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.     

HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients

In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.     

ZD 1839 in patients with brain metastases from non-small-cell lung cancer (NSCLC): report of four cases

The activity of ZD 1839 on brain metastases (BM) from Non-Small-Cell Lung Cancer (NSCLC) is unknown. We report four cases of BM responding to ZD 1839 theraphy.     

Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC)

The activity and toxicity profile of gefitinib in non-small cell lung cancer (NSCLC) patients aged 70 years or older has been only partially evaluated. The aim of this study was to evaluate the response rate and safety of gefitinib in elderly NSCLC patients. Elderly NSCLC patients pretreated with chemotherapy and with at least one measurable lesion received gefitinib at the daily dose of 250 mg until disease progression, unacceptable toxicity or refusal. From August 2001 to May 2003, 40 consecutive elderly patients have been enrolled onto the study in three Italian institutions. We observed one complete (2.5%) and one partial response (2.5%), 18 disease stabilisations (NC: 45%) lasting at least 2 months, including six patients (15%) who had disease stabilisation of 6 months or longer, for an overall disease control rate of 50% (95% CI: 34.5-65.5%). The median duration of response was 4.4 months (range 1.7-9.2). The side effects were generally mild and consisted of diarrhoea and skin toxicity. Grade 1-2 diarrhoea occurred in 23.6%, and one patient experienced grade 4 diarrhoea, requiring hospitalisation. Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne, occurred in 20 patients (52.6%). Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients. The disease-control rate achieved suggests that this drug could represent a valid option in the management of this unfavourable subgroup of patients.     

Immediate versus delayed treatment with EGFR tyrosine kinase inhibitors after first-line therapy in advanced non-small-cell lung cancer

Objective: To analyze the outcomes of patients who received TKI immediately after the first-line without progression as maintenance treatment (immediate group) vs. those received delayed treatment upon disease progression as second-line therapy (delayed group). Methods: The study included 159 no-small-cell lung cancer (NSCLC) patients who received gefitinib or erlotinib as maintenance treatment in the immediate group (85 patients) or as second-line therapy in the delayed group (74 patients). The primary end...     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum–docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

Brigatinib in Japanese patients with ALK-positive non-small-cell lung cancer: Final results of the phase 2 J-ALTA trial

The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%–49%); median duration of response was 14.8 months (95% CI, 5.5–19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7–12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%–85%); IRC-assessed ORR was 97% (95% CI, 84%–100%); the median duration of response was not reached (95% CI, 19.4–not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.     

紫杉醇联合卡铂治疗晚期非小细胞肺癌

目的 :研究紫杉醇联合卡铂 (铂尔定 ) (PC方案 )治疗晚期非小细胞肺癌的近期疗效和毒副作用。方法 :经病理组织学或细胞学证实的 4 8例非小细胞肺癌患者给予紫杉醇 5 5～ 6 0mg/m2 静滴 ,第 1、8、15天 ,卡铂按浓度 /时间曲线下面积 (AUC) =5给药 ,静滴 ,第 1天。 2 8天为一周期。结果 :全组CR 2例 ,PR 16例 ,NC 2 0例 ,PD 10例 ,总有效率为 37.5 %。其中初治组有效率为 4 6 .4 % (13/2 8) ,有两例CR ;复治组有效率为 2 5 .0 % (5 /2 0 ) ,无CR病例 ,两组差异有显著性 (P <0 .0 5 )。毒副反应为骨髓抑制 (白细胞下降及血小板减少 )、恶心 /呕吐和脱发。结论 :紫杉醇联合卡铂治疗晚期非小细胞肺癌疗效较高 ,初治组疗效优于复治组 ,且毒性可耐受。     

Gefitinib in the treatment of advanced non-small-cell lung cancer

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor, even after platinum-based chemotherapy. EGF receptor (EGFR)-targeted therapies, such as gefitinib, have been subject to comprehensive clinical development. Several Phase II and III trials have evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemo-naive patients. A Phase III trial in heavily pretreated advanced NSCLC patients, 90% of whom were refractory, demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant in the overall population. A second large Phase III trial in patients with pretreated advanced NSCLC (INTEREST) demonstrated the noninferiority of gefitinib in comparison with docetaxel for overall survival together with an improved quality of life and tolerability profiles. As a result, gefitinib is expected to have a large impact in the management of pretreated patients with NSCLC.     

EGFR-TKI在局部晚期非小细胞肺癌中的应用

随着肺癌分子生物学研究的不断深入,小分子靶点类抗肿瘤药物取得了突破性的进展,表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)是其中最受人关注的.多项研究证实了EGFR-TKI具有放射增敏性.放疗单独联合EGFR-TKI可使身体状况差的患者生存获益,但仍不能忽视肺毒性.然而,EGFR-TKI与放化疗联合能否使局部晚期NSCLC患者获益仍存在较大争议.     

PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients

Background:

Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC.

Methods:

We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.

Results:

PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).

Conclusions:

PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.     

吉非替尼联合康莱特注射液治疗晚期非小细胞肺癌探讨

目的:探讨吉非替尼联合康莱特注射液治疗晚期非小细胞肺癌的临床疗效.方法:选取我院收治的非小细胞肺癌患者,随机分为观察组和对照组.对照组患者给予吉非替尼口服治疗,观察组患者在此基础上加用康莱特静脉滴注,两组患者均以治疗21天为一个疗程,治疗持续3个疗程.结果:治疗后观察组患者的治疗有效率(69.1％)和疾病控制率(87.3％)均高于对照组(47.3％、63.6％),治疗后观察组患者生活质量的改善率(52.7％)高于对照组(27.3％),差异均有统计学意义(P＜0.05);而两组患者的毒副反应发生率间差异无统计学意义(P＞0.05).结论:吉非替尼联合康莱特注射液治疗晚期非小细胞肺癌效果显著,值得临床推广.     

New approaches in systemic treatment of advanced colorectal cancer: the molecular targets era

The prognosis of advanced colorectal cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. In this review, the authors examine the most important trials with monoclonal antibodies and tyrosine kinase inhibitors in the treatment of advanced colorectal cancer.     

长春瑞滨治疗27例高龄晚期非小细胞肺癌

目的:探讨单药长春瑞滨治疗70岁以上高龄晚期非小细胞肺癌患者的疗效及毒副反应。方法:2002年9月至2004年9月采用长春瑞滨治疗70岁以上高龄晚期非小细胞肺癌(NSCLC)27例,长春瑞滨25~30mg/m2 60ml生理盐水稀释,静注第1、8天,21天为1个周期,一般3~4周期,共进行了92周期。观察近期疗效、远期疗效、不良反应、中位缓解期和中位生存期。结果:PR9例,NC10例,PD8例,总有效率33.3%。中位缓解期4.1个月,中位生存期10.3个月。白细胞减少发生率为55.4%(51/92),Ⅲ/Ⅳ度为18.5%(17/92),血小板减少率为8.7%(8/92),静脉炎发生率为6.5%(6/92)。结论:长春瑞滨在治疗高龄晚期NSCLC患者中,有较好的近期疗效,毒副反应可耐受,临床应用安全,可以作为高龄晚期非小细胞肺癌的治疗方案选择之一。     

NP方案治疗晚期非小细胞肺癌近期疗效观察

目的 评价长春瑞滨加顺铂联合化疗方案对晚期非小细胞肺癌近期疗效。方法 对64例晚期非小细胞肺癌患应用NP方案化疗，观察近期疗效及毒副反应。结果 CR3例，PR32例，总有效率54．7％。结论 NP方案治疗晚期非小细胞肺癌近期疗效较好，毒副反应小，为可逆性，值得临床推广。     

A phase II study of 9-aminocamptothecin in advanced non-small-cell lung cancer

Background: 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 µg/m2/day × 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia.Patients and methods: Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 µg/m2/d × 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 µg/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression.Results: Fifty-eight patients were treated, thirteen at 1416 µg/m2/d and 45 at 1100 µg/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9–28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%–19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 µg/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 µg/m2/d these toxicities were observed in 12 and three of 45 patients, respectively.Conclusion: 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.     

异长春花碱单药化疗高龄晚期非小细胞肺癌

目的：评价高龄NSCLC患者用异长春花碱单药化疗的生存率,生活质量及能否耐受。方法：治疗高龄晚期非小细胞肺癌40例,治疗组20例予以持续深静脉输注异长春花碱（NVB）24小时7．5mg/m^2第1－5天,同时第一天快速静滴异长春花碱7．5mg/m^2,三周后重复;对照组20例运用中药薏芯仁提取物200ml/天静滴20天1疗程辅以其他支持治疗,每1月为1疗程,所有病例至少完成两个疗程,除非治疗中发现病情进展,结果：治疗组有效率35％（7／20）,患者中位生存期 7．2个月,一年生存率25％,对照组有效率10％（2／20）,患者中位生存期4．8个月,一年生存率5％,结论：对高龄晚期非小细胞癌患者,异长春花碱单药治疗较中药薏芯仁为主的支持治疗有更好的疗效,生活质量,更长的生存期,且毒副反应轻微,可以耐受。     

持续低剂量去甲长春碱合并顺铂治疗晚期非小细胞肺癌的疗效研究

目的：比较NP方案（去甲长春碱,顺铂）与低剂量去甲长春碱（NVB）持续静脉注射加顺铂（DDP）治疗晚期非小细胞肺癌的疗效及毒副反应,方法：65例晚期非小细胞肺癌患者,持续组31例,应用低剂量NVB持续静脉注射加DDP方案,DDP 20mg静脉注射第1－7天,NVB 10mg静脉注射24小时第1－7天,21天为一周期,两周期评价疗效及毒副反应,对照组34例应用NP方案,NVB 25mg/m^2静脉注射第1,8天,DDP 30mg/m^2静脉注射第1－3天,结果：治疗组CR1例,PR12例,SD15例,PD3例,治疗有效率41．9％,对照组CR1例,PR14例,SD15例,PD4例,治疗有效率44．1％,两组无显著性差异（P＞0．05）,毒副反应：持续组胃肠道反应,静脉炎发生,白细胞减少程度显著低于对照组,结论：低剂量持续NVB静脉注射顺铂治疗非小细胞肺癌与NP方案疗效相似,毒副反应明显减少。