PD-1单抗治疗21例恶性肿瘤晚期患者安全性和疗效的临床观察

目的 观察程序性死亡受体1(PD-1)单抗治疗晚期恶性肿瘤的近期疗效和不良反应.方法 回顾性分析采用PD-1单抗治疗的21例多种恶性肿瘤晚期患者的临床资料,根据治疗方案不同分为Nivolumab(Nivo)治疗11例和Pembrolizumab(Pem)治疗10例.分别采用RECIST 1.1与NCI-CTC 4.0标准评价21例患者的近期疗效和不良反应.结果 采用PD-1单抗治疗的21例患者中,17例可评估疗效,其中9例可评估疗效的Nivo治疗患者中,8例采用PD-1单抗单药治疗,疗效评估为CR 0例、PR 3例(膀胱尿路上皮细胞癌、肾尿路上皮细胞癌、非小细胞肺癌各1例)、SD 5例(膀胱尿路上皮细胞癌、肾尿路上皮细胞癌、恶性黑色素瘤、肾透明细胞癌、非小细胞肺癌各1例)、PD 0例;1例联合用药,疗效评估为SD(肝癌患者采用PD-1单抗联合乐伐替尼治疗).8例可评估疗效的Pem治疗患者中,5例采用PD-1单抗单药治疗,疗效评估为CR 0例、PR 1例(非小细胞肺癌)、SD 3例(肝胆管细胞癌、结肠腺癌合并子宫内膜癌、恶性胸腺瘤各1例)、PD 1例(非小细胞肺癌);3例联合用药,疗效评估为PD 2例(1例前列腺癌患者采用PD-1单抗联合阿比特龙治疗,1例乳腺癌合并宫颈癌患者采用PD-1单抗联合依维莫司、依西美坦治疗)、SD 1例(恶性纤维组织瘤患者采用PD-1单抗联合帕唑帕尼治疗).常见的不良反应多为1~2级,主要表现为疲乏、皮疹和消化道反应等.结论 晚期恶性肿瘤患者对PD-1单抗的耐受性良好,可以选择其作为晚期恶性肿瘤的一种治疗方法.     

Place de l’immunothérapie dans le cancer bronchique non à petites cellules localement avancé

Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15–30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.     

Impact of ERCC1 expression on treatment outcome in small-cell lung cancer patients treated with platinum-based chemotherapy

IntroductionThe excision repair cross-complementing 1 (ERCC1) protein is an extensively investigated molecular marker because it may decrease sensitivity to platinum-based chemotherapy. Low ERCC1 expression has already been correlated with better treatment efficacy in non-small-cell lung cancer patients treated with platinum-based chemotherapy. However, the data on a prognostic and/or predictive value of ERCC1 in small-cell lung cancer (SCLC) are still very limited.MethodsThis retrospective pilot study evaluated the impact of ERCC1 expression levels on response to first-line platinum-based chemotherapy with or without radiotherapy and survival outcomes of 77 SCLC patients. ERCC1 protein expression was determined immunohistochemically in primary tumour tissue.ResultsERCC1 protein expression was positive in 40/77 (51.9%) of our patients. No significant association was found between ERCC1 protein expression and response rate to first-line platinum-based chemotherapy, progression-free survival (PFS), or overall survival (OS), either in the overall population or in patients stratified by disease stage.ConclusionsIn our limited group of 77 SCLC patients, ERCC1 protein expression was not found to correlate with either response rate to platinum-based chemotherapy or survival outcomes. Multi-centric prospective trials using a validated method of ERCC1 determination are mandatory in order to obtain a definitive answer on the predictive value of ERCC1 in SCLC.     

Current standards of care in small-cell and non-small-cell lung cancer

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.     

Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath

BackgroundImmune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients.MethodsThis was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis.ResultsExhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82–0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75–0.96).ConclusionENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.     

Survival Outcomes and Treatment Patterns in Patients With NFE2L2 and/or KEAP1 Mutation-Positive Advanced Squamous Cell NSCLC Using a Real-World Clinico-Genomic Database

BackgroundNFE2L2 and/or KEAP1 mutations are associated with worse prognosis in all non-small cell lung cancer (NSCLC). We determined real-world survival outcomes and treatment patterns among patients with advanced squamous cell NSCLC by NFE2L2 and KEAP1 mutation status.Patients and MethodsA retrospective study (January 2011-December 2018) was conducted using a de-identified US-based clinico-genomic database. Adult patients with advanced squamous cell NSCLC with ≥ 2 in-network visits and comprehensive genomic profiling during the study period were included. Outcomes included real-world progression free survival (rwPFS) by line of therapy and overall survival (OS). The real-world effectiveness of anti-PD-1/PD-L1 first-line therapy was also evaluated in patients with a NFE2L2 and/or KEAP1 mutation.ResultsOf 703 patients included (median age: 70.0 years), 31.6% had a NFE2L2 and/or KEAP1 mutation. The most common first- and second-line treatments regardless of mutation status were platinum-based chemotherapies and anti-PD-1/PD-L1 therapies. The most common third-line treatment was anti-PD-1/PD-L1 therapy in patients with a NFE2L2 and/or KEAP1 mutation and single-agent chemotherapy in patients with wild-type disease. Patients with a NFE2L2 and/or KEAP1 mutation versus wild-type disease had significantly shorter rwPFS (4.54 vs. 6.25 months; P = .003) following first- but not second- or third-line therapy and shorter median OS (13.59 vs. 17.37 months; P  =  .4105). No survival differences were observed in patients with a NFE2L2 and/or KEAP1 mutation receiving first-line anti-PD-1/PD-L1 therapies versus other therapies.ConclusionsPatients with advanced squamous cell NSCLC with a NFE2L2 and/or KEAP1 mutation have poor real-world survival, highlighting the need for a genotype-directed therapeutic strategy in this population.     

Clinical insights into small cell lung cancer: Tumor heterogeneity,diagnosis, therapy,and future directions

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.     

Advanced Non–Small-Cell Lung Cancer in the Elderly

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non–small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater.     

The efficacy and safety of anti‐PD‐1/PD‐L1 antibodies combined with chemotherapy or CTLA4 antibody as a first‐line treatment for advanced lung cancer

Checkpoint inhibitors show promising efficacy in advanced lung cancer, especially in non‐small‐cell lung cancer (NSCLC). This meta‐analysis was conducted to explore the therapeutic efficacy and safety of anti‐PD‐1/PD‐L1 antibodies combined with chemotherapy or CTLA4 antibody as first‐line treatments for patients with advanced lung cancer. A systematic search was performed in databases for this system review and quantitative meta‐analysis. Twelve trials were finally enrolled in the meta‐analysis. Our analyses revealed that the combined overall response rate (ORR) and disease control rate (DCR) for immune checkpoint inhibitors combined with chemotherapy for the treatment of NSCLC were 47.0% (95% CI: 34.2%‐60.2%) and 80.9% (95% CI: 69.4%‐88.7%), respectively. The combined ORR and DCR for CTLA4 antibody combined with chemotherapy for the treatment of small‐cell lung cancer (SCLC) were 65.4% (61.1%‐69.5%) and 87.6% (84.5%‐90.2%), respectively. The combined six‐month progression‐free survival rates (PFSRs_6m) for NSCLC and SCLC were 50.2% (95% CI: 21.9%‐78.4%) and 30.7% (21.2%‐40.3%), respectively, and the OSRs_1y were 56.4% (39.1%‐73.7%) and 36.9% (33.3%‐40.5%), respectively. In addition, the combined ORR and DCR for the checkpoint inhibitors plus CTLA4 antibody treatment group in NSCLC were 29.6% (95% CI: 11.4%‐57.8%) and 48.7% (16.8%‐81.7%), respectively. In subgroup analyses, a significant improvement in PFS was observed in NSCLC and SCLC, with a combined hazard ratio and 95% confidence interval of 0.841 (0.737‐0.961) and 0.856 (0.756‐0.968), respectively. In summary, synergistic activity and an acceptable safety profile were observed with checkpoint inhibitor plus chemotherapy combination treatment in lung cancer.     

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non–small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial

BackgroundDostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non–small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284).Materials and MethodsHere, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety.ResultsAs of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients.ConclusionDostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.     

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study

BackgroundHistone deacetylase (HDAC) inhibitors have potential to augment the effectiveness of immune checkpoint inhibitors and overcome treatment resistance. This dose-escalation/expansion study (NCT02805660) investigated mocetinostat (class I/IV HDAC inhibitor) plus durvalumab in patients with advanced non-small cell lung cancer (NSCLC) across cohorts defined by tumor programmed death-ligand 1 (PD-L1) expression and prior experience with anti-programmed cell death protein-1 (anti-PD-1) or anti-PD-L1 regimens.Patients and MethodsSequential cohorts of patients with solid tumors received mocetinostat (starting dose: 50 mg TIW) plus durvalumab at a standard dose (1500 mg Q4W) to determine the recommended phase II dose (RP2D: phase I primary endpoint), based on the observed safety profile. RP2D was administered to patients with advanced NSCLC across 4 cohorts grouped by tumor PD-L1 expression (none or low/high) and prior experience with anti-PD-L1 /anti-PD-1 agents (naïve, clinical benefit: yes/no). The phase II primary endpoint was objective response rate (ORR, RECIST v1.1).ResultsEighty-three patients were enrolled (phase I [n = 20], phase II [n = 63]). RP2D was mocetinostat 70 mg TIW plus durvalumab. ORR was 11.5% across the phase II cohorts, and responses were durable (median 329 days). Clinical activity was observed in NSCLC patients with disease refractory to prior checkpoint inhibitor treatment: ORR 23.1%. Across all patients, fatigue (41%), nausea (40%), and diarrhea (31%) were the most frequent treatment-related adverse events.ConclusionMocetinostat 70 mg TIW plus durvalumab at the standard dose was generally well tolerated. Clinical activity was observed in patients with NSCLC unresponsive to prior anti-PD­(L)1 therapy.     

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients Aged ≥ 75 Years With Non–small-cell Lung Cancer (NSCLC): An Italian,Multicenter, Retrospective Study

IntroductionNon–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy.Material and MethodsInclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events.ResultsEighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years.ConclusionsIn the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.     

Thalidomide Combined with Chemotherapy in Treating Patients with Advanced lung Cancer

Objectives: To evaluate efficacy and toxicity in patients with advanced lung cancer, including non-small cell and small cell variants (NSCLC and SCLC), treated with thalidomide plus chemotherapy. Methods: Fourteen patients with advanced lung cancer were scheduled to receive chemotherapy combined with thalidomide. All patients in this study received thalidomide (100 mg orally per night before sleeping, produced by Changzhou Pharmaceutical Factory Co.Ltd) after the start of chemotherapy for at least 14 days. Chemotherapy was administered according to the condition of patients. After at least 14 days of treatment, efficacy and toxicity were evaluated. Results: There were 6 female and 8 male patients with advanced lung cancer recruited into this study, including 2 with SCLC and 12 with NSCLC. The median age was 56.7 (44-65) years. Progressive disease was observed in 12 patients (12/14), and stable disease in 2 (2/14). Grade 1 to 2 myelosuppression was observed in 4/14 patients, and Grade 1 to 2 elevation of hepatic enzymes was recorded in 5/14 patients. Adverse effects on the gastrointestinal tract were documented in 2/14 patients, all beingGrade 1. No Grade 3-4 toxicity was recorded. No treatment related deaths occurred. Conclusions: Our results demonstrate that thalidomide combined with chemotherapy is mildly effective and safe for treating patients with advanced lung cancer. However, further evaluation of this combination is warranted.     

A Phase IB Trial of Autologous Cytokine‐Induced Killer Cells in Combination with Sintilimab,Monoclonal Antibody Against Programmed Cell Death‐1, plus Chemotherapy in Patients with Advanced Non‐Small‐Cell Lung Cancer

IntroductionCan the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients.Patients and MethodsPatients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR).ResultsThirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available).ConclusionAutologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).     

顺铂或卡铂加足叶乙甙治疗晚期肺癌105例临床分析

我所自1992年1月至1995年8月，用顺铂或卡钻加足叶乙甙治疗晚期肺癌105例，其中小细胞肺癌49例，非小细胞肺癌56例。顺铂组有效率小细胞肺癌为72．0％，非小细胞肺癌为38．5％；卡钥组有效率小细胞肺癌为79．2％，非小细胞肺癌为26．7％。两方案的主要毒性为胃肠道毒性和骨髓抑制，胃肠道毒性顺钥组较卡铂组为重，而骨髓抑制以卡铂组为明显。本文结果提示顺铂或卡铂加足叶乙甙治疗小细胞肺癌的有效率高，可作为治疗小细胞肺癌的首选方案。治疗非小细胞肺癌的有效率顺铂组稍高于卡铂组，但两组疗效均欠理想，为寻找治疗非小细胞肺癌更为有效的化疗方案，仍有待临床进一步探讨。     

2007年肺癌治疗新热点-来自ASCO的证据

 【摘要】　可手术切除非小细胞肺癌（NSCLC）术前化疗的价值尚未肯定，局部晚期NSCLC同期化放疗后巩固化疗仍需进一步验证。贝伐单抗与化疗联合应用一线治疗晚期NSCLC优于单用化疗，目前尚无证据显示吉非替尼二线治疗晚期NSCLC的总生存优于多西紫杉醇。细胞分子信号通路和药理基因组学的研究结果可能指导肺癌的个体化治疗。伊立替康与铂类联合一线治疗广泛期小细胞肺癌（SCLC）优于EP方案，所有化疗取得缓解的广泛期SCLC接受预防性脑放疗（PCI）可延长生存。     

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.     

A new frontier for targeted therapy in NSCLC: clinical efficacy of pembrolizumab in the inhibition of programmed cell death 1 (PD-1)

Non-small-cell lung cancer (NSCLC) is the main pathological type among lung cancers, and it is often diagnosed at an advanced stage of the disease when it is no longer amenable to curative treatments. During recent decades, the survival rate for lung cancer patients has improved significantly in only those whose tumours harbour a driver mutation. Immune checkpoint inhibition is a promising therapeutic strategy for lung cancer. The Keynote 024 is randomized, open-label, international, phase III study to evaluate the efficacy of pembrolizumab, an antibody directed to programmed death 1 (PD-1), an immune checkpoint inhibitor, compared with platinum-based chemotherapy in patients with previously untreated advanced NSCLC and PD-L1 expression in at least 50% of the tumour cells. Pembrolizumab treatment achieved statistically significant clinical benefits in terms of progression free survival, overall survival and objective responses. The high quality of data and the novelty of the information obtained created the conditions for a new standard of care driven by the expression of PD-L1.     

Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.

PURPOSE: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. EXPERIMENTAL DESIGN: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. RESULTS: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. CONCLUSION: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.     

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out

Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.