New avenues for second-line treatment of metastatic non-small-cell lung cancer

Platinum-based doublets are the standard first-line therapy for patients with advanced non-small-cell lung cancer, with approximately a third of patients obtaining an objective response with first-line chemotherapy and another 20–30% achieving temporary disease stabilization. However, all patients inevitably experience disease progression. Three agents are approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed and erlotinib. Erlotinib is the only agent approved for use in the third-line setting. Although these agents have yielded similar outcomes in terms of anti-tumor activity and efficacy, they have different toxicity profiles, and some factors that can help in the choice among them have begun to emerge, such as smoking history and histotype. Several new molecularly targeted agents have shown activity in Phase II trials and may be integrated into second-line therapy as single agents or in combination with current agents in the future. In particular, the most encouraging data in this clinical setting have been reported with the antiangiogenetic drugs bevacizumab (already approved for use in the first-line setting), vandetanib and sunitinib. Phase III trials with these agents are ongoing.     

Docetaxel in second-line treatment of non-small-cell lung cancer

The survival and quality-of-life benefits of docetaxel in the second-line treatment of non-small-cell lung cancer (NSCLC) are supported by two phase III trials: TAX 317 and TAX 320. In TAX 317, 204 patients were randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) intravenously every 3 weeks, or best supportive care (BSC). Median survival was 9.0 months with D75 versus 4.6 months for BSC (P = 0.016); 1-year survival was 40% for D75 versus 16% for BSC (P = 0.016). Quality-of-life analysis showed significant improvement in several disease-related symptoms in patients who received docetaxel. TAX 320 was a supportive trial, in which 373 patients were randomized to receive D100, D75, or the control treatment of vinorelbine or ifosfamide (V/I). The partial response rate was 12% with D100 and 8% with D75 versus 1% with V/I (D100, P = 0.001 and D75, P = 0.036). Median response duration was 7+ months. One-year survival was 32% with D75 and 19% with V/I (P = 0.025). In TAX 320, prior paclitaxel exposure had no bearing on the response rate and survival advantage of second-line treatment with docetaxel. Response rates to docetaxel were equivalent in the cohort of patients who had received prior paclitaxel (10.5%) and the group of patients who had not received prior paclitaxel (8.5%). Furthermore, 1-year survival rates for patients with no prior paclitaxel therapy were 33% (D75) and 20% (V/I); 1-year survival rates for patients who had received prior paclitaxel were 30% (D75) and 17% (V/I). Docetaxel at a dose of 75 mg/m2 every 3 weeks offers a clinically meaningful improvement in response rate, time to progression, survival, and quality of life in the second-line treatment of advanced NSCLC. Furthermore, prior paclitaxel did not decrease the likelihood of response to docetaxel, nor did it lessen the survival advantage seen with docetaxel.     

Advances in the treatment of second-line non-small-cell lung cancer

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.     

A randomized,double-blind,phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC)

BackgroundCombined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC).Patients and methodsThis randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review.ResultsOne hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%).ConclusionsThe addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.     

Therapeutic advances in second-line treatment of advanced non-small-cell lung cancer

A majority of patients with lung cancer present with advanced disease: approximately 30% with locally advanced disease and 45% with metastatic disease. The prognosis for these patients is poor, with 5-year survival rates ranging from 5% to 15% for stage IIIB disease and < 5% for stage IV disease. For patients confronting advanced disease, chemotherapy is an essential option for disease control and palliation. Although a number of effective first-line regimens exist, virtually all patients with advanced non-small-cell lung cancer (NSCLC) will have disease relapse. For these patients, identifying the optimal treatment course remains a challenge. This article reviews approved and investigational second-line therapeutic options in patients with relapsed advanced NSCLC. Recently, docetaxel has been shown to improve survival in patients with advanced NSCLC who had progressive disease following treatment with platinum-containing chemotherapy. Subsequently, permetrexed was compared with docetaxel in a second-line treatment study that showed survival for both patient groups was virtually identical. Recently, erlotinib was associated with significantly longer survival compared with best supportive care in the second- or third-line treatment settings. Salvage treatment for NSCLC is reviewed, and the relative merits of the currently available treatments as well as agents that are pending Food and Drug Administration approval as second-line treatments are discussed.     

Response to second-line erlotinib in an EGFR mutation-negative patient with non-small-cell lung cancer: make no assumptions

Erlotinib-an oral tyrosine kinase inhibitor (tki) of the epidermal growth factor receptor (egfr)-has commonly been used as a therapeutic option in metastatic non-small-cell lung cancer (nsclc) patients in the second- or third-line treatment setting. A mutation in the EGFR gene (EGFR M+) confers an increased response to this class of drugs. In the first-line setting, use of tkis is restricted to patients having a mutation. The importance of this biomarker has been questioned in subsequent treatment lines.Here, we report a case showing a positive response to erlotinib treatment in the second-line setting. The patient, an elderly male smoker with stage iv nsclc, had a tumour that was EGFR mutation-negative (wild-type EGFR). Based on this clinical case, we discuss the controversy concerning the need for, and impact of, testing for EGFR mutation after first-line treatment.     

Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer

Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcinoma histology, with manageable toxicity. Here, we present an analytical review of literature regarding nintedanib and we focus on its particular importance in NSCLC treatment.     

厄罗替尼治疗晚期非小细胞肺癌19例临床疗效

目的评价厄罗替尼治疗ⅢB～Ⅳ期非小细胞肺癌（NSCLC）的疗效和患者不良反应。方法19例患者均为经病理证实的、至少接受过一种方案全身化疗的晚期NSCLC患者。厄罗替尼150mg／次,1次／d,口服,直至病情进展或出现不能耐受的不良反应。采用实体瘤疗效评价标准（RECIST）评价疗效,美国国立癌症研究所毒性评价标准（CTCAE）评价不良反应。结果19例患者客观缓解率（ORR）为21．1％（4／19）。疾病控制率（完全缓解＋部分缓解＋稳定）为84．2％（16／19）,疾病无进展生存时间（PFS）3～36个月,中位PFS7．5个月;生存时间9～39个月,中位生存时间15．9个月。不良反应主要是皮疹16例（84．2％）,腹泻11例（57．9％）,多为Ⅰ～Ⅱ度;Ⅲ度丙氨酸氨基转移酶升高1例;未出现Ⅳ度药物相关不良反应。结论厄罗替尼对既往化疗失败的局部晚期或转移性NSCLC患者有较好的疗效和安全性。     

Safety of erlotinib treatment in outpatients with previously treated non-small-cell lung cancer in Japan

Purpose  

Erlotinib is the first epidermal growth factor receptor–tyrosine kinase inhibitor shown to provide a survival benefit for advanced non-small-cell lung cancer (NSCLC) patients. Adverse drug reactions of erlotinib in Japanese, which may be very different from those in Caucasians because of differences in genetic background, have not been fully reported. Therefore, we aimed to clarify the safety profile of erlotinib.     

A cross-market cost comparison of erlotinib versus pemetrexed for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer

Erlotinib and pemetrexed were approved by the European Medicines Agency for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) to prolong overall survival after first-line therapy. An adjusted, matched, indirect comparison of erlotinib and pemetrexed suggested that survival benefits were not statistically significantly different between treatments. We conducted a cost-comparison analysis of erlotinib versus pemetrexed in first-line maintenance treatment of locally advanced or metastatic, non-squamous NSCLC in France, Germany, Italy and Spain, performed from the perspective of national health-care decision-makers or purchasers. The analysis was limited to direct costs and comprised drug-acquisition costs, administration costs and costs of treating adverse events (AEs). A one-way sensitivity analysis on administration, acquisition and AE costs was also performed. Total monthly per-patient treatment costs for erlotinib in France, Germany, Italy and Spain were €2140, €2732, €1518 and €2048, respectively, and for pemetrexed €3453, €5534, €2921 and €3164, respectively. AE cost was greater for pemetrexed in all countries, as was administration cost. As an oral treatment, erlotinib is not associated with any administration costs, except in Germany, where the cost is lower than for pemetrexed. The sensitivity analysis showed acquisition costs to be the main driver of total monthly per-patient costs. Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on an indirect comparison, at a lower cost.     

Safety profiles of erlotinib therapy in patients with advanced non-small-cell lung cancer

Erlotinib is an orally available, small-molecule EGF receptor tyrosine kinase inhibitor. It has shown promising activity in chemotherapy-relapsed patients with advanced non-small-cell lung cancer and is now approved in many countries. To date, there have been a number of clinical studies of erlotinib therapy demonstrating its safety as well as its efficacy. This article summarizes clinical study results in advanced non-small-cell lung cancer, so that we can comprehensively understand the toxicities expected with erlotinib in non-small-cell lung cancer patients.     

Retrospective study of erlotinib in patients with advanced squamous lung cancer

Background: The effective targeted therapy for lung squamous cell carcinoma (SCC) is needed. The epidermal growth factor receptor (EGFR) mutation rate is low in lung SCC. The aim of this study was to evaluate the status of erlotinib treatment and EGFR mutation in lung SCC patients.Methods: We retrospectively enrolled lung cancer patients with SCC histology and history of erlotinib treatment. The primary objective was to assess overall response rate (ORR) and disease control rate (DCR) and the secondary objective was to assess progression-free survival (PFS) and overall survival (OS). EGFR mutations were assessed in parts of patients using both direct sequencing and protein nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp methods.Results: In total, 92 patients were analyzed (75 men and 17 women, median age 69 years, and 74 current or former smokers). Sixteen patients achieved partial response and 9 had stable disease. The ORR was 17.4% and the DCR was 27.2%. The PFS and OS were longer in patients with disease control than with progressive disease (PFS 7.8 versus 1.3 months and OS 20.7 versus 2.7 months, both p < 0.0001). The 1-year survival rate was 21.7%. In 27 patients with adequate specimens for molecular analysis (including 4 PR and 4 SD), two (7.4%) had EGFR complex mutations. One patient experienced response to erlotinib and the other did not.Conclusions: A significant proportion of lung SCC patients would derive a clinical benefit from erlotinib treatment. The relatively higher response rate than the EGFR mutation rate in present study needs further evaluation.     

Clinical effect of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer

Purpose

To evaluate the efficacy and toxicities of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods

Untreated patients with advanced NSCLC were included in this study; erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity or for other reasons.

Results

A total of 35 patients were enrolled. Patient characteristics were as follows: mean age 75.6 years (ranged 70–81 years), 24 (68.6%) male, 16 (45.7%) former or current smokers, 13 (37.1%) adenocarcinoma, 18 (51.4%) squamous cell carcinoma and 4 (11.4%) bronchioloalveolar carcinoma. Out of 35 patients, 1 CR, 16 PR and 10 SD, resulting in an overall response rate (CR + PR) of 48.6% and disease control rate (DCR = CR + PR + SD) of 77.1%. The median TTP was 6.4 months, and the median OS was 12.7 months. The CBR was 80%, and the 1-year survival rate was 48.6%. The most common adverse event (AE) was mild skin rash and diarrhea (CTC AE 1/2). Among them, the female never smokers with a non-squamous cell carcinoma histology was superior to the male smokers with a squamous cell carcinoma in disease control rate, with significant differences (P < 0.05).

Conclusion

The results suggest that erlotinib monotherapy is an effective and well-tolerated treatment option for Asian elderly patients with advanced NSCLC.     

一线序贯应用厄洛替尼与化疗治疗晚期非小细胞肺癌的临床研究

 目的　评价化疗后序贯给予厄洛替尼在一线治疗非小细胞肺癌（NSCLC）中的客观缓解率和不良反应。方法　23例PS 0～1分的ⅢB～Ⅳ期NSCLC患者一线接受GC化疗方案（吉西他滨1250 mg／m2 第1、8天,顺铂75 mg／m2 第1天或卡铂AUC＝5第1天）,并序贯给予厄洛替尼（150 mg,第15天至第28天）,每28 d为1个周期,观察患者的客观疗效及不良反应。结果　23例患者接受95个周期的化疗,所有患者均可评价疗效。完全缓解（CR）0例,部分缓解（PR）7例（30.4 %）,疾病稳定（SD）14例（60.9 %）,疾病进展（PD）2 例（8.7 %）;总体客观缓解（RR）30.4 %,疾病控制（DCR ）91.3 %。Ⅲ度以上不良反应为白细胞减少3例（13.0 %）,皮疹2例（8.7 %）,恶心呕吐、血小板减少各2例（8.7 %）,没有出现治疗相关的间质性肺病。结论　GC化疗方案序贯厄洛替尼治疗模式的近期疗效较好,不良反应在患者可耐受范围内,远期疗效有待进一步观察。