First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients

BackgroundWe aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma.Patients and MethodsNever-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib.ResultsBetween June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR–wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms.ConclusionsIntercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.     

Gefitinib versus pemetrexed as second‐line treatment in patients with nonsmall cell lung cancer previously treated with platinum‐based chemotherapy (KCSG‐LU08‐01)

BACKGROUND:

Gefitinib was compared with pemetrexed as second‐line therapy in a clinically selected population previously treated with platinum‐based chemotherapy.

METHODS:

A phase 3 trial of gefitinib (250 mg/day) versus pemetrexed (500 mg/m² on day 1, every 3 weeks) was conducted in patients who had never smoked and who had advanced pulmonary adenocarcinoma treated with 1 previous platinum‐based regimen. The primary endpoint was progression‐free survival (PFS).

RESULTS:

A total of 135 patients were analyzed. The gefitinib group had significantly longer PFS compared with the pemetrexed group, with a median PFS time of 9.0 versus 3.0 months (P = .0006). The objective response rates were 58.8% and 22.4% for gefitinib and pemetrexed, respectively (P < .001). However, there was no statistically significant difference in overall survival between the 2 groups (22.2 vs 18.9 months; P = .37). The difference of PFS was increased in a subgroup analysis of 33 patients with activating epidermal growth factor receptor mutation (15.7 vs 2.9 months; hazard ratio, 0.3; 95% confidence interval, 0.13‐0.72; P = .005), with numerical superiority of gefitinib in the 38 patients testing negative for epidermal growth factor receptor mutation (5.9 vs 2.7 months; P = .099). Both regimens were well tolerated. There were no significantly different changes in quality of life between the 2 groups, except that symptom scores for dyspnea and diarrhea favored the gefitinib and pemetrexed arms, respectively.

CONCLUSIONS:

Gefitinib showed superior efficacy to pemetrexed as second‐line therapy in Korean never‐smokers with pulmonary adenocarcinoma. Cancer 2012. © 2012 American Cancer Society.     

EGFR敏感突变的晚期肺腺癌一线化疗与吉非替尼联合治疗的随机对照研究

背景与目的：表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的晚期肺腺癌患者目前标准一线治疗方案为表皮生长因子受体-酪氨酸激酶抑制剂(epithelial growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)单药治疗。该研究探索化疗联合吉非替尼与单用化疗、单用吉非替尼在EGFR基因敏感突变的晚期肺腺癌一线治疗中的疗效及安全性比较。方法：本研究共纳入了61例EGFR基因敏感突变(19外显子缺失突变或21外显子L858R点突变)、PS 0～1分的初治晚期肺腺癌患者,并用随机数字法随机分成3组。A组20例,给予AC方案化疗(培美曲塞500 mg/m²,第1天;卡铂AUC 5,第1天)联合口服吉非替尼(250 mg/d,第5~21天),每4周为1个周期,最多6个周期,然后每4周进行1次培美曲塞单药联合吉非替尼口服(用药方法及剂量同前)维持治疗;B组20例,给予AC方案化疗(培美曲塞500 mg/m²,第1天;卡铂AUC 5,第1天),每4周为1个周期,最多6个周期,然后每4周进行1次培美曲塞单药维持治疗;C组21例,口服吉非替尼治疗(250 mg/d)。3组的治疗均持续至患者出现疾病进展或出现无法耐受的不良反应或死亡。研究的主要终点为中位无进展生存时间(progression-free survival,PFS)和12个月PFS率,次要终点为总体缓解率、安全性/不良反应。结果：随访中A、C组各失访1例。A组患者中位PFS为20.1个月(95%CI：18.0～22.2个月),B组患者中位PFS为5.5个月(95%CI：3.9～7.2个月),C组患者中位PFS为9.8个月(95%CI：6.8～12.8个月)。A组的12个月PFS率为78.9%,B组为15.0%,C组为40.0%。总体缓解率：A组为84.2%,B组为35.0%,C组为65.0%。安全性方面,严重不良反应的发生率A组为36.8%,B组为30.0%,C组为5.0%。最常见的3～4度不良反应为中性粒细胞减少(A组3例、B组4例)、乏力(A组2例、B组2例)及肝功能损害(A组2例、C组1例)。结论：一线接受化疗与吉非替尼联合治疗的EGFR敏感突变的晚期肺腺癌患者PFS更长。长期的生存结果仍在进一步随访中。     

Pemetrexed-based chemotherapy in patients with advanced,ALK-positive non-small cell lung cancer

BackgroundAnaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) is highly responsive to crizotinib. To determine whether ALK-positive NSCLC is also sensitive to pemetrexed, we retrospectively evaluated progression-free survival (PFS) of ALK-positive versus ALK-negative patients who had been treated with pemetrexed-based chemotherapy for advanced NSCLC.Patients and methodsWe identified 121 patients with advanced, ALK-positive NSCLC in the USA, Australia, and Italy. For comparison, we evaluated 266 patients with advanced, ALK-negative, epidermal growth factor receptor (EGFR)-wild-type NSCLC, including 79 with KRAS mutations and 187 with wild-type KRAS (WT/WT/WT). We determined PFS on different pemetrexed regimens.ResultsAmong 70 ALK-positive patients treated with a platinum/pemetrexed regimen, the median PFS (mPFS) was 7.3 months (95% confidence interval (CI) 5.5–9.5). The mPFS of 51 ALK-positive patients treated with single-agent pemetrexed or nonplatinum/pemetrexed combinations was 5.5 months (2.8–9.0). For ALK-negative patients, PFS on all pemetrexed-based regimens was similar to that of ALK-positive patients, except in the specific setting of first-line platinum/pemetrexed where the mPFS was only 4.2 and 5.4 months in KRAS and WT/WT/WT patients, respectively. However, among patients with a never/light-smoking history (0–10 pack-year smoking history) treated with first-line platinum/pemetrexed, there was no difference in PFS between ALK-positive and ALK-negative patients.ConclusionsPFS on pemetrexed or nonplatinum/pemetrexed combinations was similar in ALK-positive and ALK-negative patients. PFS on first-line platinum/pemetrexed may be prolonged in never/light-smoking patients regardless of ALK status.     

Combination of chemotherapy and gefitinib as first‐line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head‐to‐head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first‐line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression‐free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, p < 0.001) and 0.48 (95% CI, 0.29–0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.     

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised,phase 3 trial

BackgroundIn the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population.MethodsIn this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0–1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874.FindingsBetween 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N = 114) and gefitinib monotherapy (N = 118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p = 0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63–1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p = 0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3–4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p = 0.002).InterpretationIn the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer.FundingEli Lilly and Company.     

Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial

BackgroundCTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR).Patients and methodsPatients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m²) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.ResultsFrom February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877).ConclusionsCTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.ClinicalTrials.gov IdentifierNCT00891579.     

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advancedEGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label,randomized study

BackgroundIcotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.Patients and methodsEligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.ResultsBetween January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43–0.87;P = 0.006). No significant difference for OS was observed between treatments in the overall population or inEGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%;P < 0.001) and treatment-related AEs (54.1% versus 90.5%;P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.ConclusionsFirst-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients withEGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.     

Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901

BackgroundThe role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS).Patients and MethodsEligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months.ResultsA total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049).ConclusionMaintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.     

A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis

IntroductionClinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib.MethodsThis was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m² intravenously 3-weekly + 250 mg/day orally) or gefitinib.ResultsIn total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event.ConclusionsAddition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.     

A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect.Patients and methodsA randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS).ResultsTwo hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58–1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49–0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively.ConclusionsPFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology.Study Registration numberNCT00835471.     

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902

Background

Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population.

Patients and methods

This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500?mg/m²) combined with carboplatin (area under the curve: AUC 6) every 3?weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90?%) patients completed four cycles, and 33 (67?%) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51?%) and stable disease in 18 patients (37?%). Median progression-free survival (PFS) and overall survival (OS) were 6.3?months and 24.3?months, respectively. The median PFS and OS were 7.9?months and 24.3?months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3?months and 21.0?months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p?=?0.09) and OS (p?=?0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33?%) and 9 (18?%) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).     

EGFR-TKIs或联合化疗一线治疗77例晚期肺腺癌临床分析

目的随着肺癌靶向治疗耐药问题的出现,靶向治疗与传统化疗联合成为研究热点。本研究对比表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)联合化疗或单药一线治疗驱动表皮生长因子受体(epidermal growth factor receptor,EGFR)基因阳性晚期肺腺癌的临床疗效及安全性差异,筛选联合治疗优势人群。方法回顾性收集2016-12-01-2018-12-01河南省人民医院收治的初治晚期EGFR(+)肺腺癌77例,依据治疗方案分为联合组和单药组。联合组36例采用培美曲塞+铂类方案化疗,同步口服靶向药物;单药组41例口服EGFR-TKIs。观察随访其治疗后临床疗效及不良反应。采用Kaplan-Meier法行生存分析,Cox回归模型进行多因素分析。结果治疗3个月后联合组客观有效率(objective response rate,ORR)为66.7%(24/36),与单药组53.7%(22/41)相比,差异无统计学意义,χ^2=1.349,P=0.246。疾病控制率(disease control rate,DCR)联合组为100.0%(36/36),单药组为97.6%(40/41),差异无统计学意义,P=1.000。随访截至2019-06-30,总体中位无进展生存期(median progression-free survival,mPFS)为11.5个月,其中联合组mPFS为12个月(95%CI:9.864~14.136),单药组为8个月(95%CI:2.981~13.019),联合组PFS明显优于单药组,差异有统计学意义,χ^2=4.469,P=0.035。胸腔内转移(M1a期)亚组,2组间mPFS差异有统计学意义(HR=0.389,95%CI:0.173~0.874,χ^2=5.873,P=0.015)。联合组血液系统及消化系统不良反应事件发生率更高,差异有统计学意义,P<0.05。2组不良反应均集中在Ⅰ~Ⅱ级,均可耐受。结论 EGFR(+)肺腺癌一线治疗中,1代EGFR-TKIs同步联合培美曲塞+铂类化疗可改善患者PFS,在转移程度较低的M1a期患者中,这种优势更突出。联合治疗增加不良反应事件发生率,但均符合预期并可耐受。     

Phase II randomized trial of radiation therapy,cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer

BackgroundWe previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF).Patients and methodsPatients with previously untreated stage III–IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL).ResultsSeventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69–0.92; P < 0.0001] for arm A and 75% (90% CI 0.64–0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment.ConclusionsRT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR–VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.     

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

BackgroundIn LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.Patients and methodsLUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.ResultsTwo-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.ConclusionIn LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.Clinicaltrials.gov identifierNCT01466660.     

不同化疗方案治疗EGFR常见突变肺腺癌疗效的回顾性研究

目的:探究EGFR常见突变的肺腺癌患者最佳化疗方案。方法:回顾性收集2007年6月至2014年6月于广东省肺癌研究所就诊的晚期原发性肺腺癌患者的临床资料,分析不同化疗方案对于携带EGFR常见突变肺癌患者的疗效。结果:205例携带EGFR常见突变的肺腺癌患者纳入研究,接受吉西他滨+铂类、培美曲塞+铂类和紫杉醇类+铂类方案治疗的患者分别为119、60和26例,客观缓解率及无进展生存期分别为25.2%、25.0%、30.8%及5.5、5.2、6.2个月,差异均无统计学意义(P=0.979;P=0.811)。结论:以吉西他滨、培美曲塞和紫杉醇类为基础的含铂化疗方案在携带EGFR常见突变肺腺癌患者中的疗效并无差异。     

Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis

BackgroundThe efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC.Patients and methodsLiterature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3–4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status ≥1 and hepatic metastases.ResultsForty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1–17.9] versus 31.9% [95% CI 27.3–36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3–4 toxicity were seen between the two groups.ConclusionsDespite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.     

培美曲塞联合顺铂对比吉西他滨联合顺铂一线治疗晚期非鳞非小细胞肺癌的随机、对照、多中心临床研究

背景与目的目前晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的标准治疗仍是含铂两药方案,国内外多项临床研究显示培美曲塞联合顺铂在晚期非鳞NSCLC具有较好的疗效及安全性,本研究拟评估国产培美曲塞二钠联合顺铂一线治疗晚期NSCLC的疗效与安全性。方法本研究是一项多中心、随机、阳性药物平行对照的临床试验。入组患者按1:1随机分为两组,分别接受培美曲塞二钠联合顺铂(PC组)或吉西他滨联合顺铂(GC组)治疗,21天为一个周期。主要研究终点为无进展生存期,次要研究终点主要包括1年生存率、客观缓解率、无3度或4度毒性生存期及其安全性。结果全国20家研究中心共纳入288例患者(各组144例),基于全分析集进行分析,PC组与GC组患者的中位无进展生存期分别为168天(5.6个月)和140天(4.7个月)(P=0.16);1年生存率分别为50.0%和54.9%(P=0.47);客观缓解率分别为24.4%和14.2%(P=0.06);无3度/4度毒性生存期分别为11.3个月和8.1个月(P=0.23)。总体不良反应发生率PC组明显低于GC组(81.95%vs93.75%,P=0.003)。结论两种含铂方案治疗晚期非鳞NSCLC具有相似的疗效,但PC方案不良反应更轻,有望成为晚期非鳞NSCLC一线治疗的新选择。     

EGFR基因敏感突变晚期肺腺癌一线培美曲塞同药维持化疗疗效分析

目的:分析表皮生长因子受体(EGFR)基因敏感突变晚期肺腺癌患者一线培美曲塞维持化疗疗效。方法:对我院2012年6月始至今收治的伴有EGFR基因19或21外显子敏感突变的IIIb-IV期肺腺癌患者,一线接受培美曲塞联合顺铂后同药维持化疗的无进展生存时间(PFS)进行回顾性分析。结果:10例EGFR基因19和/或21外显子敏感突变的IIIb-IV期肺腺癌患者一线接受培美曲塞联合顺铂同药维持治疗,完全缓解(CR) 0例,部分缓解（PR）6例（60%）,稳定（SD）4例（40%）,疾病控制率（DCR）10例（100%）,中位无进展生存时间（PFS）12.0个月（95%可信区间:7.60~16.30）,1年生存率100%。主要毒副反应为骨髓抑制、恶心呕吐、疲劳乏力、神经毒性,安全可耐受。结论:EGFR基因敏感突变晚期肺腺癌患者一线培美曲塞维持化疗可取得较好疗效。