Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint inhibitors (ICIs) in nonsmall cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD), compared to those without COPD. This study aimed to investigate the clinical impact of COPD on the treatment response to ICIs in a large number of patients with NSCLC. In total, 133 patients with spirometry test results were retrospectively identified among those who received palliative pembrolizumab for NSCLC. COPD was defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.7. Overall survival (OS), progression-free survival (PFS), and objective response rate were analyzed according to the presence of COPD. Spirometry-based COPD was present in 59 (44%) patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45; 95% confidence interval [CI], 0.26–0.78) and PFS (HR for disease progression or death, 0.50; 95% CI, 0.31–0.79) than those without COPD. These associations persisted after adjusting for potential confounders including smoking history. The response rate was also higher in patients with COPD than in those without COPD (38.2% vs. 20.5%, p = 0.028). Spirometry-defined COPD was associated with a significantly longer OS and PFS in patients with NSCLC treated with palliative pembrolizumab. Identifying coexisting COPD could predict favorable treatment outcomes in patients with NSCLC treated with pembrolizumab.     

免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析

目的：探讨免疫检查点抑制剂(ICI)治疗非小细胞肺癌(NSCLC)产生的免疫相关不良反应(irAE)及ICI相关肺炎(ICI-P)的特点及其危险影响因素。方法：回顾性分析2019年1月到2021年12月间在山西白求恩医院胸部肿瘤科接受至少1次ICI治疗的114例NSCLC患者的一般性资料和临床特征的基线特征、治疗细节和发生irAE、ICI-P的数据,分析患者临床特征与irAE及ICI-P的关系,分析ICI-P发生的危险因素。观察ICI-P患者临床特点和治疗效果。结果：114例接受ICI治疗的NSCLC患者中有48例(42.11%)发生68次irAE,整体和严重irAE的发生率分别是59.65%、9.65%;从高到低排列发生率(仅列出前四位)：消化系统>呼吸系统>皮肤>内分泌系统;使用信迪利单抗>度伐利尤单抗>卡瑞利珠单抗=帕博利珠单抗;临床特征中的年龄与irAE发生有关联。15例患者发生ICI-P,整体发生率为13.16%,占irAE患者的31.25%,其中4例为重症,占irAE数的8.33%、ICI-P数的26.66%;发生于联合治疗的多于单药治疗(73...     

Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer

IntroductionPresently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindels with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindels in the clinical outcomes and immune landscape of patients with NSCLC treated with ICIs.MethodsWe utilized The Cancer Genome Atlas data set to analyze tumor mutational burden, neoantigen burden, and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindels on disease response rates and survival outcomes.ResultsA positive correlation between fsindel burden and tumor mutational burden and activated CD4/CD8 T-cell infiltration was shown. Presence of fsindels was also associated with significant prolongation of progression-free survival in patients treated with ICIs (median 6.2 versus 2.7 months [p = 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p = 0.04]) and disease control rates (68% versus 48% [p = 0.02]) were observed in patients with fsindels.ConclusionOur findings suggest that fsindels may have a predictive role for ICI response in NSCLC.     

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

BackgroundImmune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC.MethodsIn this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).ResultsOverall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001).ConclusionsThis report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.     

A Phase 2 Study of Atezolizumab for Pretreated NSCLC With Idiopathic Interstitial Pneumonitis

IntroductionInterstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP.MethodsPatients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set.ResultsThis study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n = 10) with grade 1 pneumonitis was found.ConclusionsPatients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor–induced pneumonitis.     

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC

IntroductionProgrammed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.MethodsPD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.ResultsPD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%–49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.ConclusionsPD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.     

药物选择剂量分割顺序对放疗联合免疫治疗晚期非小细胞肺癌疗效的影响

非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌总数的85％,53％的患者在确诊时即为晚期.近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)在晚期肿瘤治疗中效果显著.放疗在晚期NSCLC主要用于局部姑息治疗.研究显示免疫治疗协同放疗治...     

Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non–Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors

IntroductionPneumonitis is one of the immune-related adverse events of programmed death 1 (PD-1) inhibitors that sometimes cause lethal outcomes. Although some recent reports have described PD-1 inhibitors as more effective in non–small-cell lung cancer (NSCLC) patients with immune-related adverse events than in those without, few data are available on the prognosis of those treated with PD-1 inhibitors who developed immune-related pneumonitis (IRP). Additionally, the robust risk factors of IRP have not been well elucidated.Patients and MethodsA retrospective review of patients with recurrent or advanced NSCLC who took a PD-1 inhibitor (nivolumab or pembrolizumab monotherapy) between January 2016 and March 2018 was undertaken. Radiologic findings such as unilateral infiltration were also defined as IRP as long as they were deemed relevant to PD-1 inhibitors.ResultsTwenty-seven (16%) of 170 patients developed IRP. Although 22 (81%) of 27 patients with IRP recovered with drug cessation with or without corticosteroid therapy, 8-week landmark analysis showed the overall survival after administration of the PD-1 inhibitor was significantly shorter in patients with IRP than in those without (8.7 vs. 23.0 months, P = .015). Patients with IRP tended to not receive next-line treatment and choose best supportive care after cessation of PD-1 inhibitor therapy. In the multivariate analysis, pembrolizumab (vs. nivolumab) and low serum albumin were independent risk factors for IRP.ConclusionDevelopment of IRP was correlated with poor prognosis in patients with NSCLC. Further study is necessary for establishing the best prediction and management strategies for IRP.     

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.     

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.     

Immunotherapy as Single Treatment for Patients With NSCLC With Brain Metastases: A Systematic Review and Meta-Analysis—the META-L-BRAIN Study

IntroductionBrain metastases (BMs) occur in 40% of patients with lung cancer. The activity of immunotherapy in these patients, however, remains controversial, as the cornerstone treatment is radiotherapy (RT). Because RT is associated with adverse events that may impair the quality of life, the possibility of substituting it with a single systemic approach is attractive. Therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of immune checkpoint inhibitors (ICIs) in patients with NSCLC with untreated BM (unBM).MethodsStudies that enrolled patients with NSCLC treated with ICIs and specifically allowed for unBM were identified by searching the EMBASE, PubMed, Cochrane, and other databases. The outcomes evaluated were intracerebral overall response rate (icORR) and intracerebral disease control rate (icDCR) for unBM, and grades 3 and 4 toxicity rate.ResultsWe included 12 studies with a total of 566 individuals in the final analysis. Anti–programmed cell death protein-1 therapy seems to be active in the central nervous system, with an icORR of 16.4% (95% confidence interval [CI]: 9.8%–24%; I² = 33.17%) and an icDCR of 45% (95% CI: 33.4%–56.9%; I² = 46.91%). In the meta-analysis for icORR (risk ratio = 1.26, 95% CI: 0.57–2.79) and icDCR (risk ratio = 0.88, 95% CI: 0.55–1.43) we did not observe any difference among patients with BM who were treated with RT before ICI start and those who were treated with ICI only.ConclusionsICI seems to be effective as a single treatment for active BM in selected patients with advanced NSCLC.     

Efficacy and Safety of Combined Brain Radiotherapy and Immunotherapy in Non-Small-Cell Lung Cancer With Brain Metastases: A Systematic Review and Meta-Analysis

BackgroundImmune checkpoint inhibitors (ICIs) are recommended to treat advanced non-small-cell lung cancer (NSCLC), whereas brain radiotherapy (RT) is the mainstream therapy for patients with brain metastases (BMs). This systematic review and meta-analysis investigated whether the combination of brain RT and ICIs would generate a synergistic effect without unacceptable toxicity to treat NSCLC with BMs.MethodsLiterature searching was performed in PubMed, Embase, Web Of Science, and The Cochrane Library up to December 20, 2020. Heterogeneity, sensitivity analysis, forest plots, and publication bias were analyzed using Stata 15.0.ResultsNineteen studies were included. In the comparison of the brain RT+ICIs arm and brain RT alone arm, the pooled effect size (ES) for overall survival (OS) (hazard ratio [HR] = 0.77; 95% confidence interval [CI] 0.71–0.83; I² = 0; P < .001; n = 4) and grade 3–4 neurological adverse events (AEs) (risk ratio [RR] = 0.91; 95% CI 0.41–2.02; I² = 26.5; P = .809; n = 4) indicated that the brain RT+ICIs model had significantly better systemic efficacy and similar neurological AEs compared with brain RT alone for NSCLC. Concurrent RT+ICIs were identified as the optimal model, which achieved the best efficacy without significantly increased AEs compared with sequential RT+ICIs.ConclusionsCombined ICIs and brain RT exhibited favorable efficacy and acceptable toxicity for NSCLC patients with BMs, among which, the concurrent model might be the optimal option. Our results could guide the design of future randomized controlled trials and clinical practice.     

晚期非小细胞肺癌免疫治疗相关不良反应与疗效的相关性研究进展

非小细胞肺癌(Non-small cell lung cancer, NSCLC)是肺癌最常见的组织学类型,诊断时多为晚期,病死率较高。免疫检查点抑制剂(Immune checkpoint inhibitors, ICIs)的应用显著提高了晚期NSCLC患者的5年生存率,但带来生存获益的同时,也导致免疫相关不良事件(Immune-related adverse events, irAEs)的发生。近年来,irAEs和ICIs临床疗效之间的关联性成为研究的热点。本文就晚期NSCLC中irAEs与免疫治疗疗效的相关性研究进展进行综述。     

Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?

Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75 years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients.     

Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing,Non-interventional VARGADO Study

AimsTo evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy.Materials and methodsVARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy.ResultsThe median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%).ConclusionsNintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.     

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer

Objective: To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 89 patients with stage ⅢB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results: A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. Conclusions: The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.     

Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors

IntroductionThe efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non–small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC.Patients and MethodsThis retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes.ResultsAmong 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI.ConclusionHER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.     

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non–Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study

IntroductionRetrospective studies have shown immune-related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy.MethodsWe conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals.ResultsA total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1–positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression-free survival than those without (6.4 months [95% confidence interval: 2.5–not reached] versus 1.5 months [95% confidence interval: 1.2–2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment.ConclusionsEarly irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.     

Immune checkpoint inhibitors in advanced non–small cell lung cancer: A metacentric experience from India

BackgroundImmune check point inhibitors (ICIs) have changed the treatment paradigm of driver mutation negative non–small cell lung cancer (NSCLC) and they are increasingly incorporated in first-line treatment. Real-world experience of use of these drugs is limited. We aim to evaluate the real-world experience of use of ICIs in patients with advanced NSCLC.Patients and methodsMedical records of patients with NSCLC treated with ICIs at 4 major academic cancer centers in India between January 2016 and December 2018 were analyzed. The type of ICI taken, response rates, survival, and toxicity profiles were analyzed.ResultsThe median age at presentation was 60 years (range: 27-79 years). Nivolumab was the most commonly used ICI drug [80%, n = 70] followed by pembrolizumab [10%, n = 9], and atezolizumab [10%, n = 9]. The median number of ICIs cycles received were 4 (range 2-65). Among the evaluable responses in 74 patients, the objective response rates was 25.6% and clinical benefit rate was 46%. Immune related toxicity occurred in 39.9% of patients but, severe toxicity of Grade III and Grade IV occurred in 5 (5.6%) patients. After a median follow-up time of 8.86 months (95%CI 5.2-11.1) the progression-free survival was 4.73 months (95%CI 3.7-8.9), and overall survival was 11.6 months (95%CI 7.33-NR). ECOG PS at the time of start of ICIs was found to be significant determinant of Progression-free survival and overall survival.ConclusionOur study demonstrates the feasibility of usage of ICIs in advanced NSCLC in Indian setting with acceptable safety profile and comparable responses with the published studies.     

Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non–Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery

ObjectiveThe aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non–small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery.Materials and MethodsA total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (−37 C/A) polymorphisms with response and survival.ResultsThe median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03).ConclusionThe XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients.