Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in non-small cell lung cancer.

BACKGROUND: Predictive biomarkers and models of immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC). However, evidence for many biomarkers remains inconclusive, and the opaqueness of machine learning models hinders practicality. We aimed to provide compelling evidence for biomarkers and develop a transparent decision tree model. METHODS: We consolidated data from 3,288 ICI-treated patients with NSCLC across real-world multicenter, public cohorts and the Choice-01 trial (ClinicalTrials.gov: NCT03856411). Over 50 features were examined for predicting durable clinical benefits (DCBs) from ICIs. Noteworthy biomarkers were identified to establish a decision tree model. Additionally, we explored the tumor microenvironment and peripheral CD8+ programmed death-1 (PD-1)+ T cell receptor (TCR) profiles. FINDINGS: Multivariate logistic regression analysis identified tumor histology, PD-ligand 1 (PD-L1) expression, tumor mutational burden, line, and regimen of ICI treatment as significant factors. Mutation subtypes of EGFR, KRAS, KEAP1, STK11, and disruptive TP53 mutations were associated with DCB. The decision tree (DT10) model, using the ten clinicopathological and genomic markers, showed superior performance in predicting DCB in the training set (area under the curve [AUC] = 0.82) and consistently outperformed other models in test sets. DT10-predicted-DCB patients manifested longer survival, an enriched inflamed tumor immune phenotype (67%), and higher peripheral TCR diversity, whereas the DT10-predicted-NDB (non-durable benefit) group showed an enriched desert immune phenotype (86%) and higher peripheral TCR clonality. CONCLUSIONS: The model effectively predicted DCB after front-/subsequent-line ICI treatment, with or without chemotherapy, for squamous and non-squamous lung cancer, offering clinicians valuable insights into efficacy prediction using cost-effective variables. FUNDING: This study was supported by the National Key R&D Program of China.

Host immune-inflammatory markers to unravel the heterogeneous outcome and assessment of patients with PD-L1 ≥50% metastatic non-small cell lung cancer and poor performance status receiving first-line immunotherapy.

BACKGROUND: Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (mNSCLC) and ECOG performance status (PS) of 2 treated with first-line immunotherapy have heterogeneous clinical assessment and outcomes. METHODS: To explore the role of immune-inflammatory surrogates by the validated lung immuno-oncology prognostic score (LIPS) score, including the neutrophil-to-lymphocyte ratio (NLR) and the pretreatment use of steroids, alongside other prognostic variables. A retrospective analysis of 128 patients with PS2 and PD-L1 ≥50% mNSCLC treated between April 2018 and September 2019 with first-line pembrolizumab in a real-world setting was performed. RESULTS: With a median follow-up of 15.3 months, the 1-year overall survival (OS) and median progression-free survival (PFS) were 32.3% (95% CI: 30.9-33.9) and 3.3 months (95% CI: 1.8-4.7), respectively. The NLR, lactate dehydrogenase (LDH) and pretreatment steroids results were the only significant prognostic factors on the univariate analysis and independent prognostic factors by the multivariate analysis on both OS and PFS. The LIPS score, including the NLR and pretreatment steroids, identified 29 (23%) favourable-risk patients, with 0 factors, 1-year OS of 67.6% and median PFS of 8.2 months; 57 (45%) intermediate-risk patients, with 1 factor, 1-year OS 32.1% and median PFS 2.7 months; 42 (33%) poor-risk patients, with both factors, 1-year OS of 10.7% and median PFS of 1.2 months. CONCLUSIONS: The assessment of pre-existing imbalance of the host immune response by combined blood and clinical immune-inflammatory markers may represent a way to unravel the heterogeneous outcome and assessment of patients with mNSCLC and poor PS in the immune-oncology setting.

Expression signature, prognosis value and immune characteristics of cathepsin F in non-small cell lung cancer identified by bioinformatics assessment.

BACKGROUND: In recent years, immunotherapies and targeted therapies contribute to population-level improvement in NSCLC cancer-specific survival, however, the two novel therapeutic options have mainly benefit patients containing mutated driven genes. Thus, to explore other potential genes related with immunity or targeted therapies may provide novel options to improve survival of lung cancer patients without mutated driven genes. CTSF is unique in human cysteine proteinases. Presently, CTSF has been detected in several cell lines of lung cancer, but its role in progression and prognosis of lung cancer remains unclear. METHODS: CTSF expression and clinical datasets of lung cancer patients were obtained from GTEx, TIMER, CCLE, THPA, and TCGA, respectively. Association of CTSF expression with clinicopathological parameters and prognosis of lung cancer patients was analyzed using UALCAN and Kaplan-Meier Plotter, respectively. LinkedOmics were used to analyze correlation between CTSF and CTSF co-expressed genes. Protein-protein interaction and gene-gene interaction were analyzed using STRING and GeneMANIA, respectively. Association of CTSF with molecular markers of immune cells and immunomodulators was analyzed with Immunedeconv and TISIDB, respectively. RESULTS: CTSF expression was currently only available for patients with NSCLC. Compared to normal tissues, CTSF was downregulated in NSCLC samples and high expressed CTSF was correlated with favorable prognosis of NSCLC. Additionally, CTSF expression was correlated with that of immune cell molecular markers and immunomodulators both in LUAD and LUSC. Noticeably, high expression of CTSF-related CTLA-4 was found to be associated with better OS of LUAD patients. Increased expression of CTSF-related LAG-3 was related with poor prognosis of LUAD patients while there was no association between CTSF-related PD-1/PD-L1 and prognosis of LUAD patients. Moreover, increased expression of CTSF-related CD27 was related with poor prognosis of LUAD patients while favorable prognosis of LUSC patients. CONCLUSIONS: CTSF might play an anti-tumor effect via regulating immune response of NSCLC.

A novel immune-related long non-coding RNAs risk model for prognosis assessment of lung adenocarcinoma.

BACKGROUND: The abundant immune-related long non-coding RNA (IRLNRs) in immune cells and immune microenvironment have the potential to forecast prognosis and evaluate the effect of immunotherapy. IRLNRs analysis will provide a new perspective for LUAC research. METHODS: We calculated the immune score of each sample according to the expression levels of immune-related genes (IRGs) and screened the survival-related IRLNRs (sIRLNRs) by Cox regression analysis. The expression levels of AC068338.3 and AL691432.2 in tissues and cell lines were confirmed by RT-qPCR. RESULTS: 36 IRLNRs were selected by Pearson correlation analysis. Ten sIRLNRs were significantly correlated with the clinical outcomes of LUAC patients. Five sIRLNRs were identified by multivariate COX regression analysis to establish the immune-related risk score model (IRRS). The overall survival (OS) in the high-risk group was shorter than that in the low-risk group. IRRS could be an independent prognostic factor with significant survival correlation The distributions of immune gene concentrations were different between high-risk group and low-risk group. Furthermore, we further verified that the expression levels of AC068338.3 and AL691432.2 in different LUAC cell lines and tumor tissues were lower than that in Human bronchial epithelial cell (HBE) and adjacent tissues respectively. The lower expression levels of AC068338.3 and AL691432.2 were detected with the more advance T-stages. CONCLUSIONS: Our results highlighted some sIRLNRs with significant clinical correlations and demonstrated their monitored and prognostic values for LUAC patients. The results of this study may provide a new perspective for immunological research and immunotherapy strategies.

Determining the optimal PD-1/PD-L1 inhibitors for the first-line treatment of non-small-cell lung cancer with high-level PD-L1 expression in China.

BACKGROUND AND OBJECTIVE: The programmed death 1 and ligand (PD-1/PD-L1) inhibitors have significantly altered therapeutic perspectives on non-small-cell lung cancer (NSCLC). However, their efficacy and safety are unknown since direct clinical trials have not yet been performed on them. It is also necessary to determine the economics of PD-1/PD-L1 inhibitors due to their high cost. The aim was to evaluate the efficacy, safety, and cost-effectiveness of PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients in China with high PD-L1 expression as first-line treatment. METHODS: From the PubMed, Cochrane, and Web of Science databases, we retrieved survival, progression, and safety data on PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients. A network meta-analysis (NMA) was performed to consider PD-1/PD-L1 inhibitors in efficacy and safety. A Markov model with a full-lifetime horizon was adopted. Clinical and utility data were collected through the trial. The cost per quality-adjusted life year (QALY) was as incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. RESULTS: This study included five phase III clinical trials using four drugs: nivolumab, pembrolizumab, atezolizumab, and durvalumab. The NMA demonstrated that the four drugs had similar efficacy and safety, while pembrolizumab and atezolizumab were better for than for nivolumab (hazard ratio (HR) = 0.66, 95% confidence intervals (CIs): 0.46-0.95 and HR = 0.59, 95%CI: 0.37-0.94) in progression-free survival (PFS), and the risk of a severe adverse event was higher for atezolizumab than for nivolumab and pembrolizumab. Compared with nivolumab, durvalumab, pembrolizumab, and atezolizumab had QALY of 0.19, 0.38, and 0.53, respectively, which induced ICERs of $ 197,028.8/QALY, $ 111,859.0/QALY, and $ 76,182.3/QALY, respectively. CONCLUSION: The efficacy and safety are similar among types of PD-1/PD-L1-inhibitor monotherapy. The cost-effectiveness of nivolumab appears optimal, but the other PD-1/PD-L1 inhibitors are not as cost-effective for the first-line treatment of advanced NSCLC in China.

[Ongoing Evaluation of Immune-related Response Assessment in Brain Metastases].

Brain metastases are the major cause of adult malignant nervous system tumors. For this part of population, treatment options are limited and the prognosis is poor. In recent years, immunotherapy based on inhibitors of programmed cell death protein 1 (PD-1) and programmed cell death receptor ligand 1 (PD-L1), have brought innovation to the treatment of malignant tumors. Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Encouraging results have suggested that ICIs could be active in selected advanced NSCLC brain metastases with driver-negative patients. However, for patients with brain metastases, not only the corresponding clinical data are limited, but also the evaluation of its efficacy lacks a unified standard. This article aims to review the relevant efficacy evaluation standards and their application in clinical researches, compare the similarities and differences, and look forward to future trends.
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Lung cancer LDCT screening and mortality reduction - evidence, pitfalls and future perspectives.

In the past decade, the introduction of molecularly targeted agents and immune-checkpoint inhibitors has led to improved survival outcomes for patients with advanced-stage lung cancer; however, this disease remains the leading cause of cancer-related mortality worldwide. Two large randomized controlled trials of low-dose CT (LDCT)-based lung cancer screening in high-risk populations - the US National Lung Screening Trial (NLST) and NELSON - have provided evidence of a statistically significant mortality reduction in patients. LDCT-based screening programmes for individuals at a high risk of lung cancer have already been implemented in the USA. Furthermore, implementation programmes are currently underway in the UK following the success of the UK Lung Cancer Screening (UKLS) trial, which included the Liverpool Health Lung Project, Manchester Lung Health Check, the Lung Screen Uptake Trial, the West London Lung Cancer Screening pilot and the Yorkshire Lung Screening trial. In this Review, we focus on the current evidence on LDCT-based lung cancer screening and discuss the clinical developments in high-risk populations worldwide; additionally, we address aspects such as cost-effectiveness. We present a framework to define the scope of future implementation research on lung cancer screening programmes referred to as Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL).

Digital Monitoring and Management of Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Treated With Cancer Immunotherapy and Its Impact on Quality of Clinical Care: Interview and Survey Study Among Health Care Professionals and Patients.

BACKGROUND: Cancer immunotherapy (CIT), as a monotherapy or in combination with chemotherapy, has been shown to extend overall survival in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, patients experience treatment-related symptoms that they are required to recall between hospital visits. Digital patient monitoring and management (DPMM) tools may improve clinical practice by allowing real-time symptom reporting. OBJECTIVE: This proof-of-concept pilot study assessed patient and health care professional (HCP) adoption of our DPMM tool, which was designed specifically for patients with advanced or metastatic NSCLC treated with CIT, and the tool's impact on clinical care. METHODS: Four advisory boards were assembled in order to co-develop a drug- and indication-specific CIT (CIT+) module, based on a generic CIT DPMM tool from Kaiku Health, Helsinki, Finland. A total of 45 patients treated with second-line single-agent CIT (ie, atezolizumab or otherwise) for advanced or metastatic NSCLC, as well as HCPs, whose exact number was decided by the clinics, were recruited from 10 clinics in Germany, Finland, and Switzerland between February and May 2019. All clinics were provided with the Kaiku Health generic CIT DPMM tool, including our CIT+ module. Data on user experience, overall satisfaction, and impact of the tool on clinical practice were collected using anonymized surveys-answers ranged from 1 (low agreement) to 5 (high agreement)-and HCP interviews; surveys and interviews consisted of closed-ended Likert scales and open-ended questions, respectively. The first survey was conducted after 2 months of DPMM use, and a second survey and HCP interviews were conducted at study end (ie, after ≥3 months of DPMM use); only a subgroup of HCPs from each clinic responded to the surveys and interviews. Survey data were analyzed quantitatively; interviews were recorded, transcribed verbatim, and translated into English, where applicable, for coding and qualitative thematic analysis. RESULTS: Among interim survey respondents (N=51: 13 [25%] nurses, 11 [22%] physicians, and 27 [53%] patients), mean rankings of the tool's seven usability attributes ranged from 3.2 to 4.4 (nurses), 3.7 to 4.5 (physicians), and 3.7 to 4.2 (patients). At the end-of-study survey (N=48: 19 [40%] nurses, 8 [17%] physicians, and 21 [44%] patients), most respondents agreed that the tool facilitated more efficient and focused discussions between patients and HCPs (nurses and patients: mean rating 4.2, SD 0.8; physicians: mean rating 4.4, SD 0.8) and allowed HCPs to tailor discussions with patients (mean rating 4.35, SD 0.65). The standalone tool was well integrated into HCP daily clinical workflow (mean rating 3.80, SD 0.75), enabled workflow optimization between physicians and nurses (mean rating 3.75, SD 0.80), and saved time by decreasing phone consultations (mean rating 3.75, SD 1.00) and patient visits (mean rating 3.45, SD 1.20). Workload was the most common challenge of tool use among respondents (12/19, 63%). CONCLUSIONS: Our results demonstrate high user satisfaction and acceptance of DPMM tools by HCPs and patients, and highlight the improvements to clinical care in patients with advanced or metastatic NSCLC treated with CIT monotherapy. However, further integration of the tool into the clinical information technology data flow is required. Future studies or registries using our DPMM tool may provide insights into significant effects on patient quality of life or health-economic benefits.

Gustave Roussy Immune Score based on a three-category risk assessment scale serves as a novel and effective prognostic indicator for surgically resectable early-stage non-small-cell lung cancer: A propensity score matching retrospective cohort study.

BACKGROUNDS: The Gustave Roussy Immune score (GRIm-Score) emerges as a novel prognostic scoring system for patient selection in phase I trials testing targeted immunotherapy for advanced-stage cancer. We tried to assess potential prognostic roles of preoperative GRIm-Score in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for stage I-II non-small-cell lung cancer (NSCLC) by propensity score-matching (PSM) analysis. METHODS: This PSM-based analysis was performed on our single-center prospectively-maintained database between January 2014 and October 2015. A Kaplan-Meier survival analysis using the log-rank test was used to distinguish differences in both overall survival (OS) and disease-free survival (DFS) between the patients stratified by preoperative GRIm-Score. Multivariable Cox-proportional hazards regression analysis and PSM analysis were both carried out to determine the final independent prognostic parameters. RESULTS: There were 405 patients with surgically resectable stage I-II NSCLC included. Both OS and DFS were significantly shortened along with each number increase in the GRIm-Score group, showing a step-wise fashion. Such strong correlations between preoperative GRIm-Score estimated by a modified 3-category risk scale and survival outcomes still remained validated after PSM analysis. In addition, this GRIm-Score held the superior discriminatory power for predicting both OS and DFS to the other peripheral blood biomarkers. Multivariable analyses on the entire cohort and the PSM cohort demonstrated that GRIm-Score based on a 3-category risk assessment scale could be independently predictive of both OS and DFS. CONCLUSIONS: The GRIm-Score tool can also serve as an effective and noninvasive marker to optimize prognostic prediction for surgically resectable stage I-II NSCLC.

Assessment of long non-coding RNA expression reveals novel mediators of the lung tumour immune response.

The tumour immune microenvironment is a crucial mediator of lung tumourigenesis, and characterizing the immune landscape of patient tumours may guide immunotherapy treatment regimens and uncover novel intervention points. We sought to identify the landscape of tumour-infiltrating immune cells in the context of long non-coding RNA (lncRNAs), known regulators of gene expression. We examined the lncRNA profiles of lung adenocarcinoma (LUAD) tumours by interrogating RNA sequencing data from microdissected and non-microdissected samples (BCCRC and TCGA). Subsequently, analysis of single-cell RNA sequencing data from lung tumours and flow-sorted healthy peripheral blood mononuclear cells identified lncRNAs in immune cells, highlighting their biological and prognostic relevance. We discovered lncRNA expression patterns indicative of regulatory relationships with immune-related protein-coding genes, including the relationship between AC008750.1 and NKG7 in NK cells. Activation of NK cells in vitro was sufficient to induce AC008750.1 expression. Finally, siRNA-mediated knockdown of AC008750.1 significantly impaired both the expression of NKG7 and the anti-tumour capacity of NK cells. We present an atlas of cancer-cell extrinsic immune cell-expressed lncRNAs, in vitro evidence for a functional role of lncRNAs in anti-tumour immune activity, which upon further exploration may reveal novel clinical utility as markers of immune infiltration.

Cost-effectiveness of a new autoantibody test added to Computed Tomography (CT) compared to CT surveillance alone in the diagnosis of lung cancer amongst patients with indeterminate pulmonary nodules.

Oncimmune's EarlyCDT®-Lung is a simple ELISA blood test that measures seven lung cancer specific autoantibodies and is used in the assessment of malignancy risk in patients with indeterminate pulmonary nodules (IPNs). The objective of this study was to examine the cost-effectiveness of EarlyCDT-Lung in the diagnosis of lung cancer amongst patients with IPNs in addition to CT surveillance, compared to CT surveillance alone which is the current recommendation by the British Thoracic Society guidelines. A model consisting of a combination of a decision tree and Markov model was developed using the outcome measure of the quality adjusted life year (QALY). A life-time time horizon was adopted. The model was parameterized using a range of secondary sources. At £70 per test, EarlyCDT-Lung and CT surveillance was found to be cost-effective compared to CT surveillance alone with an incremental cost-effectiveness ratio (ICER) of less than £2,500 depending on the test accuracy parameters used. It was also found that EarlyCDT-Lung can be priced up to £1,177 and still be cost-effective based on cost-effectiveness acceptance threshold of £20,000 / QALY. Further research to resolve parameter uncertainty, was not found to be of value. The results here demonstrate that at £70 per test the EarlyCDT-Lung will have a positive impact on patient outcomes and coupled with CT surveillance is a cost-effective approach to the management of patients with IPNs. The conclusions drawn from this analysis are robust to realistic variation in the parameters used in the model.

Assessment of associations between clinical and immune microenvironmental factors and tumor mutation burden in resected nonsmall cell lung cancer by applying machine learning to whole-slide images.

BACKGROUND: It is unclear whether clinical factors and immune microenvironment (IME) factors are associated with tumor mutation burden (TMB) in patients with nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: We assessed TMB in surgical tumor specimens by performing whole exome sequencing. IME profiles, including PD-L1 tumor proportion score (TPS), stromal CD8 tumor-infiltrating lymphocyte (TIL) density, and stromal Foxp3 TIL density, were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, clinical data, and IME factors were assessed by means of a multiple regression model. RESULTS: We analyzed tumors from 200 of the 246 surgically resected NSCLC patients between September 2014 and September 2015. Patient background: median age (range) 70 years (39-87); male 37.5%; smoker 27.5%; pathological stage (p-stage) I/II/III, 63.5/22.5/14.0%; histological type Ad/Sq, 77.0/23.0%; primary tumor location upper/lower, 58.5/41.5%; median PET SUV 7.5 (0.86-29.8); median serum CEA (sCEA) level 3.4 ng/mL (0.5-144.3); median serum CYFRA 21-1 (sCYFRA) level 1.2 ng/mL (1.0-38.0); median TMB 2.19/ Mb (0.12-64.38); median PD-L1 TPS 15.1% (0.09-77.4); median stromal CD8 TIL density 582.1/mm2 (120.0-4967.6);, and median stromal Foxp3 TIL density 183.7/mm2 (6.3-544.0). The multiple regression analysis identified three factors associated with higher TMB: smoking status: smoker, increase PET SUV, and sCEA level: >5 ng/mL (P < .001, P < .001, and P = .006, respectively). CONCLUSIONS: The IME factors assessed were not associated with TMB, but our findings showed that, in addition to smoking, PET SUV and sCEA levels may be independent predictors of TMB. TMB and IME factors are independent factors in resected NSCLC.

Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm.

Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.

Tumor neoantigenicity assessment with CSiN score incorporates clonality and immunogenicity to predict immunotherapy outcomes.

Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally. Neoantigen load has been linked with treatment response and prognosis in some studies but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to better account for the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike total neoantigen load determinations, CSiN incorporates the effect of both clonality and MHC binding affinity of neoantigens when characterizing tumor neoantigen profiles. By analyzing the clinical responses in 501 treated patients with cancer (with most receiving checkpoint inhibitors) and the overall survival of 1978 patients with cancer at baseline, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in patients with melanoma, lung cancer, and kidney cancer. CSiN score substantially outperformed prior genetics-based prediction methods of responsiveness and fills an important gap in research involving assessment of tumor neoantigen burden.

Patterns of care for older patients with stage IV non-small cell lung cancer in the immunotherapy era.

BACKGROUND: Historically, older patients with advanced lung cancer have often received no systemic treatment. Immunotherapy has improved outcomes in clinical trials, but its dissemination and implementation at the population level is not well-understood. METHODS: A retrospective cohort study of patients with stage IV non-small cell lung cancer (NSCLC) diagnosed age 66 or older from 2012 to 2015 was conducted using SEER-Medicare. Treatment patterns within one year of diagnosis were ascertained. Outcomes included delivery of (a) any systemic therapy; (b) any second-line infusional therapy, following first-line infusional therapy; and (c) any second-line immunotherapy, following first-line infusional therapy. Trends in care patterns associated with second-line immunotherapy approvals in 2015 were assessed using generalized additive models. Sociodemographic and clinical predictors of treatment were explored using logistic regression. RESULTS: Among 10 303 patients, 5173 (50.2%) received first-line systemic therapy, with little change between the years 2012 (47.5%) and 2015 (50.3%). Among 3943 patients completing first-line infusional therapy, the proportion starting second-line infusional treatment remained stable from 2012 (30.5%) through 2014 (32.9%), before increasing in 2015 (42.4%) concurrent with second-line immunotherapy approvals. Factors associated with decreased utilization of any therapy included age, black race, Medicaid eligibility, residence in a high-poverty area, nonadenocarcinoma histology, and comorbidity; factors associated with increased utilization of any therapy included Asian race and Hispanic ethnicity. Among patients who received first-line infusional therapy, factors associated with decreased utilization of second-line infusional therapy included age, Medicaid eligibility, nonadenocarcinoma histology, and comorbidity; Asian race was associated with increased utilization of second-line infusional therapy. CONCLUSION: United States Food and Drug Administration (FDA) approvals of immunotherapy for the second-line treatment of advanced NSCLC in 2015 were associated with increased rates of any second-line treatment, but disparities based on social determinants of health persisted.

Poor-Performance Status Assessment of Patients with Non-small Cell Lung Cancer Remains Vague and Blurred in the Immunotherapy Era.

PURPOSE OF REVIEW: In the latest decade, the introduction of immune-checkpoint inhibitors (ICIs) has dramatically improved the prognosis of patients with NSCLC. First-line ICIs or chemo-ICI trials have demonstrated OS advantages but the accrual was limited to Eastern Cooperative Oncology Group (ECOG) performance status (PS)0-1 patients. ICI studies have for the vast majority excluded patients with poor performance status. PS 2 particularly is known as a negative prognostic factor for survival and a predictive factor of adverse events and poor response to treatments. Data on the activity of ICIs in PS2 patients are limited and come from heterogeneous meta-analyses and small phase II or expanded access trials. Often, terms such as "unfit" or "frail" ascertain the eligibility of patients to undergo cytotoxic chemotherapy, without specifying PS. RECENT FINDINGS: Other tools exist to aid in decision-making, and one simple, rapid, and validated screening test for frailty is the FRAIL scale consisting of 5 straightforward questions that can be self-administered and may represent an efficient and cost-effective way to screen large groups of patients for frailty. The Comprehensive Geriatric Assessment (CGA) is a widely used method to determine the medical, psychological, and functional capabilities of older patients. However, CGA is time-consuming and this could represent a real barrier to its adoption in clinical practice. For this reason, a quick screening tool, the G8 questionnaire, has been developed and demonstrated validity also in a younger population. A complementary tool to assess patients' frailty is Charlson comorbidity index (CCI) which has become the most widely used clinical index for a variety of disorders and cancers. Yet, none of these tools has been validated as predictive in ICI. In conclusion, solid data regarding the benefit of ICIs in ECOG PS2 NSCLC patients are currently lacking and the role of immunotherapy remains uncertain for PS2 patients. Prospective randomized trials addressing this question are warranted or ongoing. However, we are concerned that without a more extensive and objective assessment of patients' fitness and frailty by using and validating appropriate tools a clear answer may not come to light.

Cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advanced or metastatic non-small cell lung cancer with PD-L1 tumor proportion score 1% or greater.

OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness analysis of pembrolizumab versus chemotherapy as first-line treatment in locally advance or metastatic non-small cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) 1% or greater from the United States (US) payer perspective. MATERIALS AND METHODS: This Markov structure was developed to estimate cost and effectiveness of pembrolizumab vs chemotherapy in the first-line treatment of locally advance or metastatic NSCLC based on the data from KEYNOTE-042. Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in three PD-L1 TPS populations (≥50%, ≥20% and ≥1%). One-way, two-way and probabilistic sensitivity analysis were to test the model stability. Subgroup analysis were performed in three PD-L1 TPS populations (≥50%, ≥20% and ≥1%). RESULTS: The incremental costs and QALYs that pembrolizumab yielded, compared with chemotherapy, were $86164.87 and 0.63, $74562.25 and 0.46 and $70886.65 and 0.39 for the populations with a PD-L1 TPS ≥ 50%, TPS ≥ 20% and TPS ≥ 1%, leading an incremental cost-effective ratio (ICER) of $136,228.82, $160,625.98 and $179,530.17 per QALY, respectively. CONCLUSION: First-line treatment with pembrolizumab is a cost-effective strategy compared with platinum-based chemotherapy when the value of WTP was $150,000 per QALY in locally advanced or metastatic NSCLC patients with PD-L1 TPS ≥ 50% and without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations, but not in the TPS ≥ 20% and 1% populations.

Variation in the Assessment of Immune-Related Adverse Event Occurrence, Grade, and Timing in Patients Receiving Immune Checkpoint Inhibitors.

Importance: Toxic effects of conventional chemotherapy and molecularly targeted cancer therapies are generally well defined and occur at predictable points. By contrast, owing to their heterogeneous manifestations, unpredictable timing, and clinical overlap with other conditions, immune-related adverse events (irAE) may be more difficult to diagnose and characterize. Objective: To determine concordance of algorithm-driven medical record review by medical oncologists for the characterization of 8 irAE in patients treated with immune checkpoint inhibitors. Design, Setting, and Participants: Cross-sectional study of patients treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center from November 30, 2015, to March 7, 2018. A sample size of 52 patients provided 80% power to distinguish substantial agreement (κ = 0.85) from poor agreement (κ = 0.5) based on the Cohen κ. Main Outcomes and Measures: Interrater agreement of 2 observers in the occurrence and grade of irAE. Results: Of 52 patients (32 [61.5%] male; mean [SD] age, 69 [9] years) analyzed, 42 (80.8%) had non-small cell lung cancer and all received anti-programmed cell death 1 or anti-programmed cell death ligand 1 antibodies, with 3 patients (5.8%) receiving combinations with anti-cytotoxic T-lymphocyte antigen 4 antibodies. A median (interquartile range) of 82 (47-180) documents were reviewed per case. There was limited or poor interrater agreement on irAE occurrence (Cohen κ, 0.37-0.64), with the exception of hypothyroidism (κ = 0.8). Weighted κ similarly showed limited or poor agreement for irAE grade (κ = 0.31-0.75). Differences in assessed time of onset ranged from 5 to 188 days. As a control for data availability and access, observers had a high degree of agreement for the exact start date (98%) and end date (96%) of immunotherapy administration, suggesting that information interpretation rather than identification largely accounted for assessment differences. In multivariable analysis, therapy duration (adjusted odds ratio, 4.80; 95% CI, 1.34-17.17; P = .02) and Charlson Comorbidity Index (adjusted odds ratio, 4.09; 95% CI, 1.10-15.18; P = .03) were significantly associated with discordant irAE assessment. Conclusions and Relevance: These findings underscore critical challenges in assessing the occurrence, type, timing, and severity of irAE. Apart from hypothyroidism (a condition that has a discrete diagnostic laboratory test and few other likely etiologies during immunotherapy treatment), interobserver agreement was poor. Given the importance of accurate and timely assessment of toxic effects for clinical trials and real-world disease management, efforts to improve irAE diagnosis and characterization are needed.

Immunotherapy in first-line for advanced non-small cell lung cancer: a cost-effective choice?

Introduction: The present evaluation was restricted to pivotal phase III randomized controlled trials (RCTs) in first-line for metastatic non-small cell lung cancer (NSCLC). Materials and methods: We calculated the pharmacological costs necessary to get the benefit in overall survival (OS), for each trial. Results: Our analysis evaluated 10 phase III RCTs, including 9485 patients. The most relevant increase of cost € per month of OS-gain was associated with bevacizumab (66,720 €) and the lowest with the use of pembrolizumab (2734 €). Conclusion: Combining pharmacological costs of drugs with the measure of efficacy represented by OS, pembrolizumab is a cost-effective first-line treatment for patients with metastatic NSCLC.