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.     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in young children and the elderly. Despite its clinical importance, there is no licensed vaccine available at present. Vaccine development has been hampered by observations of increased pathology after RSV infection in infants vaccinated with formalin-inactivated RSV; incomplete immunity following natural infection; and the need to be effective during the neonatal period when levels of maternal antibody are high. Four categories of RSV vaccine carriers – live-attenuated RSVs, recombinant vectors expressing the protective antigens of RSV, DNA vaccines and subunit vaccines – have been evaluated in animal models and/or clinical trials. So far, studies with live-attenuated virus vaccines highlight the need to improve immunogenicity whilst maintaining a suitable level of attenuation. Studies with recombinant vectors, DNA and subunit vaccines illustrate the pivotal nature of the vaccine carrier in determining the balance between immune-mediated protection against infection and the induction of immune-mediated pulmonary pathology.     

抗人非小细胞肺癌单克隆抗体的制备及鉴定

摘要：目的：制备抗人非小细胞肺癌（NSCLC）的单克隆抗体(McAb),并对其生物学特性及特异性进行鉴定。 方法：以人肺腺癌细胞株SPC-A1为抗原,免疫BALB/c小鼠,常规细胞融合,间接细胞ELISA法筛选阳性细胞克隆;多种细胞间接ELISA及间接免疫荧光法鉴定其特异性;western blot分析其特异性结合抗原的相对分子量;免疫组化染色分析单抗的组织特异性。 结果：得到1株高效价的、稳定分泌IgG1抗人NSCLC单抗的细胞株（NJ488-1）,纯化后效价为2×10⁶;间接细胞ELISA 及间接免疫荧光法证实NJ488-1能特异地识别肺癌细胞系,其识别抗原定位于SPC-A1细胞胞浆区;western blot显示NJ488-1特异性结合的抗原相对分子量(Mr)为70 000左右;免疫组化结果表明NJ488-1与NSCLC组织有强阳性反应。 结论:成功地制备并鉴定了抗人NSCLC单抗NJ488-1,为肺癌的进一步研究及NJ488-1的临床应用奠定了基础。     

Targeted therapies for non-small cell lung cancer

Despite recent advances in current chemotherapy, the prognosis for locally advanced and metastatic nonsmall-cell cancer remains poor, and new approaches are required. An increased understanding of the biology of lung cancer has identified pathways mediated by receptor tyrosine kinases as an important target. The epidermal growth factor receptor (EGFR) is frequently expressed on the surface of the lung cancer cell. EGFR can be targeted by inhibitors of receptor tyrosine kinase activity such as erlotinib and gefitinib and by antibodies specific for the extracellular domain. Subset analysis of responders to the receptor tyrosine kinase inhibitors suggests that clinical benefit may correlate with the presence of EGFR mutations. Other drugs in earlier clinical development include those directed against HER-2, VEGF, farnesyl transferase, COX-2 and retinoid receptor.     

紫杉醇联合顺铂治疗晚期非小细胞肺癌的临床研究

目的：观察紫杉醇联合顺铂治疗晚期非小细胞肺癌的近期疗效厦不良反应。方法：国产紫杉醇85mg／m^2静脉滴注第1，8，15d用药；顺铂20mg／m^2静脉滴注1～5d用药。28d为1周期，连用3周期。结果：30例可评价疗效总有效率（CR＋PR）53．3％，其中CR1例为初治患者，有效率60％，复治患者有效率33．3％。不良反应为骨髓抑制、脱发、关节肌肉疼痛、消化道反应，其他不良反应轻微均可耐受。结论：紫杉醇联合顺铂治疗晚期非小细胞肺癌可获得较好疗效且不良反应可耐受。     

Pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer.

Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC.

Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.     

立体定向放射治疗非小细胞肺癌的临床观察

目的　观察立体定向放射治疗 (体部伽玛刀 )非小细胞肺癌近期疗效和不良反应。方法　采用国产OUR QGD型体部伽玛刀治疗Ⅰ～Ⅲa期非小细胞肺癌 5 3例 ,比较治疗前后临床症状、有效率和不良反应。结果　 5 3例患者临床症状明显改善 ,治疗总有效率 88 6 % ,完全缓解 (CR) 10例 (2 2 6 % ) ,部分缓解(PR) 35例 (6 6 % ) ;治疗效果与肿瘤大小呈显著相关 (χ2 =2 4 5 6 ,P <0 0 1) ;治疗前后血常规、肺功能无明显变化 (P >0 0 5 ) ;19例患者于治疗后出现轻度乏力、食欲减退。结论　体部伽玛刀治疗非小细胞肺癌有较好近期疗效 ,不良反应少且轻。     

CIMAvax-EGF,a therapeutic non-small cell lung cancer vaccine

Introduction: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy.

The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction.

Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials.

Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.     

Current knowledge of Ipilimumab and its use in treating non-small cell lung cancer

Introduction: The systemic treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the identification of actionable mutations and the use of targeted agents. Unfortunately, many tumors will acquire resistance and >75% of NSCLC cases lack for an actionable gene aberration. In this setting, immunotherapy rises as effective therapeutic where immune checkpoint inhibitors have entered or are entering the market in many neoplasms, including NSCLC. Ipilimumab is a monoclonal antibody targeting CTLA-4, promoting T-cell activation and its subsequent anti-tumoral immune effect. Ipilimumab might have a very important role in NSCLC as it does in melanoma because of its synergistic effect with PD-1/PDL-1 inhibitors.

Areas covered: We summarize current results of clinical studies of ipilimumab for efficacy and safety in NSCLC and also the current knowledge about potential biomarkers for its efficacy.

Expert Opinion: Combined use of PD-1/PDL-1 and anti-CTL4 inhibitors increases the efficacy against NSCLC and it is a very promising approach not only in NSCLC but also in small cell lung cancer (SCLC) for first or second-line therapy. It’s very important to identify biomarkers that can better select the population of patients that benefit the most with these checkpoint inhibitors.     

The development of immunotherapies for non-small cell lung cancer

Standard of care for non-small cell lung cancer (NSCLC) (surgery, chemotherapy and radiation) may enhance patient survival but the enhancement is typically transient and quite uncommon with advanced disease. Researchers and medical professionals are using new approaches to improve patient mortality and morbidity. One of these approaches, immunotherapy, seeks to stimulate antitumour immunity above a threshold level needed for tumour regression or to induce stability in the face of progression. Among the most established approaches are vaccines involving monoclonal antibodies (mAbs) or immune effector cells. These approaches stimulate the humoral and cell-mediated arms of the immune system, respectively. As the development of humanised or fully human antibodies has spurred exploration of radioimmunoconjugates and immunotoxins, mAbs have enjoyed a revival of sorts. Cell-based therapies using the tumour cell itself as a vaccine component has resulted in disease stabilisation or regression. In addition, immune cells (e.g., T-lymphocytes and dendritic cells [DCs]) are the focal point of numerous patient trials in which meaningful clinical impact was achieved. In general, there are many tactics under development for the treatment of NSCLC. This review primarily concerns immunotherapeutic cancer treatments that are either already in clinical trial or well progressed into preclinical studies.     

复方苦参注射液联合TP方案治疗非小细胞肺癌的临床观察

目的观察复方苦参注射液联合TP方案(紫杉醇联合顺铂)治疗非小细胞肺癌(NSCLC)的近期疗效及不良反应。方法 112例非小细胞肺癌患者随机分成两组,治疗组56例用复方苦参注射液联合TP方案,对照组56例只用TP方案治疗,连用2～4个周期,对比分析两组近期疗效、生活质量、毒副反应等方面变化。结果治疗组近期疗效优于对照组,差异有统计学意义(P0.05)。治疗组较对照组生活质量有明显改善,毒副作用明显降低,差异均有统计学意义(P0.05)。结论复方苦参注射液对小细胞肺癌化疗具有增效、减毒作用。     

Immunotherapy alone or chemo-immunotherapy as front-line treatment for advanced non-small cell lung cancer

Introduction: Immunotherapy, either as monotherapy or in combination with chemotherapy, has demonstrated superior efficacy to chemotherapy alone in the frontline setting. To date, there has been no randomized study comparing immunotherapy alone with chemo-immunotherapy.

Areas Covered: This paper reviews the immunobiological rationale for combining chemotherapy with checkpoint inhibitors as well as the data from recent phase-3 studies to understand the risks and benefits associated with either therapeutic approach for diverse patient populations.

Expert opinion: Frontline pembrolizumab monotherapy remains the treatment of choice for patients with high PD-L1 expression. For those with low PD-L1 expression, pembrolizumab in combination with chemotherapy can be considered.     

胃泌素释放肽前体对小细胞肺癌诊断的临床意义

目的探讨胃泌素释放肽前体(ProGRP)在小细胞肺癌(SCLC)诊断中的意义。方法收集2016年4月15日至7月19日明确诊断的SCLC 23例,非小细胞肺癌(NSCLC)40例,良性肺疾病患者(BPD)43例及健康对照组40例,检测患者血清中的ProGRP水平,评估其对SCLC的临床价值。结果 SCLC组中的ProGRP水平显著高于NSCLC组、BPD组和健康对照组,广泛期SCLC组的ProGRP水平高于局限期SCLC组,差异均有统计学意义(P0.05)。各组内ProGRP阳性率在性别和年龄间的差异无统计学意义(P0.05)。ProGRP诊断SCLC的临界值为65.66ng/L,敏感度和特异性分别为90.9%和89.9%。结论 ProGRP是1种敏感且特异的SCLC诊断指标,ProGRP水平的高低还可用于SCLC的病情监测。     

Surgical management of non-small cell lung cancer

OBJECTIVES: To provide an overview of the surgical management of early stage non-small cell lung cancer (NSCLC) and its impact on survival and quality of life. DATA SOURCES: Published articles, book chapters, websites, and research studies. CONCLUSION: The primary treatment choice for early stage NSCLC is surgical resection. Advances have been made in all phases of care from diagnosis to rehabilitation, including better technology for staging, less invasive surgical techniques, and intra-operative and post-operative care that focuses on decreasing complications and improving survival and quality of life. New indications for the addition of adjuvant therapy to surgery can improve disease-free and long-term survival in a disease where the 5-year survival of stage I and II can be less than 50% and overall survival regardless of stage only 15%. IMPLICATIONS FOR NURSING PRACTICE: As health care educators and caregivers, nurses should be informed of the advancements in staging and surgical technique associated with early stage NSCLC and its impact on survival and quality of life.     

非小细胞肺癌的靶向治疗

肺癌的发病率和死亡率在全球恶性肿瘤中居首位。其中,非小细胞肺癌（NSCLC）占80%~85%。绝大多数NSCLC在临床确诊时正处于复发或转移性的晚期阶段,化疗是这部分人群的主要治疗手段。但是,作为标准一线治疗的含铂两药联合化疗方案已进入平台期,无进展生存期（PFS）为4~6个月,总生存期（OS）仅为8~10个月。近年来,靶向药物的临床应用让人们看到了跨越这一平台的希望和曙光,靶向治疗作为一支生力军正逐渐登上非小细胞肺癌综合治疗的历史舞台。     

多西他赛单药一线治疗晚期非小细胞肺癌临床研究

目的探讨多西他赛单药一线治疗晚期非小细胞肺癌临床疗效及不良反应。方法48例晚期非小细胞肺癌患者,多西他赛75m4g／lm2静脉滴注,第1天。21d为1个周期,治疗2～4个周期后评价临床疗效及不良反应。结果48例患者共化疗140个周期,中位化疗2．9个周期。RR为25．O％,DCR为56．3％,中位无进展生存期5．3个月,中位生存期8．6个月,1年生存率35．4％。不良反应以粒细胞减少、贫血、腹泻、脱发为主。结论多西他赛单药一线治疗晚期非小细胞肺癌临床疗效良好,患者耐受性较好。     

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.     

Transformation of non-small cell lung cancer into small cell lung cancer in a patient with advanced lung cancer: a case report

Targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often fails because of drug resistance. Here, we report a 57-year-old male patient with stage IV small cell lung cancer (SCLC) transformation during targeted therapy. Chest computerized tomography (CT), hematoxylin and eosin histological examination, immunohistochemistry, allele refractory mutation system‐based quantitative polymerase chain reaction analysis of EGFR point mutations, and next-generation sequencing were performed for diagnosis and therapeutic efficacy evaluation. A combination of chest CT, histological examination, and immunohistochemistry confirmed the initial NSCLC diagnosis. Next-generation sequencing detected only EGFR exon 19 deletion (ex19del) before treatment and later identified EGFR exon20p.T790M point mutation, EGFR amplification, myc proto-oncogene (MYC) amplification, retinoblastoma 1 (RB1) mutation, and tumor protein 53 (TP53) mutation. Histology and immunohistochemistry revealed transformation from NSCLC to SCLC during treatment, which eventually returned to NSCLC. Drug resistance to targeted therapy for patients with NSCLC frequently occurs because of EGFR exon20p.T790M point mutation, TP53 mutation, RB1 mutation, and MYC amplification. These mutations are also the major determining factors of NSCLC outcomes. Therefore, next-generation sequencing should be performed to confirm drug efficacy during targeted therapy for NSCLC.     

晚期非小细胞肺癌综合治疗的前瞻性研究

目的探讨提高Ⅲ期非小细胞肺癌治疗效果的方法。方法85例Ⅲ期非小细胞肺癌患者随机分为3组,并进行不同顺序的治疗,A组(化疗+手术+放疗)28例,放疗后配合辅助化疗;B组(手术+化疗+放疗)28例;C组(手术+放疗+化疗)29例。比较各组3年生存率、局部区域复发率和远处转移率的差异性。结果A、B、C3组3年生存率分别为75.00%,53.57%,44.83%,其中A组与C组比较差异有显著性意义(P<0.05);3组局部区域复发率分别为7.14%,32.14%,17.24%,其中A组与B组比较差异有显著性意义(P<0.05);各组远处转移率分别为7.14%,10.71%,37.93%,其中A组与C组及B组与C组比较,差异均有显著性意义(P<0.05)。结论术前化疗再手术,配合术后放疗及辅助化疗,可提高治疗Ⅲ期非小细胞肺癌的疗效。     

紫杉醇联合奈达铂治疗晚期非小细胞肺癌的临床观察

目的观察紫杉醇（PTX）联合奈达铂（NDP）治疗晚期非小细胞肺癌的疗效及不良反应。方法 48例晚期非小细胞肺癌患者应用紫杉醇（PTX）联合奈达铂（NDP）方案化疗：PTX 135~175 mg/m2,静脉滴注,第1天;NDP 80~100 mg/m2,静脉滴注,第2天,21 d为1个周期。结果全组48例患者中,完全缓解率（CR）3例（6.3%）,部分缓解率（PR）16例（33.3%）,稳定（SD）22例（45.8%）,病情进展（PD）7例（14.6%）。有效率（RR）为39.6%,疾病控制率（DCR）为85.4%。主要不良反应为骨髓抑制及胃肠道反应,肝、肾毒性较轻。结论紫杉醇联合奈达铂治疗晚期非小细胞肺癌不良反应轻,疗效较好,值得临床推广。