Pemetrexed in advanced non-small cell lung cancer

Introduction: For patients with advanced NSCLC, treatment outcomes are still disappointing and the search for new active and safe drugs is warranted. The chemotherapeutic agent pemetrexed has produced, in the last years, an innovation of therapeutic algorithms of this disease, and this review is aimed at describing the role of pemetrexed in the treatment of NSCLC.

Areas covered: In the present review, we discuss the mechanism of action of pemetrexed, its safety profile and the main clinical data on pemetrexed in NSCLC treatment. The reader will gain information on pemetrexed efficacy in the first-line, second-line and maintenance treatment of advanced NSCLC. Moreover, the histotype-based approach to NSCLC treatment, which is important for the selection of patients to be treated with pemetrexed, is clarified.

Expert opinion: The recent introduction of pemetrexed in the first-line and maintenance treatment of advanced non-squamous NSCLC represents, in our opinion, a significant step forward in the treatment of this disease in the last 3 years. Furthermore, cisplatin plus pemetrexed has a more favorable safety profile as compared with those of pre-existing cisplatin-based regimens.     

Safety profile of platinum-based chemotherapy in the treatment of advanced non-small cell lung cancer in elderly patients

Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. More than 50% of NSCLC patients are diagnosed at > 65 years of age and approximately one-third of all patients are > 70 years of age. Elderly patients tolerate chemotherapy poorly compared with their younger counterpart because of the progressive reduction of organ function and comorbidities related to age. For this reason, these patients are often not considered eligible for aggressive platinum-based chemotherapy, the standard medical treatment for advanced NSCLC. In clinical practice, single-agent chemotherapy should remain the standard treatment. Feasibility of platinum-based chemotherapy remains an open issue and has to be proven prospectively. Moreover, a multidimensional geriatric assessment for individualised treatment choice in NSCLC elderly patients is mandatory. This review focuses on the currently-available evidences for the treatment of elderly patients affected by advanced NSCLC with regards to the role and safety of platinum-based chemotherapy.     

Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer

Background: Because gemcitabine andvinorelbine have demonstrated single-agentactivity in non-small cell lung cancer(NSCLC), we conducted this phase I/II studyto determine the maximum tolerated dose(MTD) and activity of these drugs combined. Patients and methods: Patients withinoperable or advanced NSCLC and no priorchemotherapy were treated with gemcitabineplus vinorelbine on days 1 and 8 every 21days. The initial doses of gemcitabine1,000 mg/m² and vinorelbine25 mg/m² were escalated by250 mg/m² and 5 mg/m²,respectively, in separate patient cohortsuntil the MTD was established. Results: In phase I, 32 patientsreceived a total of 115 cycles. Dose-limiting toxicities were neutropeniaand hepatotoxicity, occurring at the doselevel of 1,500 mg/m² and30 mg/m². Thus, the MTD used forphase II was 1,250 mg/m² and30 mg/m². Of 41 patients in phase II,16 (39%) achieved objective responses(95% confidence interval [CI] 24% to54%), with a median time to progression of4.2 months. Overall survival was 9 months(95% CI 5.7 to 12.7 months) and the 1-yearsurvival rate was 31%. World HealthOrganization (WHO) grade 3neutropenia and reversible thrombocytosisoccurred in 15% and 65% of patients,respectively. Non-hematologic toxicity wasmild at all dose levels. Grades 3 and 4hepatotoxicity were reported in one patienteach. Conclusion: The combination of1,250 mg/m² gemcitabine and30 mg/m² vinorelbine on days 1 and 8every 21 days is well tolerated and activein patients with NSCLC. These resultsshould be confirmed in comparativestudies.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

Phase II trial of alternating intravenous and oral vinorelbine in combination with cisplatin in advanced non-small cell lung cancer

Summary Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Several platinum-based doublets have been tested in phase II/III trials with equivalent results in terms of tumour response and survival. Our study was designed to evaluate activity, tolerability and convenience of alternating intravenous (i.v.) and oral vinorelbine in combination with cisplatin in advanced NSCLC. Forty chemo-naive patients with stage IV or relapsed unresectable disease and good performance status were enrolled to receive i.v. cisplatin 40 mg/m² on days 1 and 2 plus i.v. vinorelbine 25 mg/m² on day 1, every 3 weeks. Oral vinorelbine 60 mg/m² was given at home on day 5, without checking of blood cell count. A total of 175 treatment cycles were delivered. The overall response rate was 30% (one complete, 11 partial responses). Median time to progression and overall survival were 5 and 10 months, respectively. The main toxicity was haematological, with grade 3–4 neutropenia observed in 75% of patients, without febrile neutropenia. Non-haematological toxicity was mild. This schedule of cisplatin and vinorelbine treatment showed a good toxicity profile and an efficacy similar to other standard regimens. Oral vinorelbine could be administered safely at home on day 5.     

Emerging treatment using tubulin inhibitors in advanced non-small cell lung cancer

Introduction: Tubulin inhibitors including taxanes and vinca alkaloids are important components of chemotherapy regimens used in advanced non-small cell lung cancer (NSCLC). Despite a treatment paradigm shift due to molecularly-targeted therapies and immunotherapy, a majority of patients will receive chemotherapy during their treatment course. Either used alone or in combination, tubulin inhibitors have demonstrated clinical benefits in different settings of lung cancer management.

Areas covered: This review first discusses FDA-approved tubulin inhibitors for NSCLC, such as paclitaxel, docetaxel, vinorelbine, and nab-paclitaxel. The article then provides a summary of novel tubulin inhibitors, including cabazitaxel, eribulin, ixabepilone, patupilone, plinabulin, new colchicine analogues and others. It also discusses new tubulin inhibitor combinations with immunotherapy (PD-1/PD-L1 inhibitors) and molecularly-targeted therapies (e.g. anti-angiogenic agents, mTOR inhibitors, heat shock protein 90 inhibitors, MEK inhibitors, and anti-HER3 agents). Lastly, emerging data on potential resistance mechanisms and predictive biomarkers for tubulin inhibitors are explored.

Expert opinion: Tubulin inhibitors will likely continue to play important roles in NSCLC management due to the advent of novel agents and combinations. Through further understanding of tumor biology, investigation of drug resistance, and development of predictive biomarkers, we will be better positioned to incorporate microtubule inhibition into patient specific treatment strategies.     

Sorafenib in non-small cell lung cancer

ISIS 2302 is a 20 base phosphorothioate oligodeoxynucleotide (ODN) that inhibits intercellular adhesion molecule 1 (ICAM-1) expression through an antisense mechanism. Murine and rat analogues have been effective at doses of 0.06 - 10 mg/kg in a spectrum of models of human inflammatory diseases and allograft transplantation, and ISIS 2302 inhibits the upregulation of ICAM-1 expression in a variety of human cells in vitro. In animals, including primates, plasma distribution half-life ranges from 30 - 60 min, but tissue elimination half-lives range from 1 - 5 days, and the compound is metabolised as other nucleic acids. In a Phase I iv. study, the pharmacokinetic behaviour of ISIS 2302 was similar to that in other primates, and single and multiple every other day doses from 0.06 - 2 mg/kg infused over 2 h were well-tolerated. Phase IIa studies have been completed in Crohn’s disease, rheumatoid arthritis, and psoriasis, and a combined Phase I/II renal allograft acute rejection prophylaxis study has just completed enrolment. In these studies, ISIS 2302, 0.5 - 2 mg/kg, or placebo was administered iv. every 2 - 3 days over 14 - 26 days (7 - 13 infusions) to 17 - 52 patients, with follow up for 6 months. In the Crohn’s study, evidence of highly durable (5+ month) remission-inducing and steroid-sparing properties were demonstrated, without clinically important adverse events. A 300-patient, pivotal quality trial investigating the steroid-sparing and remission-inducing qualities of ISIS 2302 in patients with steroid-dependent Crohn’s disease is completely enrolled, with results expected in the first half of 2000. Modest efficacy and excellent tolerability were demonstrated in the psoriasis and rheumatoid arthritis trials. A Phase IIa trial of a topical formulation in patients with psoriasis is expected to commence in late 1999, as is a trial of an enema formulation in distal ulcerative colitis. Administration by nebulisation for asthma is undergoing preclinical evaluation. Execution of future plans in organ transplantation will await the results of the ongoing Phase I/II trial.     

Vinorelbine in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains a fatal disease: the majority of patients are diagnosed as having metastases or advanced inoperable tumors. The activity of chemotherapy in NSCLC patients is low with objective response rarely complete and sustained. Cisplatin-based combinations are considered as the standard chemotherapy treatment. Recently., the introduction of new and less toxic chemotherapeutic agents., such as vinorelbine., has led investigators to research for active non-cisplatin-containing combinations to treat patients with advanced disease having as primary needs symptom relief and an acceptable quality of life. This review will focus on the pharmacological properties of vinorelbine and its role in adjuvant chemotherapy., in combined chemo-radiotherapy., in advanced disease and in the particular setting of the elderly. The oral use of vinorelbine will be among the future developments of this drug.     

Emerging drugs for EGFR-mutated non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity.

Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance.

Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.     

Emerging angiogenesis inhibitors for non-small cell lung cancer

Introduction: Angiogenesis represents a complex process crucial during embryo development, wound healing, and collateral formation for improved organ perfusion. Numerous stimulatory and inhibitory pathways through their balance regulate angiogenesis and vascular homeostasis. Targeting the pathways implicated in the regulation of angiogenesis and neo-angiogenesis plays an important role in cancer research, treatment, and patients’ outcome. Antiangiogenic strategies, including monoclonal antibodies binding vascular endothelial growth factor (VEGF) or the corresponding receptor and small molecules which inhibit the function of different angio–related tyrosine kinase, produced interesting results in cancer treatments including non-small-cell lung cancer (NSCLC).

Areas covered: The current state-of-the-art of anti-angiogenesis treatment in the management of NSCLC patients is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken in order to discuss about emerging angiogenesis inhibitors in NSCLC.

Expert opinion: Targeting angiogenesis remains an important therapeutic strategy in the management of NSCLC. Moreover, VEGF has been recognized having also an immunosuppressive action leading to investigate the potential activity of angiogenic inhibitors in restoring the antitumor immunity by targeting VEGF/VEGF-Receptor. Furthermore, new anti-angiogenic drugs for which there is also the availability of predictive biomarkers are welcome.     

Osimertinib for the treatment of non-small cell lung cancer

Introduction: The T790 M mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR TKI, shows robust clinical efficacy in patients with T790 M-mutated lung cancer.

Areas covered: We analyzed and reviewed clinical data for which patients who experienced acquired resistance to first- or second-generation EGFR TKIs. In addition, we briefly reviewed the potential role of osimertinib as a first-line therapy.

Expert opinion: Osimertinib was recently licensed for use in NSCLC patients with acquired resistance to other EGFR TKIs due to a T790 M mutation. However, unresolved issues surrounding the optimal application of osimertinib remain, specifically the development of a plasma-based mutation test to overcome the difficulty of repeat biopsy, the efficacy of osimertinib for brain or leptomeningeal metastases, the development of resistance to osimertinib, and the use of osimertinib therapy as a first-line treatment. Many ongoing studies are currently exploring these issues.     

Twist基因在非小细胞肺癌中的表达及意义

目的：探讨转录调节因子Twist在非小细胞肺癌（NSCLC）组织中的表达及临床意义。方法：应用兔抗人Twist多克隆抗体采用SP免疫组织化学方法检测45例NSCLC组织及12例癌旁正常肺组织中Twist蛋白表达情况。结果：在45例肺癌组织标本中,Twist基因阳性表达为31例（68．9％）,癌旁组织中为2例（16．7％）,两者比较差异有统计学意义（Х^2=10．599,P〈0．01）。Twist高表达与肺癌分化程度相关（P〈0．05）。结论：NSCLC组织中存在Twist基因的高表达,Twist基因表达的上调,对肿瘤的发生、发展起着重要作用。     

Efficacy of S-1 in non-small cell lung cancer

Introduction: S-1 is an oral fluoropyrimidine derivative, including three pharmacological compounds: tegafur, gimeracil and oteracil, in a molar ratio of 1: 0.4: 1.

Areas covered: This review addresses the clinical evidence of S-1 in NSCLC in various clinical settings. Currently, S-1 for NSCLC is approved only in Japan. Prospective studies of S-1 as front-line and second-line chemotherapy with or without other agents and concurrent chemoradiotherapy are mainly reviewed. Only two Phase III clinical trials were published or presented for advanced NSCLC. S-1 and cisplatin is an active first-line chemotherapy regimen for advanced NSCLC and S-1 and carboplatin is noninferior to a carboplatin and paclitaexel regimen. The combination of S-1 and a platinum agent is active against NSCLC, regardless of tumor histology.

Expert opinion: It is becoming possible to design effective regimens with S-1 against NSCLC in various clinical settings considering the ethnic differences in pharmacokinetics and a greater understanding of the underlying molecular pathways or biomarkers of NSCLC. Further Phase III studies with S-1 for both early and advanced NSCLC are warranted worldwide.     

Developments in pharmacotherapy for treating metastatic non-small cell lung cancer

Introduction: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available.

Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.     

Reviewing the safety of erlotinib in non-small cell lung cancer

Importance of the field: Erlotinib, a potent inhibitor of EGFR activity, is approved as a monotherapy for the treatment of advanced NSCLC and in combination with gemcitabine for advanced pancreatic cancer. The oral administration and manageable toxicity of erlotinib, along with its similar efficacy to chemotherapy, make it an important option as either maintenance therapy or in second-/third-line for patients with NSCLC who have previously received first-line chemotherapy. It is also an emerging option in other treatment settings in NSCLC.

Areas covered in this review: This review summarizes safety data from major clinical trials of erlotinib in patients with advanced NSCLC, as well as post-marketing data obtained in the 5 years since this drug was first approved.

What the reader will gain: An understanding of the common toxicities expected with erlotinib in patients with advanced NSCLC.

Take home message: Erlotinib is a well-tolerated treatment option for patients with advanced NSCLC. The main adverse events of rash and diarrhea are typically mild or moderate in severity, and rarely lead to treatment withdrawal. When necessary, rash and diarrhea can be easily managed prophylactically, by active intervention or through dose reduction.     

长春瑞滨联合顺铂治疗晚期非小细胞肺癌64例疗效观察

目的观察长春瑞滨联合顺铂化疗治疗晚期非小细胞肺癌的疗效和毒副反应。方法长春瑞滨25mg/m2,第1、8天静滴;DDP40mg,第1、2、3天滴注,21d为1个周期。最少应用两个周期。结果 CR0例,PR28例,SD26例,PD10例,有效率为43.75%。主要不良反应为骨髓抑制、消化道反应及静脉炎。结论 NVB+DDP方案治疗NSCLC疗效较好,毒副反应较轻,可以耐受。     

长春瑞滨联合奥沙利铂治疗晚期非小细胞肺癌疗效观察

目的:探索长春瑞滨(NVB)+奥沙利铂(N0方案)与长春瑞滨+顺铂(NP方案)治疗晚期非小细胞肺癌的疗效.方法:59例非小细胞肺癌患者随机分为治疗组29例和对照组30例.治疗组给予长春瑞滨+奥沙利铂治疗;对照组给予长春瑞滨+顺铂治疗,两组均21天为1个周期,用药2周期.结果:总有效率治疗组为41.1%,对照组为46.7%(P>0.05).不良反应以白细胞减少、恶心、呕吐以及周围神经炎为主.Ⅲ～Ⅳ度的恶心、呕吐,肾功能损害及心功能不全主要发生在对照组,周围神经炎主要发生在治疗组(P<0.05).结论:长春瑞滨+奥沙利铂治疗晚期非小细胞肺癌疗效确切,患者耐受性良好,为晚期非小细胞肺癌的治疗提供了一种新的选择,更适宜老年及心肺功能不全的患者.     

EGFR TKI combination with immunotherapy in non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation.

Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo naïve NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%). The treatment related Grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib.

Expert opinion: Given the relatively high incidence of treatment-related toxicities associated with combination of EGFR TKI and immunotherapy, further development of this approach remains controversial. Until now, the combination of EGFR TKI and immunotherapy should be investigational.     

Vinorelbine in advanced non-small cell lung cancer. A pharmacoeconomic review.

Vinorelbine is a semisynthetic vinca alkaloid that is effective against advanced non-small cell lung cancer (NSCLC). Myelosuppression is the primary dose-limiting toxicity; vinorelbine is otherwise relatively well tolerated. Two studies assessed the cost effectiveness of vinorelbine with or without cisplatin based primarily on data from a phase III comparison with vindesine plus cisplatin. Survival and cost data from this study were supplemented with those from other sources. One model simulated total management costs for the 4986 patients diagnosed with stage IV NSCLC in Canada in 1992. The other applied US cost data to the outcomes from the phase III trial. Using vinorelbine monotherapy or vinorelbine plus cisplatin produced a survival benefit and net cost savings compared with best supportive care according to the Canadian model (and preliminary data from a third analysis, conducted in the US). In the Canadian analysis, incremental cost effectiveness for inpatient or outpatient vinorelbine plus cisplatin ranged from 7450 Canadian dollars ($Can) to $Can30,770 (1993 values) per year of life saved (YLS) compared with outpatient cisplatin plus either etoposide or vinblastine. Cost-effectiveness ratios for vinorelbine plus cisplatin in the US analysis (1994 values) were $US18,000 (vs cisplatin plus etoposide) and $US15,500 (vs cisplatin plus vindesine) per YLS [all inpatient administration]. Detailed pharmacoeconomic comparisons with other current standard regimens (e.g. paclitaxel plus either cisplatin or carboplatin) are not available. Sensitivity analyses suggest that the cost effectiveness of vinorelbine-based therapy is robust to changes in assumptions regarding efficacy and the cost of managing toxicity. Limitations of the available pharmacoeconomic data include the retrospective nature of the analyses, inclusion of data from sources other than the main phase III trial (e.g. those for best supportive care and some chemotherapy regimens), and exclusion of some costs for hospitalisation and/or management of toxicity. CONCLUSIONS: Although some limitations apply, the available data suggest that vinorelbine alone or in combination with cisplatin is cost saving compared with best supportive care for NSCLC, and that vinorelbine plus cisplatin is cost effective compared with some other combination regimens. The pharmacoeconomic placing of vinorelbine in relation to a number of other currently recommended first-line treatments for NSCLC has yet to be resolved, and data from ongoing multicentre phase III trials are awaited with interest. In the meantime, vinorelbine-based chemotherapy appears to be a suitable choice for first-line treatment of advanced NSCLC from both clinical and pharmacoeconomic perspectives.     

吉西他滨联合热疗治疗晚期非小细胞肺癌64例临床研究

目的研究吉西他滨联合局部热疗治疗晚期非小细胞肺癌（NSCLC）的临床效果。方法对2009年2月至2010年12月我院入院治疗的128例晚期非小细胞肺癌患者进行了研究,将128例患者随机分为2组,对照组患者采用吉西他滨化疗,21d为一个周期,两个周期为一个疗程;治疗组患者在对照组化疗基础上,联合局部热疗,一个疗程结束后评价治疗效果及不良反应。结果经过一个疗程的治疗,对照组治疗总有效率为25．0％,冶疗组总有效率为43．8％,两组比较差异明显,有统计学意义（P〈0．05）;不良反应比较中,两组患者不良反应发生情况相当,差异无统计学意义（P〉0．05）。结论吉西他滨联合局部热疗治疗晚期非小细胞肺癌临床效果显著,好于单一药物化疗,且不良反应发生情况与单药治疗无差异,值得临床推广应用。