Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

VEGF在非小细胞肺癌(NSCLC)组织中的表达及意义

目的:研究血管内皮生长因子(VEGF)在非小细胞肺癌中的表达及其临床意义.方法:应用免疫组化(IHC)染色技术检测101例非小细胞肺癌及20例肺良性病变组织VEGF的表达水平并结合临床资料进行综合分析.结果:经χ2检验VEGF在非小细胞肺癌组织和良性病变组织中,两组对比差异具有显著性(P＜0.01).VEGF的表达与组织学类型无关(P＞0.05),VEGF表达水平与NSCLC的TNM分期呈正相关,而与NSCLC组织分化程度无关,与淋巴结转移成正相关,与原发灶大小有关,VEGF的阳性表达与术后生存时间呈负相关具有较强的侵袭和转移能力.结论:VEGF可作为预测NSCLC患者术后复发转移情况及临床预后的生物学参考指标.     

Safety of gefitinib in non-small cell lung cancer treatment

ABSTRACT

Introduction: The development of EGFR TKI and the subsequent identification of activating EGFR mutations have dramatically changed how NSCLC is treated. With its recent approval by the US Food and Drug Administration, gefitinib adds to the list of recommended first-line treatments for lung cancer harboring EGFR mutations, which hitherto includes erlotinib and afatinib.

Areas covered: This review summarizes the pharmacological property, clinical efficacy, and safety of gefitinib in major clinical trials and post-marketing studies.

Expert opinion: Gefitinib is a well-tolerated treatment for advanced NSCLC. The most common adverse events are skin reaction and diarrhea, both of which are generally mild, noncumulative, and manageable. Other side effects such as interstitial lung disease and liver toxicity are less common but can be serious. Which EGFR TKI is the preferred first-line treatment is a matter of debate. Gefitinib and erlotinib have comparable efficacy, whereas afatinib may exert superior clinical activity over gefitinib. In terms of the most common toxicities of skin reaction and diarrhea, gefitinib may be the most tolerable of the three. Hence, despite being the earliest EGFR TKI developed, gefitinib continues to be one of the first-line treatments for advanced EGFR-mutated NSCLC, especially when skin and gastrointestinal toxicity is a concern.     

Molecularly-targeted therapies for non-small cell lung cancer

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.     

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

ABSTRACT

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting.

Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC.

Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.     

Dacomitinib,a new therapy for the treatment of non-small cell lung cancer

Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 – 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.     

RET kinase inhibitors: a review of recent patents (2012–2015)

Introduction: Tyrosine kinases are involved in the control of several biological processes and have been recognized as hot spots of oncogenic transformation, thus representing a major therapeutic target. Dysregulated activation of RET kinase, either through point mutations or gene fusions, is accountable for a significant fraction of thyroid carcinomas, as well as a minor population of lung cancers. Two drugs are currently available for the treatment of medullary thyroid carcinoma and two additional compounds have been approved for differentiated thyroid carcinoma. Several other molecules are under preclinical and clinical evaluation.

Areas covered: This review covers the most recent patent literature (2012–2015) describing compounds with activity against the RET kinase, trying to catch a view of the next generation of potential anti-RET drugs.

Expert opinion: RET has been a focus of molecularly targeted efforts for over a decade. However, none of the drugs currently on the clinical stage were specifically developed to hit RET, which was rather an off-target. Besides, only two of four drugs have activity on metastatic medullary carcinoma. Therefore, there is still a need of additional, more potent and more specific RET inhibitors, which will hopefully emerge from the new generation of compounds disclosed in most recent patents.     

胸腺肽联合GP方案治疗非小细胞肺癌的临床研究

目的 观察胸腺肽联合GP方案治疗非小细胞肺癌的疗效及对免疫功能和血管内皮生长因子（VEGF）表达水平的影响。方法 选取2017年4月-2019年6月期间安康市中医医院收治的80名非小细胞肺癌患者作为研究对象,采用随机数字表法分为对照组和观察组,每组40例。对照组在第1天、第8天静脉滴注注射用盐酸吉西他滨,1.0 g/m²,1次/d,第1~3天静脉滴注注射用顺铂,25 mg/m²,1次/d。观察组在对照组的基础上口服胸腺肽肠溶片,15 mg,2次/d。21 d为1个周期,两组均治疗2个周期。观察两组患者的近期临床疗效,比较两组患者的KPS评分、免疫功能指标和血管内皮生长因子（VEGF）水平。结果 治疗后,对照组客观有效率（ORR）为47.50%,观察组为57.50%,两组差异无统计学差异。治疗后,观察组患者KPS评分优于对照组,两组比较差异具有统计学意义（P<0.05）。治疗后,两组患者的CD4⁺、CD8⁺、CD4⁺/CD8⁺及NK细胞的比例与治疗前有统计学差异（P<0.05）;治疗后,观察组患者CD4⁺、CD8⁺、CD4⁺/CD8⁺及NK细胞比例均优于对照组,差异具有统计学（P<0.05）。治疗后,两组VEGF水平均显著降低（P<0.05）;与对照组相比,观察组下降更为显著（P<0.05）。结论 胸腺肽肠溶片联合GP方案用于非小细胞肺癌的临床治疗,提高了患者的生存质量和免疫功能,降低了血清VEGF水平。     

Selumetinib for the treatment of non-small cell lung cancer

Introduction: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain ‘undruggable’, with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy.

Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit.

Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS–RAF–MEK–MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.     

Emerging protein kinase inhibitors for non-small cell lung cancer

Introduction: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC.

Areas covered: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK.

Expert opinion: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.     

Chemoradiotherapy for lung cancer

Chemoradiotherapy is a standard treatment for both unresectable locally advanced non-small cell lung cancer and limited-stage small cell lung cancer. Cisplatin-based chemotherapy with concurrent thoracic radiotherapy yields a 5-year survival rate of ～ 15% for patients with unresectable locally advanced non-small cell lung cancer. The state-of-the-art treatment for limited-stage small cell lung cancer is four cycles of chemotherapy with cisplatin plus etoposide combined with early concurrent twice-daily thoracic irradiation and prophylactic cranial irradiation after complete remission. A 5-year survival rate of ～ 25% is expected among patients treated for limited-stage small cell lung cancer. The incorporation of new agents, including target-based drugs, is one of the most promising strategies for improving the survival of patients.     

~(125)I组织间照射治疗非小细胞肺癌临床探讨

目的 :研究 1 2 5I组织间照射治疗非小细胞肺癌的临床疗效和不良反应。方法 :入选 5 2例非小细胞肺癌 (NSCL C)患者随机分成内照射组 (2 5例 )和外放疗组 (2 7例 )。内照射组采用 CT引导下经皮穿刺植入法和胸腔镜辅助小切口术中植入法。外放疗组采用常规分割放疗。结果 :内照射组治疗后 3个月有效率 88% ,12个月后局部控制率为 80 % ;外放疗组治疗后 3个月有效率 6 3% ,12个月后局部控制率 5 1.9%。两组比较有显著性差异 (P <0 .0 5 )。内照射组未出现放射损伤症状 ,未发现粒子脱落或游走等并发症 ;外放疗组出现 3例急性放射性肺炎和 8例急性放射性食道炎。结论 :1 2 5　 I组织间照射治疗 NSCL C临床疗效明显优于常规分割放疗 ,是 NSCL C的有效治疗方法。     

Erlotinib for the treatment of brain metastases in non-small cell lung cancer

Introduction: Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation.

Areas covered: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015.

Expert opinion: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naïve, EGFR mutated patients with refractory BM.     

Is there a role for vindesine in the treatment of non-small cell lung cancer?

Summary Vindesine is a semisynthetic derivative of vinblastine which has been evaluated in clinical studies since the late 1970's. The literature on vindesine in the treatment of non-small cell lung cancer has been reviewed and all aspects of vindesine treatment in this disease has been covered. It is concluded that vindesine as a single agent yields a response rate of 18% based on the treatment of 295 patients included in phase II trials (95% confidence limits 13%–22%). No difference was observed among the three major histologic types of non-small cell lung cancer. In phase III trials, the response rate and confidence limits are at a similar level. Combination chemotherapy including vindesine plus cisplatin ranks among the most active treatments in non-small cell lung cancer and is as active as etoposide plus cisplatin, both with respect to response rate and survival. It has not been documented that the addition of one or two other drugs to the combination of vindesine yields an increase in survival. When best supportive care was compared with a combination of vindesine plus cisplatin, the group with chemotherapy was attributed a survival advantage in all three studies published, and the difference was statistically significant in two of these three studies. Thus, vindesine has a well documented activity in non-small cell lung cancer and ranks among the most active single agents in this disease. Vindesine is also part of several active combination chemotherapies among which the combination of vindesine plus cisplatin is particularly interesting, because it has been repeatedly shown to prolong survival as compared to supportive care. Especially this latter point leads to the conclusion that there is a role for vindesine in the treatment of non-small cell lung cancer. However, the concept of chemotherapy in this disease remains investigational even though the advances seen in recent years clearly merit further studies.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Ramucirumab in the treatment of non-small cell lung cancer

Introduction: Therapeutic options for treating Non-Small Cell Lung Cancer (NSCLC) have recently increased. Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy.

Areas covered: We performed a comprehensive search of the literature focused on clinical trials with use of ramucirumab, targeting its evolution in the treatment of NSCLC. This review summarizes the results regarding its safety and efficacy.

Expert opinion: Angiogenesis has been widely recognized as a quintessential feature in cancer, intrinsically mediating tumor survival and progression. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients. Results from a phase III trial have demonstrated the usefulness of this combination, with benefits in progression free survival and overall survival for NSCLC patients. A greater magnitude of benefit is seen in patients with aggressive tumor behavior. Treatment with ramucirumab is generally tolerable, however, there is potential for severe toxicity. Adverse events reported with this combination include neutropenia, febrile neutropenia and hypertension. Also, there is the intrinsic risk of bleeding resulting from the mechanism of action. As such, adverse events should be identified timely, so drug-related complications can be prevented.     

New systemic strategies for overcoming resistance to targeted therapies in non-small cell lung cancer

Introduction: Although the achievements in the treatment of advanced non-small cell lung cancer (NSCLC) have been translated in improved disease control, response rate and survival, especially in the case of patients with targetable oncogenic drivers, acquired resistance is common after initial benefit; furthermore, primary resistance can occasionally be observed. Due to its clinical implications, the management of treatment-resistant NSCLC is a top topic of the current research, and many efforts are being put in the study of the mechanisms at the base of resistance and in the development of effective therapeutic countermeasures.

Areas covered: This review aims at identifying the most relevant novel chemical therapies designed to overcome resistance in NSCLC, including recently approved agents, as well as compounds in clinical development.

Expert opinion: An improved knowledge of the mechanisms causing resistance to treatments in NSCLC translates into effective innovative chemical therapies able to overcome such occurrence, and the paradigms of this progress are represented by novel inhibitors of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK); however, the study of novel systemic therapies in this setting is challenging, and further efforts in this setting are highly needed.     

Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.