奥希替尼治疗非小细胞肺癌的研究进展

表皮生长因子受体(EGFR)突变的发现以及EGFR酪氨酸激酶抑制剂(TKI)疗效的证明，标志着非小细胞肺癌(NSCLC)精准药物使用时代的到来。奥希替尼是针对EGFR TKI敏感突变和野生型EGFR T790M突变，同时保留野生型EGFR的第三代TKI。因其在临床试验中表现出的显著临床有效性和良好安全性，2015年及2016年初，美国及欧洲首次批准了奥希替尼用于接受EGFR TKI治疗后进展的EGFR T790M突变阳性的NSCLC患者的治疗，2017年3月奥西替尼正式在我国获批上市。本文主要就奥希替尼在NSCLC治疗中的研究进展进行综述。     

Modeling the Cost-Effectiveness of Adjuvant Osimertinib for Patients with Resected EGFR-mutant Non-Small Cell Lung Cancer

IntroductionThe epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib was recently approved for resected EGFR-mutant stages IB-IIIA non-small cell lung cancer due to improved disease-free survival (DFS) in this population compared with placebo. This study aimed to evaluate the cost-effectiveness (CE) of this strategy.Materials and MethodsWe constructed a Markov model using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of 3 years of adjuvant osimertinib versus placebo over a 10-year time horizon. An overall survival (OS) benefit of 5% was assumed. Costs and utility values were derived from Medicare reimbursement data and literature. A CE threshold of 3 times the gross domestic product per capita was used. Sensitivity analyses were performed.ResultsThe incremental cost-effectiveness ratio for adjuvant osimertinib was $317 119 per QALY-gained versus placebo. Initial costs of osimertinib are higher in years 1-3. Costs due to progressive disease (PD) are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2388, $379 047, and $502 937, respectively, in the placebo group, and $505 775, $255 638, and $800 697, respectively, in the osimertinib group. Sensitivity analysis of OS gains reaches CE with an hazard ratio (HR) of 0.70-0.75 benefit of osimertinib over placebo. A 50% discount to osimertinib drug cost yielded an ICER of $115 419.ConclusionsThree-years of adjuvant osimertinib is CE if one is willing to pay $317 119 more per QALY-gained. Considerable OS benefit over placebo or other economic interventions will be needed to reach CE.     

A phase I study of combination chemotherapy with gemcitabine and oral UFT for advanced non-small cell lung cancer

A phase I study was carried out to determine the optimal dose and administration schedule for combined UFT plus gemcitabine therapy in patients with non-small cell lung cancer. Twenty-four patients (including 11 patients previously treated with cisplatin as the key drug) received oral UFT 400 mg x m(-2) on days 1 to 14 with intravenous infusions of gemcitabine (800 mg x m(-2) on days 8 and 15, or 900 mg x m(-2) on days 8 and 15, or 900 mg x m(-2) on days 1, 8 and 15). The most appropriate dosing option appeared to be 400 mg x m(-2) per day of oral UFT for 14 consecutive days with 900 mg x m(-2) gemcitabine on days 8 and 15. Eight of the 24 patients achieved partial response. The combination chemotherapy UFT and gemcitabine was well tolerated and may benefit patients with advanced non-small cell lung cancer. A multicentre phase II study using a 3-weekly regimen is in progress.     

逐步递量加速超分割照射加化疗治疗非小细胞肺癌的临床Ⅱ期试验结果分析

目的　研究逐步递量加速超分割照射加化疗治疗Ⅲb期非小细胞肺癌的耐受性、副反应和疗效。方法　73例中男5 9例,女14例,中位年龄6 0岁(33～70岁)。放疗方案为2次/d ,间隔>6h ,5d/周。第1、2周,1.2Gy/次,2次/d ;第3、4、5周分别为1.3、1.4、1.5Gy/次,2次/d。肿瘤灶总剂量为6 6Gy ,5 0分次,5周完成。化疗为MVP或EP方案。结果　73例中12例未完成既定的治疗计划。完成的化疗中位疗程数为4个,完成的放疗中位肿瘤灶剂量为6 6Gy。急性放射性食管炎发生率为77% ,其中3级为15 %。急性放射性肺炎发生率为4 0 % ,其中3级为8%。73例的中位生存时间为13个月,1、2年生存率分别为5 1%、10 %。完成既定放疗的6 1例中34例出现局部复发,其中32例在照射野内,2例在野外。1、2年局部控制率分别为71%、34%。1、2年远地转移率分别为5 7%、84 %。结论　逐步递量加速超分割照射加化疗能被绝大多数Ⅲb期患者所耐受,局部控制有所改善,由于远地转移使长期生存并无明显提高。     

Results of a Five-Drug Combination Chemotherapy in Non-Small Cell Lung Cancer: A phase II trial

Twenty-six non-small lung cancer patients entered a phase II trial of a 5-drug combination chemotherapy. On day 1, patients received vinblastine, bleomycin, methotrexate, 5-FU, cisplan-tinum, leucovorin, and a similar sequence with an increased dosage was administered on day 6. Out of 22 fully evaluable patients we observed 1 CR and 7 PR. Hematological toxicity was significant, including 15 cases of neutropenia grade 4 and four grade 3, with one death during aplasia. Our results are disappointing but they are similar to most current reports on drug combinations in advanced non-small cell lung cancer. A better scheduling might improve the efficiency toxicity ratio.     

Phase I/II trial of a biweekly combination of S-1 plus docetaxel in patients with previously treated non-small cell lung cancer (KRSG-0601)

Background:

Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted.

Methods:

A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1–7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m⁻², respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD).

Results:

In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m⁻²/S-1 80 mg m⁻². In the phase II study, 34 patients were treated with docetaxel 35 mg m⁻²/S-1 80 mg m⁻² for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6–50.0%) and 62.9% (95% CI, 46.8–72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects.

Conclusion:

Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.     

国产吉西他滨或长春瑞滨联合顺铂治疗进展期非小细胞肺癌的临床观察

目的：观察国产吉西他滨联合顺铂（GP组）与长春瑞滨联合顺铂（NP组）治疗进展期非小细胞肺癌的疗效及毒副反应。方法：经病理组织学或细胞学证实的不能手术的80例非小细胞肺癌患者,随机分为两组各40例,以吉西他滨1200mg/m^2静滴,第1,8天;长春瑞滨25mg/m^2静滴,第1,8天,分别联合顺铂80mg/m^2第1天或分2-3天静滴,21天为1周期,3周期以上评价疗效。结果：两组的有效率分别为47.5%（19/40）、45.0%（18/40）,无显著性差异;中位疾病进展时间分别为4.9个月和4.1个月,组间有显著性差异（P〈0.05）;1年生存率GP组为42.5%（17/40）,NP组为40.0%（16/40）,组间无显著性差异。GP组III-IV度血小板减少高于NP组,而III-IV度白细胞减少及脱发、静脉炎明显低于NP组。结论：两种方案治疗晚期NSCLC均安全、有效,在有效率、中位生存期及1年生存率方面均较接近,毒副反应均可耐受,但中位疾病进展时间GP组稍有优势。     

A phase II trial of docetaxel plus capecitabine in patients with previously treated non-small cell lung cancer

BACKGROUND: A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. METHODS: Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m(2) i.v. on days 1 and 8 plus X 1000 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level I) or T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level II). RESULTS: A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). CONCLUSIONS: The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle.     

国产吉西他滨或长春瑞滨联合顺铂治疗进展期非小细胞肺癌的临床观察

目的:观察国产吉西他滨联合顺铂(GP组)与长春瑞滨联合顺铂(NP组)治疗进展期非小细胞肺癌的疗效及毒副反应。方法:经病理组织学或细胞学证实的不能手术的80例非小细胞肺癌患者,随机分为两组各40例,以吉西他滨1200mg/m2静滴,第1,8天;长春瑞滨25mg/m2静滴,第1,8天,分别联合顺铂80mg/m2第1天或分2~3天静滴,21天为1周期,3周期以上评价疗效。结果:两组的有效率分别为47.5%(19/40)、45.0%(18/40),无显著性差异;中位疾病进展时间分别为4.9个月和4.1个月,组间有显著性差异(P<0.05);1年生存率GP组为42.5%(17/40),NP组为40.0%(16/40),组间无显著性差异。GP组III~IV度血小板减少高于NP组,而III~IV度白细胞减少及脱发、静脉炎明显低于NP组。结论:两种方案治疗晚期NSCLC均安全、有效,在有效率、中位生存期及1年生存率方面均较接近,毒副反应均可耐受,但中位疾病进展时间GP组稍有优势。     

Spinal cord infarction in a patient with metastatic non-small cell lung cancer, receiving chemotherapy combined with bevacizumab

Bevacizumab is an anti-angiogenesis agent that has many applications in the current management of patients with cancer, including advanced non-small cell lung cancer. Its value is however, not without side effects. We present the first reported case of spinal cord infarction in the setting of bevacizumab use in a 70-year old woman with advanced non-small cell lung cancer.     

Paclitaxel, gemcitabine, and cisplatin in non-resectable non-small-cell lung cancer

Background: Paclitaxel, gemcitabine, and cisplatin are each active in non-small-cell lung cancer (NSCLC), and with different modes of action. Hence, a phase II study combining these drugs were conducted.Patients and methods: Treatment was paclitaxel 110 mg/m² and cisplatin 60 mg/m² day 1 and 15, with gemcitabine 800 mg/m² day 1, 8, and 15, every four weeks. Patients had previously untreated NSCLC, measurable disease, age 18–70 years, performance status 2, and no brain metastases.Results: Among 49 patients, 6 (group 1) received chemotherapy as described above, while 43 patients (group 2) did not receive gemcitabine day 8. In group 1, all experienced grade 4 neutropenia and four achieved a partial response (67%). In group 2, neutropenia grade 4 occured in 58%, with one episode of febrile neutropenia and no toxic death. No other grade 4 toxicities occured, while grade 3 toxicity occured with respect to thrombocytopenia (9%), nausea/vomiting (12%), neurotoxicity (12%), and nephrotoxicity (7%). There were 3 complete and 20 partial responses (response rate 54%, 95% confidence limits 38%–69%), median response duration 29 weeks (range 10–66+), median time to progression 28 weeks (range 4–66+), median survival 46 weeks (4–89+) and one-year survival rate 42%.Conclusion: This regimen of paclitaxel, gemcitabine, and cisplatin has neutropenia as dose limiting toxicity, but septicemic episodes were rare and toxic death did not occur. Other grade 4 toxicities than neutropenia did not occur. The regimen appears safe and with a noteworthy activity both in terms of response rate, time to progression, and survival.     

Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer

To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m(-2) was administered on days 1, 8 and 15, and cisplatin 80 mg m(-2) was administered on day 1. In the VDS-P arm, cisplatin 80 mg m(-2) was administered on day 1, and vindesine 3 mg m(-2) was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m(-2) was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P=0.115, CPT-P vs VDS-P; P=0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65-1.11) for CPT-P vs VDS-P and 0.83 (0.64-1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.     

康莱特联合GP方案治疗晚期非小细胞肺癌的疗效观察

目的：观察康莱特联合GP方案治疗晚期非小细胞肺癌的临床疗效及化疗不良反应。方法：将70例患者随机分成治疗组、对照组,各35例;两组均采用GP方案：吉西他滨1000 mg/m2,第1、8天,顺铂25 mg/m2,第1-3天,3周为一周期。治疗组在此基础上于化疗第一天开始加用康莱特200ml静滴连用10天。两个周期化疗结束后比较两组临床疗效、生存质量、不良反应等情况。结果：治疗组近期疗效有效率为42.86%,对照组为34.28%,两组比较有显著性差异（P〈0.05）;治疗组KPS评分有效率为68.57%,对照组为42.86%,两组比较有显著性差异（P〈0.05）;两组主要不良反应为骨髓抑制及胃肠道反应,但治疗组的反应程度较对照组轻,两组比较有显著性差异（P〈0.05）。结论：康莱特联合化疗治疗晚期非小细胞肺癌可提高临床疗效,减轻化疗的不良反应,提高患者生存质量。     

Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812)

BACKGROUND: The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS: Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly assigned to the radiotherapy alone (RT) arm, irradiation with 60 Gy; or the chemoradiotherapy (CRT) arm, the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2) per fraction up to the first 20 fractions. RESULTS: This study was terminated early when 46 patients were registered from November 1999 to February 2001. Four patients (one in the RT arm, three in the CRT arm) were considered to have died due to treatment-related causes. The JCOG Radiotherapy Committee assessed these treatment-related deaths (TRDs) and the compliance with radiotherapy in this trial. They found that 60% of the cases corresponded to protocol deviation and 7% were protocol violation in dose constraint to the normal lung, two of whom died due to radiation pneumonitis. As to the effectiveness for the 46 patients enrolled, the median survival time was 428 days [95% confidence interval (CI) = 212-680 days] in the RT arm versus 554 days (95% CI = 331 to not estimable) in the CRT arm. CONCLUSIONS: Due to the early termination of this study, the effectiveness of concurrent use of carboplatin remains unclear. We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee.     

CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib,in advanced/metastatic non-small cell lung cancer

Background:

A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population.

Methods:

Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs.

Results:

Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ⩾3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (⩾24 weeks) were reported.

Conclusion:

Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.     

恩度联合化疗治疗晚期非小细胞肺癌的临床研究

目的：观察恩度（重组人血管内皮抑素）联合含铂化疗方案治疗晚期非小细胞肺癌的近期疗效和安全性,并与单纯含铂化疗方案比较。方法：依照入选标准,选择60例晚期NSCLC住院患者,分恩度联合化疗组28例和单纯化疗组32例,观察有效率（RR）、疾病控制率（DCR）、生活质量改善情况及不良反应。结果：恩度联合化疗组和单纯化疗组的有效率分别为28.57%和28.13%,无统计学差异（P〉0.05）;疾病控制率分别为96.43%和93.75%,无统计学差异（P〉0.05）。治疗后两组ECOG评分均较治疗前明显降低,具有统计学差异（P〈0.05）,但两组间比较,无统计学差异（P〉0.05）。恩度联合化疗组的临床症状缓解率较单纯化疗组高：咳嗽缓解率分别为80%和71.43%、气短缓解率分别为78.57%和75%、咯血缓解率分别为90%和81.82%、疼痛缓解率分别为75%和71.43%,但无统计学差异（P〉0.05）。两组的主要不良反应均为恶心/呕吐、疲乏及骨髓抑制,骨髓抑制以白细胞、中性粒细胞减少为主,患者均可耐受,两组间不良反应发生率均无统计学差异（P〉0.05）。结论：恩度与含铂化疗联合应用,未改善近期疗效,未增加不良反应,但具有提高生活质量的趋势,值得临床进一步研究。