The safety of ramucirumab for the treatment of colorectal cancer

Introduction: Ramucirumab, a human monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), is an antiangiogenic therapy that has been approved in combination with FOLFIRI in second-line treatment of metastatic colorectal cancer (mCRC), after progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A thorough review of the safety of ramucirumab in this setting and in the context of other antiangiogenic agents is merited.

Areas covered: We provide an overview of activity and summarize in detail the overall safety and tolerability profile of ramucirumab in mCRC patients on the basis of a literature review of all published clinical trials in this setting, including both single-agent and combination studies. A focus on adverse events of interest and specific populations is included, as well as a critical comparison with other antiangiogenic therapies.

Expert opinion: As an effective agent in pretreated mCRC patients, the toxicity profile of ramucirumab is similar to those of other angiogenesis inhibitors used in the second-line mCRC setting. The next challenge will be to find biomarkers of response and toxicity to antiangiogenic therapies in order to more effectively implement personalized medicine in these patients.     

Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies

INTRODUCTION: The typical class side effect of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab and cetuximab) is a cutaneous maculopapular rash, although hypomagnesemia is also described to be a frequent adverse event. The purpose of our meta-analysis is to evaluate the frequency and the relative risk of hypomagnesemia in patients treated with cetuximab or panitumumab in randomized trials. AREA COVERED: Eligible studies included prospective randomized Phase III controlled trials in which cetuximab or panitumumab were compared with standard anti-neoplastic therapy or best supportive care. Summary incidence rates and relative risks with 95% confidence intervals were calculated. EXPERT OPINION: The overall incidence of hypomagnesemia was 17% among the patients who received the treatment, whose risk of developing hypomagnesemia turned out to be significantly increased compared with the patients treated with control medication, with an overall relative risk of 5.83 (p < 0.00001), where 3.87 refers to cetuximab and 12.55 to panitumumab. The addition of anti-EGFR monoclonal antibodies to standard anticancer therapy showed a significantly increased risk of hypomagnesemia compared with controls. The risk seems to be even higher for panitumumab, probably correlated with the increased risk of other adverse events (e.g., diarrhea and dehydration). Hypomagnesemia does not seem to be linked with any serious complications.     

Targeted therapy in colorectal cancer: current status and future challenges

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.     

Use of monoclonal antibodies for metastatic colorectal cancer in the andalusian public health system

Background The place of monoclonal antibodies in metastatic colorectal cancer has not been clearly defined. Objective To determine the treatment pattern of monoclonal antibodies in colorectal cancer patients in the Andalusian Public Healthcare System. Method Data were collected from all patients treated with these drugs from July 2009 to December 2010 from pharmacy programs and medical records. Results Three hundred patients were included, of whom 227 received the antibody at the forefront. The proportion of patients who received bevacizumab in the first line is greater than that of cetuximab (62.1 vs. 37.5 % respectively) and similar in the second line and subsequent (47.8 vs. 53.8 % and 48.5 vs. 46.2 % respectively). XELOXbevacizumab was the most frequently prescribed scheme (35.3 %) followed by FOLFOX-monoclonal antibody schemes, regardless that this was bevacizumab or cetuximab (22.5 %). The median progression free survival (PFS) was 11.7 months for patients receiving cetuximab, 9.6 months for patients receiving bevacizumab and 8.2 months for those who received no monoclonal antibody in the first line. Conclusion Bevacizumab was the antibody of choice in first line, showing utilization rates similar to cetuximab in second line and subsequent. The median PFS in our study is related to the PFS of the major clinical trials.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS .     

Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer

Introduction: Colorectal cancer is the third most common cancer worldwide. The prognosis of colorectal cancer patients still remains dismal and half of them will develop metastatic disease. Angiogenesis plays an essential role in colorectal tumorigenesis, and the VEGF pathway is one of the targets that has been validated up to now. The use of antiangiogenics along with chemotherapy has become an accepted standard for colorectal cancer.

Areas covered: This review discusses the efficacy and safety profile of ramucirumab, a fully human immunoglobulin G1 monoclonal antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2), for the treatment of second-line metastatic colorectal cancer upon progression to first-line chemotherapy including anti-angiogenics.

Expert opinion: Ramucirumab in combination with chemotherapy represents a valid option in second-line treatment of advanced colorectal cancer patients, who progressed on previous bevacizumab-based combinations. This agent demonstrates a similar benefit in terms of overall survival to other angiogenesis inhibitors (bevacizumab and ziv-aflibercept) used in this setting.     

Small molecule dipeptidylpeptidase IV inhibitors under investigation for diabetes mellitus therapy

Importance of the field: Fluoropyrimidines with oxaliplatin or irinotecan, bevacizumab, cetuximab and panitumumab constitute the drugs currently approved by the FDA for the treatment of patients with metastatic colorectal cancer (mCRC). Patients who have progressed on the approved drugs pose a major challenge for medical oncologists, as the therapeutic choices outside the context of a clinical trial are limited.

Areas covered in this review: Mitomycin C is an old drug that acts synergistically with capecitabine and irinotecan. Relevant studies were identified in PubMed (years 1950 – 2009), Ovid, Cochrane database and the American Society of Clinical Oncology abstracts (years 1995 – 2009) using the following search terms: mitomycin C, fluorouracil, capecitabine, irinotecan, oxaliplatin, and colorectal cancer. Only studies using the combination of mitomycin C with one of the aforementioned agents were selected.

What the reader will gain: An overview of the clinical trials where mitomycin has been used in combination with modern compounds in the various settings of metastatic colorectal cancer.

Take home message: Mitomycin C combinations are less efficacious than modern drugs in the first-line treatment of colorectal cancer. However, they are acceptable alternatives for best supportive care in colorectal cancer that is refractory to standard regimens, as they show some modest efficacy at low cost.     

Pharmacogenetics of EGFR and VEGF inhibition

Even though treatment of several types of solid tumours has improved in the past few years with the introduction of the monoclonal antibodies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), response rates to these targeted therapies are modest. Pharmacogenetic factors have the potential to select patients with higher chance of response to agents that target these pathways. This review provides an overview over germ-line variations in genes that are potentially involved in the pharmacodynamics of the monoclonal antibodies cetuximab, panitumumab and bevacizumab, and which may underlie variable anti-tumour response.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

贝伐珠单抗相关不良反应的文献分析

目的 分析贝伐珠单抗不良反应(ADR)发生率、发生类型和严重程度,为临床安全合理使用提供参考.方法 采用文献计量分析的方法,以"贝伐珠单抗""安维汀""阿瓦斯汀""avastin""bevacizumab""不良反应""副作用""adverse reaction"为关键词,检索万方、中国知网、维普、PubMed、Spr...     

Novel anti-angiogenic therapeutic strategies in colorectal cancer

Introduction: Anti-angiogenetic agents are currently the standard of care in metastatic CRC patients. Bevacizumab, aflibercept, regorafenib and recently ramucirumab have significantly improved both progression-free and overall survival in different lines of treatment. Since bevacizumab’s approval, a number of novel anti-VEGF agents have been tested in preclinical and clinical models.

Areas covered: This review is focused on the most recent clinical results of novel agents targeting VEGF and its receptors with a major focus on those investigated recently in clinical trials.

Expert opinion: In the last 15 years, a number of new anti-angiogenetic agents have been tested. Unfortunately, most of them have demonstrated unacceptable toxicities or failed to show activity. When tested as single agents, encouraging preliminary results were reported with fruquintinib, famitinib, and nintedanib. Interesting novel mechanisms of action are also being explored: VGX-100 is a monoclonal antibody (mAb) which binds to VEGF-C, inhibiting activation of VEGFR-2 and VEGFR-3 when combined with bevacizumab; tanibirumab is a mAb which binds to VEGFR-2 and vanucizumab is a bispecific mAb binding both to VEGF-A and Angiopoietin-2. Data about the combination of these agents with chemotherapy are very encouraging, even though preliminary. However, the definition of specific predictive biomarkers remains a priority.     

国内靶向药物治疗结直肠癌的经济学研究系统评价

目的 了解国内靶向药物治疗结直肠癌的经济学评价研究进展,总结其模型结构、参数纳入与研究结果。方法 计算机检索PubMed、Web of Science、Embase、Scopus、CNKI、VIP、Wanfang Data数据库,搜集结直肠癌靶向药物的经济学研究,检索时限为建库至2022年7月31日。利用Excel提取文献信息,使用CHEERS 2022版质量评价表评估文献质量。结果 初检共获得871篇文献,最终纳入17篇,文献质量整体较好,涉及5种靶向药物,均为成本-效用分析,除1篇使用前瞻性队列研究外,其余均使用模型研究。西妥昔单抗、贝伐珠单抗、帕尼单抗与标准化疗相比均不具经济性。抗表皮生长因子受体单克隆抗体(Anti-EGFR mAb)一线治疗RAS野生型左侧转移性结直肠癌较贝伐珠单抗更具经济性。呋喹替尼相较瑞戈非尼具有经济学优势。结论 未来建议综合比较多种靶向治疗方案的经济性并关注更多靶向治疗选择,并注意生物标志物和原发肿瘤部位的影响。国家医保报销、企业优惠政策和国产新药研发均可促进药品惠及患者。     

Patterns of treatment with chemotherapy and monoclonal antibodies for metastatic colorectal cancer in Western Europe

Abstract

Background and objectives:

Treatment outcomes improved in metastatic colorectal cancer (mCRC) due to the introduction of new chemotherapies and monoclonal antibodies. This study describes current patterns of pharmacological treatment for mCRC in clinical practice in four European countries.     

西妥昔单抗或贝伐单抗联合FOLFOX4方案治疗野生型KRAS晚期直肠癌的临床疗效

目的 比较西妥昔单抗联合FOLFOX4与贝伐单抗联合FOLFOX4两种方案治疗野生型KRAS晚期直肠癌的临床疗效及安全性。方法 选取2012年1月-2017年1月至柳州市柳江区人民医院肿瘤内科治疗的野生型KRAS晚期直肠癌患者75例,根据治疗方案的不同分为A、B、C 3组,A组23例单纯利用FOLFOX4方案治疗,B组27例采用贝伐单抗联合FOLFOX4方案,C组25例采用西妥昔单抗联合FOLFOX4方案,比较各组临床有效率,观察每组不良反应发生情况。随访后,计算各组平均无进展生存期（PFS）。结果 3组客观有效率（ORR）分别为13.04%、51.85%、60.00%,AB、AC组间比较差异均有统计学意义（P<0.01）,B、C两组间差异无统计学意义。3组疾病控制率（DCR）分别为73.91%、88.89%、92.00%,各组之间两两比较差异也均无统计学意义。A、B、C 3组中位PFS分别为8.2、10.1、9.4个月,3组间中位PFS差异无统计学意义,3组患者均未出现治疗相关的死亡,主要不良反应有骨髓抑制和呕吐,另外偶发外周神经毒性、肝损伤、手足综合症等,发生率较低。B组未出现贝伐单抗相关的高血压、鼻出血、肠穿孔等不良反应,C组出现6例皮疹（24.00%）。结论 西妥昔单抗或贝伐单抗联合FOLFOX4方案均可提高野生型KRAS晚直肠癌的临床疗效,两种方案疗效相当,不良反应均较小,值得临床推广使用。     

Combining molecular targeted therapies: clinical experience

Approximately 20 molecular targeted therapies, mainly monoclonal antibodies and tyrosine kinase inhibitors, have been approved for the treatment of various cancers. They are being increasingly investigated in combination in clinical trials. We review the rationale for combining molecular targeted therapies and the results of clinical trials to date. There have been some exciting clinical results with some combinations, for example, lapatinib/trastuzumab or bevacizumab/trastuzumab in HER2-positive metastatic breast cancer, whereas other potential combinations have provided disappointment, for example, cetuximab or panitumumab in combination with bevacizumab/chemotherapy in first-line treatment of metastatic/advanced colorectal cancer. Therefore, at this point no general guidance to study such combinations can be derived.     

Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments

The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors.     

The potential role of nintedanib in treating colorectal cancer

Introduction: Angiogenesis leads to the growth, progression, and metastases of a variety of solid tumors, including metastatic colorectal cancer (mCRC), involving particularly the family of vascular endothelial growth factors (VEGF) and their receptors (VEGFR). Several anti-angiogenic inhibitors are already registered for mCRC therapy: bevacizumab, aflibercept, ramucirumab, regorafenib. Nintedanib is a new triple angiokinase oral inhibitor that potently blocks the proangiogenic pathways mediated by VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR).

Areas covered: The current state-of-the-art of anti-angiogenic inhibitors employed in the treatment mCRC patients, and in particular the role of nintedanib in this setting, is reviewed and discussed here. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert opinion: In first-line therapy, a phase II randomized trial showed that nintedanib plus chemotherapy was not inferior to the bevacizumab-based regimen. In heavily pretreated mCRC patients nintedanib improved some outcomes. During the natural history of mCRC resistances to anti-angiogenic therapies can set in and in this context, nintedanib, due to its triple inhibition, might play a role in compensatory angiogenesis overcoming the resistance developed due to VEGF directed therapy.     

安罗替尼治疗恶性肿瘤的不良反应分析

目的 了解安罗替尼（AL3818）的安全性,以便更好地应用该药,为患者提供更安全、有效的治疗。方法 收集安罗替尼在临床应用中的常见不良反应信息,结合现有的临床数据,对比安罗替尼与同类抗肿瘤药物的不良反应类型及发生率的差别。结果 安罗替尼的不良反应主要为食欲减退、乏力、蛋白尿、血尿、腹痛、呕吐、腹泻、高血压和手足综合征等,其中1级、2级不良反应78例（96.30%）,3级不良反应3例（3.70%）。与同类抗肿瘤药物相比,安罗替尼的出血、高血压、蛋白尿等不良反应发生率明显低于阿帕替尼和贝伐珠单抗,差异均具有统计学意义（P<0.05）。结论 盐酸安罗替尼胶囊用于治疗恶性肿瘤安全性较高。     

贝伐珠单抗治疗转移性结直肠癌不良反应的Meta分析

目的 评价贝伐珠单抗联合化疗在转移性结直肠癌(mCRC)中不良反应的发生率,并分析各种不良反应的总体风险。方法 制定文献纳入、排除标准,全面检索Cochrane Library,Pubmed,EMBASE,CNKI,CBM以及万方数据库,纳入相关文献。采用Cochrane协作网提供的RevMan 5.1专用软件进行数据合并与统计分析。结果 共纳入7项研究(n=3 493),贝伐珠单抗联合化疗组患者1 889例,单纯化疗组患者1 604 例。比较各项不良反应的发生率,结果接受贝伐珠单抗治疗的mCRC患者患高血压(RR=3.93,P<0.001)、蛋白尿(RR=3.76,P=0.009)、胃肠穿孔和瘘管(RR=4.10,P=0.02)、3~4级的出血(RR=1.94,P=0.01)和血栓栓塞(RR=1.33,P=0.008)的危险性增高;肺栓塞(RR=0.78,P=0.44)、中性粒细胞减少(RR=1.15,P=0.14)和腹泻(RR=1.17,P=0.09)等风险在两组中无明显差别。所有3~4级的不良反应(RR=1.16,P<0.001)在贝伐珠单抗联合化疗组轻度增加。两组mCRC患者中治疗相关的致死性不良反应发生率相当(RR=1.09,P=0.74),贝伐珠单抗治疗组患者因不良反应中断治疗(RR=1.25,P=0.003)的风险更高。结论 与单纯接受化疗相比,接受贝伐珠单抗联合化疗治疗的mCRC患者出现高血压、蛋白尿、胃肠穿孔、血栓栓塞和出血的危险性更高,但并未增加致死性不良反应发生率。