Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations

IntroductionIn contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting.MethodsWe retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months.ConclusionsICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.     

Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings

BackgroundImmune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited.Patients and MethodsThis was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases.ResultsThe PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS.ConclusionsThe 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.     

Impact of Clinicopathologic Features on the Efficacy of PD-1/PD-L1 Inhibitors in Patients With Previously Treated Non–small-cell Lung Cancer

Background

The current study aimed to comprehensively investigate the impact of various clinicopathologic features on the efficacy of programmed cell death-1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non–small-cell lung cancer (NSCLC).

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan–Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I² of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13–1.90) for PFS and 1.69 (95% CI: 1.25–2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1–8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [−60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.     

Bloodborne Cytokines for Predicting Clinical Benefits and Immune-Related Adverse Events in Advanced Non-Small Cell Lung Cancer Treated With Anti-Programmed Cell Death 1 Inhibitors

BackgroundProgrammed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non–small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs).Patients and MethodsPatients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated.ResultsSixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset.ConclusionsSerum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment.     

长春瑞滨软胶囊单药节拍化疗一线治疗老年非小细胞肺癌临床疗效观察

目的 探讨口服长春瑞滨软胶囊单药节拍化疗在老年非小细胞肺癌患者中的临床疗效及生存时间分析。方法 选择56例年龄≥75岁初治老年非小细胞肺癌患者,给以口服长春瑞滨软胶囊50 mg每次,每周3次单药节拍化疗,观察临床疗效、不良反应及总生存期和无进展生存期。结果 全部患者疗效评价CR 1例（1.8%）,PR 9例（16.1%）,ORR为17.9%;SD 22例（39.3%）,并且稳定时间人均达12周以上,DCR达57.2%;中位无进展生存期5月（3~22月）,中位总生存期9月（4~31月）,1年生存率为35.7%（20/56）,2年生存率为16.1%（9/56）,3~4级不良反应出现较少。结论 应用长春瑞滨软胶囊单药节拍化疗安全可靠,可有效改善生活质量,为老年非小细胞肺癌患者临床综合治疗决策提供了新的思路。     

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer

BackgroundThe composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.Patients and methodsWe examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.ResultsSixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4–6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0–2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6–7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.ConclusionATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.     

Prognostic factors in elderly patients with non-small cell lung cancer: a two-center experience

Non-small cell lung cancer (NSCLC) is usually at advanced stage when it is diagnosed. There is no consensus about the standard treatment in elderly patients with advanced NSCLC. Generally, data regarding elderly patients with NSCLC are withdrawn from general NSCLC studies based on subgroup analyses and suggestions. We evaluated prognostic factors in elderly patients with advanced NSCLC. We reviewed retrospectively 338 patients from August 2005 to July 2009 in two centers in Turkey. Medical records of the patients ≥65 years with advanced NSCLC were collected. Collected data included demographic informations, clinical assessments and information on treatment, toxicities and outcomes. Survival was estimated by using Kaplan–Meier method and prognostic factors were evaluated with log-rank and Cox regression tests. The median overall survival (OS) for the entire group was 15.4 months (95% CI: 12.7–18.0). In univariate analysis, weight loss, stage, combination therapy, second-line chemotherapy and tumor response (P < 0.01) and performance status significantly affected OS (P < 0.05). The median progression-free survival (PFS) was 10 months (95% CI: 8.4–11.6). In univariate analysis, there was only a significant association between tumor response and PFS (14.6 vs. 8.5 months; P < 0.001). Multivariate analysis showed that only response to therapy was an important prognostic factor for OS (P < 0.001). Survival of elderly patients with advanced NSCLC is significantly influenced by performance status, weight loss, stage, combination therapy, second-line chemotherapy and response to therapy. Not only age but also these factors may be kept in mind in the treatment planning of the elderly patients with NSCLC. These results may be of benefit in changing clinical practice in elderly patients with NSCLC who are often undertreated.     

免疫检查点抑制剂治疗EGFR-TKI耐药晚期非小细胞肺癌的疗效及不良反应

目的:探讨免疫检查点抑制剂(immune checkpoint inhibitor,ICI)治疗表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)耐药晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及不良反应。方法:收集2015年1月至2019年3月在解放军总医院接受ICI治疗的EGFR-TKI耐药晚期NSCLC患者临床资料,采用统计学方法分析EGFR-TKI耐药晚期NSCLC患者免疫治疗疗效及不良反应,阐明临床特征与免疫治疗疗效和患者预后的关系。结果:联合治疗较单药治疗者肿瘤客观缓解率(objective response rate,ORR)显著提高(28.6%vs.7.1%,P<0.01)。肿瘤分化差、联合治疗及年龄>60岁者分别较肿瘤分化好(5.1个月vs.2.8个月,P=0.030)、单药治疗(6.8个月vs.2.3个月,P<0.001)及年龄≤60岁者(7.1个月vs.4.7个月,P=0.020)无进展生存期(progression free survival,PFS)延长。联合治疗、肿瘤治疗缓解者分别较单药治疗(26.9个月vs.7.1个月)、肿瘤稳定者和进展者(30.8个月vs.18.7个月vs.12.8个月)总生存期(overall survival,OS)延长(P<0.001)。多因素分析显示年龄>60岁和联合治疗是PFS独立保护性因素(P<0.001)。联合治疗组的总体不良反应发生率较单药治疗组升高,但≥3级不良反应发生率两组间无显著性差异(P=0.28)。结论:ICI单药治疗EGFR-TKI耐药晚期NSCLC患者的疗效较差,而联合治疗能显著提高疗效,改善患者的预后。尽管联合治疗的总体不良反应发生率较高,但大体上不良反应可控。     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC

BackgroundThe impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non–small-cell lung cancer (NSCLC) is unclear.Materials and MethodsWe identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use.ResultsA total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not.ConclusionsIn patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.     

TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究

  目的  评估TKI耐药后晚期EGFR突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）在真实世界中化疗、化疗联合抗血管和免疫治疗的临床疗效以及最佳免疫治疗联合方案和探讨优势人群临床病理特征。  方法  回顾性分析2014年1月至2022年10月于广东省人民医院肿瘤医院收治229例TKI耐药后晚期EGFR突变型NSCLC患者的临床病理资料。本研究将纳入的患者分为非ICI治疗组（化疗和化疗联合抗血管）122例,ICI治疗组（含免疫治疗）107例,分析患者临床特征与治疗疗效之间的关系。  结果  纳入患者非ICI治疗组和ICI治疗组的中位无进展生存期（progression-free survival,PFS）分别为5.2个月和5.2个月（P=0.129）,中位生存期（overall survival,OS）分别为18.2个月和14.1个月（P=0.026）。进一步分析107例ICI治疗组,使用化疗联合免疫治疗、化疗联合抗血管联合免疫治疗和免疫单药或抗血管联合免疫治疗的中位PFS分别为5.6、6.7和2.3个月（P=0.074）,中位OS分别为15.5、18.6和8个月（P=0.165）。PD-L1表达≥50%患者的中位PFS和中位OS较PD-L1表达<50%患者明显延长（中位PFS:5.6个月vs. 5.0个月,P=0.040;中位OS:19.2个月vs. 12.6个月,P=0.046）。  结论  晚期EGFR突变型NSCLC患者TKI耐药后四药联合免疫治疗似乎呈现出更好的生存获益趋势,PD-L1表达是预测该人群免疫治疗获益的生物标志物。      

IMRT联合易瑞沙对不能手术不能同步放化疗局部晚期NSCLCⅡ期临床研究初步结果

目的 观察放疗联合易瑞沙治疗不能手术且不能行同步放化疗的局部晚期非小细胞肺癌患者的客观有效率、生存和安全性。方法 选取不能手术且不能行同步放化疗的局部晚期NSCLC患者,接受胸部IMRT,同期易瑞沙250 mg 1 次/d。结果 2014—2017年入组30例,可分析29例。疗后1个月疗效评价CR、PR、SD、PD分别0、21、6、2例,疾病控制率(CR+PR+SD)为93%,客观有效率(CR+PR)为72%。中位随访25个月,死亡14例,存活15例;23例患者出现疾病进展,其中局部进展18例,远处转移14例。全组中位生存时间 26个月,中位PFS 11个月,1、2年OS和PFS分别为79%和44%、55%和18%。单因素分析显示吸烟史、分期对OS有影响(P=0.035、0.031),分期、原发灶直径、GTV和PTV对PFS有影响(P=0.000、0.016、0.039、0.030);多因素分析显示分期和PTV体积为PFS的独立预后因素(P=0.000、0.012)。3级急性不良反应共2例,2级急性放射性肺炎7例。结论 对于不能手术且不能行同步放化疗的局部晚期非小细胞肺癌,放疗联合易瑞沙的治疗,客观有效率较高,患者耐受良好,远期疗效有待进一步观察。     

Antibiotic Treatment is an Independent Poor Risk Factor in NSCLC But Not in Melanoma Patients Who had Received Anti-PD-1/L1 Monotherapy

BackgroundAntibiotic treatment may reduce the efficacy of cancer immunotherapy by disrupting gut microbiome. We aimed to study the association of antibiotics and survival outcomes in advanced cutaneous melanoma and non–small-cell lung cancer (NSCLC) patients who had received anti-PD-1/L1 monotherapy.Patients and MethodsA total of 222 melanoma and 199 NSCLC patients had received anti-PD-1/L1 monotherapy in 5 Finnish hospitals between January 2014 and December 2020. Clinical characteristics, antibiotic and corticosteroid treatment, and survival outcomes were retrospectively collected from hospital and national medical records.ResultsThere were 32% of melanoma and 31% of NSCLC patients who had received antibiotic treatment (ABT) 3 months before to 1 month after the first anti-PD-1/L1 antibody infusion. In survival analyses, early antibiotic treatment was associated with inferior overall survival (OS) (ABT 19.2 [17.6-43.7] vs. no ABT 35.6 [29.3-NA] months, P = .033) but not with inferior progression-free survival (PFS) (ABT 5.8 [3.0-12.6] vs. no ABT 10.2 [7.7-15.3] months, P = .3) in melanoma patients and with inferior OS (ABT 8.6 [6.4-12.3] vs. no ABT 18.5 [15.1-21.6] months, P < .001) and PFS (ABT 2.8 [2.1-4.5] vs. no ABT 5.6 [4.4-8.0] months, P = .0081) in NSCLC patients. In multivariable analyses, ABT was not an independent risk-factor for inferior OS and PFS in melanoma but was associated with inferior OS (hazard ratio [HR] 2.12 [1.37-3.28]) and PFS (HR 1.65 [1.10-2.47]) in NSCLC after adjusted for other risk factors.ConclusionsEarly ABT was an independent poor risk factor in NSCLC patients who had received anti-PD-1/L1 monotherapy but not in melanoma patients. The weight of ABT as a poor risk factor might depend on other prognostic factors in different cancers.     

Gemcitabine in the treatment of non-small cell lung cancer for elderly patients]

Among all 140 eligible cases in the two late phase II studies of gemcitabine monotherapy for advanced non-small cell lung cancer, response rate was 26.3% in 57 elderly patients group who were older than 70 and 21.7% in 83 non-elderly patients group who were blow 69. Median survival was 9.8 months and 9.3 months for elderly and non-elderly respectively, 1 year survival rate was 35.1% for elderly and 38.6% for non-elderly, and both groups showed good efficacy. Among elderly group, one case died from septic shock accompanied with grade 4 of leukopenia, neutropenia and thrombocytopenia, and two cases developed interstitial pneumonitis. Of these two cases, one with mild pulmonary fibrosis died of respiratory failure due to aggravation of interstitial pneumonitis. Grade 3 or more anemia was occurred significantly more often in elderly group (elderly: 24.6%, non-elderly: 12.0%). There was no significant difference between both groups in the incidence of grade 3 or more of leukopenia and gastrointestinal toxicity, which were relatively low. No significant difference between both groups was found in total gemcitabine doses, average of single dose and the number of administration. Gemcitabine can be administered in elderly cases as well as in non-elderly cases. The results suggested that this agent is well-tolerated and effective for elderly patients with normal organ functions.     

白蛋白结合型紫杉醇单药治疗老年晚期非小细胞肺癌的临床观察

目的：探讨白蛋白结合型紫杉醇单药治疗老年晚期非小细胞肺癌的耐受性和临床疗效。方法回顾性分析50例接受白蛋白结合型紫杉醇化疗的老年晚期非小细胞肺癌（NSCLC）患者的临床资料,化疗方案为白蛋白结合型紫杉醇260 mg/m2,静脉滴注,第1天或分为第1天和第8天给药;21d为一个治疗周期,至少完成2个周期后评估疗效。结果50例患者均可评估疗效,客观缓解率（ORR）为22%,疾病控制率（DCR）为78%,白蛋白紫杉醇的疗效与患者既往是否使用过紫杉类药物、病理类型及几线治疗等因素无关,差异无统计学意义（P﹥0.05）。中位无进展生存时间（PFS）为4个月,中位总生存时间（OS）为12个月。本研究主要不良反应为骨髓抑制、恶心呕吐、乏力、周围神经毒性及肝肾功能损害,且多为1～2级不良反应,药物耐受性良好。结论白蛋白结合型紫杉醇单药治疗老年晚期非小细胞肺癌疗效佳,耐受性良好。     

Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations

Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 – 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2–3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3 months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted.     

Different classes of antibiotics exhibit disparate negative impacts on the therapeutic efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients

It has been reported that antibiotics (ATBs) have adverse effect on the efficacy of treatment with immune checkpoint inhibitors (ICIs) in cancer patients. Since different classes of ATBs have different antibacterial spectrum, we aimed to study whether all ATBs had similar or different negative effects on the clinical outcomes of ICIs in patients with advanced non-small cell lung cancer (NSCLC). Patients with advanced NSCLC who received ICIs were included in this retrospective study and grouped by the class of ATBs they had used around the ICIs treatment time. The overall survival (OS) and the progression free survival (PFS) of patients among these groups were compared using Kaplan-Meier method and Cox proportional hazards model. A total of 148 eligible patients were enrolled, and 80 patients used ATBs. The results indicated that quinolones had no significant negative consequence on the clinical outcomes, while β-lactams significantly shortened the OS and PFS of patients. Furthermore, patients exposed to the combination of β-lactams and quinolones suffered the worst OS and PFS. Moreover, the subgroup analysis of β-lactams revealed that only penicillins, but not carbapenems and cephalosporins, markedly reduced both OS and PFS. In addition to the class of ATBs used, the time frame of ATBs used also affected the clinical outcomes of ICIs therapy. Patients receiving ATBs within 60 days prior to and 30 days after the initiation of ICI treatment had significantly shorter OS and PFS compared with those who did not use ATBs. This study demonstrated that different classes of ATBs had disparate negative impacts on the clinical outcomes, and the use of β-lactams, especially penicillins, should be avoided in advanced NSCLC patients who are receiving or scheduled to receive ICIs within 60 days.     

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study

IntroductionTo evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations.MethodsWe conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review.ResultsBetween January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700–1.060, 95% confidence interval: 0.531–1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm.ConclusionsThis study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.     

存在内科合并症的老年晚期非小细胞肺癌患者一线含铂双药与单药方案化疗的对照研究

目的 探讨含铂双药与第3代化疗药物单药方案化疗在有内科合并症的老年晚期非小细胞肺癌（NSCLC）患者中的疗效和安全性。方法 回顾性分析150例有内科合并症（依据察尔森指数筛选）经细胞学或病理组织学确诊的老年晚期NSCLC患者。按照接受一线化疗方案分为第3代化疗药物单药组（28例）和含铂双药组（122例）,比较两组的疗效及不良反应。结果 所有患者均可评价疗效。单药组获PR 6例（21.4％）,SD 2例（7.1％）,PD 20（71.4％）,有效率为21.4％;双药组获PR 48例（39.3％）,SD 10例（8.2％）,PD64例（52.5％）,有效率为393％,两组有效率差异无统计学意义（P＞0.05）。单药组和双药组的中位无进展时间（PFS）分别为5.0个月和7.0个月（P=0.617）,中位总生存期（OS）分别为7.4个月和10.7个月（P=0.473）。经年龄、ECOG评分和察尔森指数1～2分分层后发现,单药组与双药组的PFS或OS差异均无统计学意义（P＞0.05）;而经察尔森指数3～4分分层后发现,单药组和双药组的中位PFS分别为3.5个月和8.3个月（P=0.001）,中位OS为5.0个月和8.3个月（P=0.019）。不良反应主要包括中性粒细胞减少、贫血、血小板减少和恶心呕吐,单药组不良反应基本为1～2级,双药组3～4级不良反应发生率较单药组高。结论 含铂双药方案一线治疗有内科合并症的老年晚期NSCLC的疗效与第3代化疗药物单药方案类似,而在察尔森指数3～4分患者中前者远期疗效更好,但总体不良反应发生率略高。