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.     

Gemcitabine and carboplatin in combination for the treatment of advanced,metastatic, non-small cell lung cancer

The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent, gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile. Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.     

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer

Objective: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting.

Methods: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared.

Results: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval]?=?0.38 [0.26–0.57]; ASCEND-2: median?=?18.3 vs 7.2 months, HR?=?0.33 [0.20–0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR?=?0.33 [0.17–0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median?=?17.6 vs 8.2 months, HR?=?0.56 [0.36–0.86]; NP28673: median?=?17.6 vs 8.9 months, HR?=?0.61 [0.40–0.93]); results for OS were inconclusive (NP28761: median?=?27.6 vs 22.7 months, HR?=?0.70 [0.42–1.16]; NP28673: median?=?27.6 vs 26.0 months, HR?=?0.66 [0.39–1.09]). ORR was similar.

Conclusion: In crizotinib-refractory ALK?+?NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.     

Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non-small cell lung cancer

ABSTRACT

Introduction

Approximately 3–7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase (ALK) rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active ALK inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi.     

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.     

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.     

Vinflunine for the treatment of non-small cell lung cancer

Introduction: Vinflunine belongs to the class of vinca alkaloids and acts by disrupting the microtubule dynamics during cell cycle; this agent is currently available for previously treated advanced transitional cell carcinoma in Europe. The aim of this invited review is to evaluate the potential role of vinflunine for the treatment of non-small cell lung cancer (NSCLC).

Areas covered: The potential role of vinflunine in NSCLC is discussed on the basis of the available data, including full papers and meeting abstracts. Relevant preclinical studies describing the pharmacological properties of vinflunine are also included. The review also summarizes clinical studies, including phase I trials involving NSCLC among other tumors as well as phase II/III trials specifically addressing this malignancy. Additionally, the safety profile and the current regulatory status of vinflunine is discussed.

Expert opinion: Vinflunine is active as single agent and as part of platinum-based combinations in NSCLC. It results non-inferior to docetaxel in a randomized phase III trial including previously treated NSCLC patients; additionally, its safety profile is generally considered manageable. Ultimately, further studies are needed to confirm the role of vinflunine in NSCLC, in consideration of the evolving evidence regarding targeted therapies and immune check-point inhibitors.     

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。     

培美曲塞二线治疗晚期非小细胞肺癌的临床观察

目的观察培美曲塞二线治疗晚期非小细胞肺癌的疗效及毒副反应。方法我院2008年4月～2009年10月收治晚期NSCLC患者20例,均经病理组织学或细胞学确诊ⅢB期5例,Ⅳ期15例。均接受过2个周期以上的含铂方案化疗,肿瘤进展或复发,国产培美曲塞二钠500mg/m2D1,IV,每21天为1周期。持续用药直至肿瘤进展或出现不可耐受的不良反应。结果ORR为22.2%,DCR为75.0%,中位PFS为6个月,中位OS为10个月。全组患者临床症状均有不同程度的改善,主要表现为咳嗽、胸痛好转,胸闷、气促、乏力减轻和体力状态改善。主要不良反应有骨髓抑制、神经系统毒性、肝肾功能影响、皮疹、脱屑、皮肤搔痒、胃肠道反应如恶心、呕吐、腹泻、疲劳。不良反应主要为Ⅰ、Ⅱ级,无1例患者因出现不可耐受的不良反应而退出治疗,亦未出现药物相关死亡。结论PFS和OS不低于一线含铂化疗方案,中位总生存期甚至高于一线含铂化疗方案,且主要毒副反应耐受性较好,且可作为晚期非小细胞肺癌二线治疗首选。     

吉非替尼治疗难治性非小细胞肺癌的疗效

目的:探讨吉非替尼治疗难治性非小细胞肺癌的疗效和不良反应。方法:共入组难治性非小细胞肺癌47例,给吉非替尼250 mg每日1次口服,直至肿瘤进展或病人不能耐受治疗的毒性而中止治疗。至少服药16 wk后评价疗效。结果:全组总有效率34％[(16／47);完全缓解(CR)1例,部分缓解(PR)15例],疾病控制率为83％(39／47;CR 1例,PR 15例,稳定23例)。男性组和女性组的有效率分别为50％和20％(P<0．05), 中位生存期为297 d(118～868 d)。中位疾病进展时间(TTP)173 d(59～693 d)。1 a和6 mo生存率分别为 36％和79％。全组病人症状改善率为89％(42／47)。主要的不良反应是痤疮样皮疹(32％)、腹泻(11％)、恶心呕吐(23％),未发生明显骨髓抑制及间质性肺炎。结论:吉非替尼治疗难治性非小细胞肺癌有一定疗效, 不良反应轻微,可提高病人的生活质量。     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

转移性非小细胞肺癌的化学治疗现状与进展

近年来,吸烟、污染以及油烟等导致肺癌的发病率及病死率迅速增长。非小细胞肺癌起病隐匿,发展迅速,预后差,患者初诊时多数即发生转移(IV期),失去手术机会,化疗是其主要的治疗方法,目的在于延长生存期、提高生活质量。目前临床应用的化疗药物主要是铂类以及第三代细胞毒药物。基于功能基因组学和蛋白组学的个体化治疗,为每一位肺癌患者设计最佳治疗策略是2l世纪临床发展的方向和理想的治疗模式。本文就转移性非小细胞肺癌的化学治疗现状与进展作一文献综述。     

国产吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床观察

目的 观察国产吉西他滨(GEM)联合顺铂(DDP)治疗晚期非小细胞肺癌的近期疗效、毒副反应、中位生存期及耐受性.方法 国产吉西他滨1 000 mg·m-2,静脉滴注30 min,第1、8 天;顺铂60～70 mg·m-2,静脉滴注,分3～ 4 d应用,28 d为一个周期,治疗39 例晚期非小细胞肺癌患者.结果 39 ...     

Atezolizumab for the treatment of non-small cell lung cancer

Introduction: The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1).

Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay.

Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.     

立体定向放射治疗非小细胞肺癌疗效观察

目的 研究立体定向放射治疗非小细胞肺癌的疗效.方法 107例非小细胞肺癌由立体定向治疗计划系统设计放射治疗计划,剂量体积直方图（DVH）评价和优化放射治疗计划,计划照射剂量为60～75 Gy（中位剂量68 Gy）,每次2.2～3.0 Gy,每天1次,每周5 d,由美国瓦里安CL2100加速器照射,射野为固定野和非共面野或者大旋转弧.按照美国放射治疗协作组（RTOG）和WHO标准观察急性放射反应和疗效.结果 疗效（CR＋PR）为88%（94/107）,（NC＋PD）即无效病例为12%（13/107）.1～3年生存率分别为85.78%、49.02%、23.88%.结论 立体定向放射治疗采用大弧旋转＋固定野照射,方法可行,有较好的疗效,早期并发症较低,能为患者耐受.     

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.     

阿替利珠单抗治疗转移性非小细胞肺癌的成本效用分析

目的： 评价阿替利珠单抗联合贝伐珠单抗及化疗（ABCP方案）一线治疗转移性非鳞状非小细胞肺癌的经济性。方法： 根据IMpower150临床试验,从中国卫生体系角度建立Markov模型。模型包括疾病未进展、疾病进展和死亡3个健康状态。模型的主要结果为总成本、生命年（life-year,LY）、质量调整生命年（quality adjusted LY,QALY）和增量成本效用比,还进行了一元敏感性分析和概率敏感性分析探讨参数的不确定性。结果： 基线分析结果显示：接受ABCP方案治疗比贝伐珠单抗联合化疗（BCP方案）治疗的患者增加了0.41 QALYs（0.45 LYs）,相应的总成本也增加了690 997元;增量成本效用比为1 688 482元/QALY（1 519 390元/LY）。一元敏感性分析结果显示：对增量成本效用比影响最大的参数是阿替利珠单抗的每周期成本。概率敏感性分析结果显示：增量成本效用比大于意愿支付阈值（212 676元/QALY）的概率为100%。结论： 与BCP方案相比,ABCP方案治疗转移性非鳞状非小细胞肺癌不具有经济性。     

MEK inhibitors under development for treatment of non-small-cell lung cancer

Introduction: The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC.

Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents.

Expert opinion: Trametinib in combination with the BRAF inhibitor dabrafenib represents the first MEK1/2 inhibitor containing regimen that is approved for advanced BRAF^V600E-mutant NSCLC. Other MEK1/2 inhibitors that are also in advanced stages of clinical development include selumetinib, cobimetinib, and binimetinib. Several studies of MEK inhibitor combination therapies are underway, including trials using combined MEK inhibition and immune checkpoint blockade. Further research aimed at discovering biomarkers of response and resistance to MEK1/2 inhibitors will be needed to develop rational combination strategies for the treatment of NSCLC driven by aberrant MAPK signaling.     

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.     

The safety of nivolumab for the treatment of advanced non-small cell lung cancer

Introduction: Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC.

Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile. In addition, we summarize the most common types of immune-related adverse events (irAEs) associated with nivolumab, mainly due to organ inflammation secondary to autoimmunity.

Expert opinion: Nivolumab is the preferred treatment option for platinum-pretreated advanced NSCLC, having convincingly shown higher efficacy compared with standard docetaxel chemotherapy in phase III trials. The same trials showed far less incidence of either any grade and severe treatment-related AEs with nivolumab compared with chemotherapy. IrAEs associated with nivolumab are rarely severe in intensity, and often resolve with prompt management. Future studies will explore nivolumab in combination strategies with either platinum-based chemotherapy or other ICBs in treatment-naïve advanced NSCLC patients.