A Multicenter Double-blind Phase II Study of Metformin With Gefitinib as First-line Therapy of Locally Advanced Non–Small-cell Lung Cancer

We present the rationale and study design of the CGMT (combined gefitinib and metformin therapy) trial (www.ClinicalTrials.gov Identifier: NCT01864681), which is aimed at treating locally advanced non–small-cell lung cancer. The CGMT trial is a multicenter, phase II randomized, double-blinded, and placebo-controlled study, which is designed to evaluate the safety and efficacy of metformin in combination with gefitinib as first-line therapy in patients presenting with stage IIIb-IV non–small-cell lung cancer expressing the epidermal growth factor receptor mutant. Two therapies are proposed for this trial. The first regimen is comprised of gefitinib plus metformin. The second therapy is comprised of gefitinib plus placebo. The primary objective of this trail is to compare the progression-free survival rate at year 1 of the study. The secondary objective of this trial is to compare the 2-year overall survival, the 2-year progression-free survival, the objective response rate, and the disease-control rate, and to evaluate the relative safety of both therapies. Based on the statistical design, we plan to enroll approximately 200 patients.     

Cost-Effectiveness Analysis of Afatinib versus Gefitinib for First-Line Treatment of Advanced EGFR-Mutated Advanced Non–Small Cell Lung Cancers

IntroductionThe irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation–positive NSCLCs. Afatinib and gefitinib costs and patients’ outcomes in France were assessed.MethodsA partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation–positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted.ResultsFor all EGFR mutation–positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations.ConclusionFirst-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation–positive NSCLCs.     

Nedaplatin Plus Docetaxel Versus Cisplatin Plus Docetaxel as First-Line Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung — A Multicenter,Open-label,Randomized, Phase III Trial

Introduction

This study aimed to compare the efficacy of first-line nedaplatin (80 mg/m²) plus docetaxel (75 mg/m²) (ND) versus cisplatin (75 mg/m²) plus docetaxel (75 mg/m²) (CD) in patients with advanced squamous cell lung carcinoma.

Beyond Doublet Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Combination of Targeted Agents with First-Line Chemotherapy

The first-line treatment of advanced non–small-cell lung cancer (NSCLC) has evolved significantly over the past 5 years. As recently as 15 years ago, best supportive care (BSC) was considered an acceptable option for most patients with advanced or metastatic NSCLC, based on the concern that toxic effects of systemic chemotherapy overshadowed any potential benefits. The enhanced efficacy of platinum-based doublet chemotherapeutic regimens led to increases in overall patient survival relative to BSC. However, overall survival (OS) appeared to plateau, even with the introduction and refinement of these regimens. The addition of novel targeted agents targeting growth pathways to platinum-based regimens failed to overcome the 7.8- to 10.5-month survival barrier. After many phase III clinical trials, which involved tyrosine kinase inhibitors, matrix metalloproteinase inhibitors, protein kinase C inhibitors, and retinoids, this survival barrier had yet to be surmounted, although in some cases certain subgroups benefited, suggesting specific molecular correlations. Recently, inhibition of components of the angiogenesis pathway with the addition of bevacizumab to a platinum-based doublet led to statistically significant increases in OS, progression-free survival, and response rate relative to chemotherapy alone. This advance pushed the median survival of selected patients with advanced or metastatic NSCLC who met the eligibility criteria of the trial over the 12-month mark, thus offering patients and clinicians hope for more incremental advances in the future.     

A Phase II Clinical Trial of Apatinib in Pretreated Advanced Non-squamous Non–small-cell Lung Cancer

Objectives

Apatinib exhibits broad-spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor-2. This study evaluated the efficacy and safety of apatinib in patients with advanced non-squamous non–small-cell lung cancer who were heavily pretreated or not suitable to receive standard second-line chemotherapy.

吉非替尼单药维持治疗晚期非小细胞肺癌的疗效和安全性分析

目的 评价吉非替尼维持治疗晚期非小细胞肺癌(NSCLC)的疗效和安全性.方法 173例晚期NSCLC患者化疗后给予吉非替尼治疗,其中62例为诱导化疗后维持治疗,111例为复发后治疗.中位生存期采用Kaplan-Meier方法计算,不同因素分层生存期比较采用多因素Cox回归分析.结果 维持治疗组中位生存期为25.0个月,95%可信区间(CI)为19.3～30.7个月;复发后治疗组中位生存期为12.5个月,95%CI为9.3～15.7个月,两组差异有统计学意义(P＜0.01).维持治疗组中位无疾病进展生存期(PFS)为16.5个月,95%CI为8.7～24.3个月;复发后治疗组PFS为9.2个月,95%CI为7.5～10.9个月,两组差异有统计学意义(P＜0.01).维持治疗组生存的影响因素包括吸烟状况、病理类型、是否有肝脏转移和吉非替尼治疗的客观疗效.结论 晚期NSCLC患者化疗后给予吉非替尼维持治疗,其生存期和PFS明显长于复发后治疗的患者.     

诱导化疗后吉非替尼维持治疗晚期非小细胞肺癌的临床研究

目的：评价晚期非小细胞肺癌（ＮＳＣＬＣ）诱导化疗后给予吉非替尼单药维持治疗的临床价值。方法：２００２年５月～２００５年２月,晚期ＮＳＣＬＣ患者根据最后一个化疗方案疗效分为两组,疗效为部分缓解（ＰＲ）或稳定（ＳＤ）的为吉非替尼维持治疗组,疗效为进展（ＰＤ）的为吉非替尼解救治疗组。入组后给予口服吉非替尼治疗,每日１次,每次２５０ｍｇ,持续服用到疾病进展。结果：共有１１９例患者入组,其中吉非替尼维持治疗组为７９例,解救治疗组为４０例。维持治疗组总有效率（ＲＲ）３１.６％（２５／７７）,其中３例ＣＲ,解救治疗组ＲＲ为２７.５％（１１／４０）,两组之间无统计学差异（Ｐ＝０.６４５）。吉非替尼维持治疗组的进展时间（ＴＴＰ）为６.０个月,显著长于解救治疗组的４.０个月（Ｐ＝０.０３）。维持治疗中位生存期（ＯＳ）为１１.０个月,而解救治疗组的中位ＯＳ为７.０个月,二者差异具有统计学意义（Ｐ＝０.０１９）。维持治疗组中腺癌患者的有效率显著高于鳞癌患者（３９.７％ ｖｓ.１２.５％,Ｐ＝０.０４１）,ＴＴＰ也显著长于鳞癌患者（７.５个月ｖｓ．３.０个月,Ｐ＝０.０２）;女性患者的中位ＯＳ显著长于男性患者（１８.５个月ｖｓ．９.０个月,Ｐ＝０.００２）。毒副作用多数较轻,且可逆,以１、２级为主。结论：吉非替尼作为晚期ＮＳＣＬＣ诱导化疗后的维持治疗,有较好的疗效和安全性。与化疗进展后再使用吉非替尼方案相比,化疗未进展时使用能更好地发挥该药的优势,给予患者更大的生存获益。     

一线化疗后吉非替尼维持治疗晚期非小细胞肺癌的临床观察

 【摘要】　目的　评价晚期非小细胞肺癌（NSCLC）一线化疗获得部分缓解（PR）或稳定（SD）后予以吉非替尼单药维持治疗的临床疗效。方法　应用前瞻性随机对照临床研究方法,将71例经标准的两药含铂方案一线化疗获得PR或SD的患者按随机数字表法分为两组,治疗组患者（36例）服用吉非替尼250 mg,1次／d;对照组（35例）服用安慰剂,1次／d。两组患者均服用至疾病进展。结果　治疗组总有效率（RR）为36.1 %（13／36）,其中1例（2.8 %）完全缓解（CR）,对照组RR为14.3 %（5／35）,两组差异有统计学意义（χ2＝4.633,P＝0.036）。治疗组疾病控制率（CR+PR+SD,DCR）为83.3 %（30／36）,对照组为42.9 %（15／35）,两组差异有统计学意义（χ2＝14.782,P＜0.001）。治疗组无进展生存期（PFS）较安慰剂组显著延长（分别为13周和11周）（χ2＝10.401,P＝0.001）。治疗组中位生存期（OS）为13.2个月,对照组为10.4个月,两组差异有统计学意义（χ2＝7.696,P＝0.006）。治疗组女性患者中位OS（18.5个月）显著长于男性（11.2个月）（χ2＝22.864,P＝0.011）;不吸烟者中位OS（15.3个月）亦长于吸烟者（10.3个月）（χ2＝0.389,P＝0.007）;腺癌及肺泡细胞癌患者中位OS（16.0个月）亦显著长于鳞状细胞癌患者（10.2个月）（χ2＝4.638,P＝0.001）。治疗组不良反应以皮疹、腹泻、皮肤干燥瘙痒及乏力为主,多为Ⅰ、Ⅱ度。结论　晚期NSCLC一线化疗后吉非替尼维持治疗可以提高疗效、延长患者生存期,不良反应轻,可以耐受。     

吉非替尼一线治疗局部晚期或转移性非小细胞肺癌的临床观察

目的：评价吉非替尼一线治疗局部晚期或转移性非小细胞肺癌（ＮＳＣＬＣ）的疗效和安全性。方法：４５例局部晚期或转移性ＮＳＣＬＣ一线应用吉非替尼２５０ｍｇ／ｄ,直至出现肿瘤进展或不可耐受的毒副反应。结果：４５例可评价病例中,无完全缓解（ＣＲ）,部分缓解（ＰＲ）１５例,病情稳定（ＳＤ）１７例,疾病进展（ＰＤ）１３例。全组有效率为３３.３％,疾病控制率为７１.１％。疾病相关症状缓解率为７２.５％,中位缓解时间为８天。中位生存期１５.３个月,中位无进展生存期为６.０个月。主要的毒副作用为皮疹２４例（５３.３％）,腹泻１５例（３３.３％）,皮肤干燥脱屑１２例（２６.７％）,皮肤瘙痒１０例（２２.２％）,恶性呕吐８例（１７.８％）,转氨酶升高３例（６.７％）及口腔溃疡２例（４.４％）。结论：吉非替尼一线治疗局部晚期或转移性ＮＳＣＬＣ有较好的疗效和安全性。     

Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy

Purpose

Gefitinib and erlotinib are potent EGFR TKIs, with antitumor activity. In this randomized, single-center, non-comparative phase II trial, the efficacy and safety of gefitinib and erlotinib was evaluated as the second-line therapy for advanced non-small cell lung cancer (NSCLC).

Patients and methods

Patients with locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least two out of three clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker) were eligible.

Results

A total of 96 (48 per arm) patients were randomly assigned to gefitinib- or erlotinib-arm, respectively. Baseline characteristics were well-balanced between the two arms. The response rates (RR) were 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9 months (95% CI, 1.3-8.5) in the gefitinib arm and 3.1 months (95% CI, 0.0-6.4) in the erlotinib arm. The most common grade 3/4 toxicity was skin rash. Exploratory analyses showed that there was no significant difference in RR and PFS in the gefitinib arm compared to the erlotinib arm (RR (%) 47.9 vs. 39.6, p = 0.269; median survival (months) 4.9 vs. 3.1, p = 0.336). There was no significant difference in QOL between the two arms.

Conclusion

Both gefitinib and erlotinib showed effective activity and tolerable toxicity profiles as second-line treatment for the selected population of NSCLC. We may consider conducting a phase III trial to directly compare the efficacy and toxicity between gefitinib and erlotinib in an enriched patient population.     

厄洛替尼治疗吉非替尼耐药的进展期非小细胞肺癌的临床观察

目的　评价厄洛替尼对吉非替尼耐药的进展期非小细胞肺癌（ＮＳＣＬＣ）患者的疗效和安全性。方法　回顾性分析２００６年６月至２００９年２月１５例ＮＳＣＬＣ患者,均口服吉非替尼并出现病情进展,改换为厄洛替尼１５０ｍｇ,１次／日,直到病情进展或不良反应不能耐受为止。观察疗效、不良反应以及疗效与临床特征之间的关系。结果　厄洛替尼治疗吉非替尼耐药共１５例进展期ＮＳＣＬＣ患者,１例获得ＰＲ,４例获得ＳＤ,客观有效率为６.７％,疾病控制率为３３.３％。获有效和稳定的５例患者中４例曾吉非替尼治疗获益。厄洛替尼治疗的中位疾病进展期（ＴＴＰ）和中位总生存期（ＯＳ）分别为１１１天和２２３天。厄洛替尼获益的５例患者较未获益的１０例患者获得更长的ＴＴＰ（１１１天ｖｓ．３５.５天,Ｐ＜０.０５）。厄洛替尼最常见的副反应为轻度皮疹和腹泻。结论　厄洛替尼似乎是治疗吉非替尼耐药的进展期ＮＳＣＬＣ的有效药物,尤其是对于曾予吉非替尼治疗可以获益的患者,但厄洛替尼不应作为常规的二线选择,对患者谨慎筛选很有必要。     

吉非替尼一线治疗非小细胞肺癌脑膜转移１２例分析

目的　观察吉非替尼作为非小细胞肺癌（ＮＳＣＬＣ）脑膜转移一线治疗方案的疗效和不良反应。方法　１２例ＮＳＣＬＣ脑膜转移患者服用吉非替尼２５０ｍｇ,１／日,直至疾病进展。结果　１２例患者获ＣＲ８.３％,ＰＲ４１.７％,ＤＣＲ７５.０％,中位总生存期１０.２个月,中位无进展生存期７.８个月。药物引起的毒副反应大部分为１～２级,未因不良反应而减停。结论　吉非替尼一线用于ＮＳＣＬＣ脑膜转移安全有效,值得进一步研究。     

Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: meta-analysis of phase III trials

Background

Gefitinib is an oral tyrosine kinase inhibitor against the epidermal growth factor receptor (EGFR). It has been shown to be active in patients with advanced non-small cell lung cancer (NSCLC) whose tumors contain EGFR mutations.

Methods

We performed a meta-analysis of four randomized studies that compared gefitinib with chemotherapy in the first-line treatment of patients with advanced NSCLC: IPASS, North-East Japan, West Japan and first-SIGNAL studies. Patients were selected either on the basis of known EGFR mutations or based on clinicopathologic criteria - non-smokers with adenocarcinomas - associated with increased likelihood of EGFR mutations.

Results

Nearly 2000 patients were enrolled on these four trials. Median ages ranged from 57 to 64 years. Seventy-six percent were women and 86% were non-smokers. Overall, gefitinib was associated with significantly less toxicity than chemotherapy and improved quality-of-life. Gefitinib also produced higher response rates in the EGFR mutation-positive patients (72% vs. 38%, odds ratio 4.04, p < 10⁻¹⁵), as well as improved progression-free survival (PFS; hazard ratio 0.45, p < 10⁻¹⁶). Overall survival (OS) was not significantly different between treatment groups (p = 0.35).

Conclusions

This meta-analysis confirms the results of each individual study and narrows the confidence intervals of these results. In patients with known EGFR mutations or whose tumors are likely to harbor a mutation, upfront gefitinib or chemotherapy are associated with similar OS. Gefitinib is associated with less fatigue, myelosuppression and nausea than chemotherapy (but produces more skin rash, diarrhea and pneumonitis). Patients receiving gefitinib have improved quality-of-life compared to those receiving chemotherapy, making it an appropriate first-line choice.     

晚期非小细胞肺癌的中医维持治疗

晚期非小细胞肺癌（ＮＳＣＬＣ）维持治疗是肿瘤学专家在化疗疗效达到“瓶颈”后为延长患者生存时间所提出的一种新型治疗模式,主要包括化疗维持和靶向维持,目前维持治疗尚存在较多的争议,临床上尚未完全推行。本文通过论述中医药治疗晚期ＮＳＣＬＣ的现状及优势,分析中医药进行维持治疗的优势及可行性,并对维持治疗的发展进行探索,希望中医药在晚期ＮＳＣＬＣ维持治疗中能有新的突破和进展。     

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

Retrospective analysis has shown that activating mutations in exons 18–21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48–93%). After a median follow-up of 12.7 months (range, 3.1–16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7–11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.