safety of these combinations are currently underway. To date, IMC-C225 has been well-tolerated, with skin rashes and allergic reactions being the most clinically important adverse events reported. IMC-C225 displays dose-dependent elimination characteristics and a half-life of approximately 7 days. Current recommendations for dosing include a 400 mg/m² loading dose, followed by weekly infusions of 250 mg/m².     

Treg、Ki67和VEGF在结直肠癌中的表达及意义

目的 探讨调节性T细胞(Treg)、增殖细胞核抗原(Ki67)和血管内皮生长因子(VEGF)在结直肠癌(CRC)患者肿瘤微环境中的表达,以及Treg与Ki67、VEGF的相关性.方法 采用流式细胞术测定21例CRC患者的外周血以及肿瘤微环境和24例健康人外周血中Treg的表达,同时应用免疫组化法检测CRC组织中Ki67和VEGF的表达.结果 CRC患者肿瘤微环境中Treg比较[(26.84±10.22)%]明显高于外周血单个核细胞(PBMC)[(7.01±3.08)%],差异有统计学意义(P<0.01).Treg细胞表达频率在Dukes C期和D期(晚期)的肿瘤组织中[(35.01±6.78)%],明显高于Dukes A期和B期(早期)[(24.40±8.95)%],差异有统计学意义(P<0.05).相关分析表明Treg与Dukes临床分期呈正相关(r=0.511,P<0.05);Treg与Ki67的表达呈正相关(r=0.455,P<0.05);Treg与VEGF的表达呈正相关(r=0.198,P>0.05),但无统计学意义.结论 Treg与Ki67、VEGF的相互作用可能促进了肿瘤的发生、发展与转移,对CRC的预后评价有着重要的参考价值.