Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer.

Objectives: Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps. Methods: A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS. Results: Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]). Conclusion: PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.

Incidence of Pneumonitis Among Limited Stage Small Cell Lung Cancer Patients Exposed to Concurrent Chemoradiation: A Systematic Literature Review and Meta-Analysis.

Severe pneumonitis (≥ grade 3 by Common Terminology Criteria for Adverse Events [CTCAE]) is a toxicity associated with concurrent chemoradiation therapy (CCRT), which is the standard first-line treatment for patients with limited-stage small cell lung cancer (LS-SCLC). We summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT. A systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines. Electronic databases were searched to identify relevant randomized controlled trials (RCTs), observational studies, and non-randomized trials between 2014 to July 16, 2020. The primary outcome was incidence of pneumonitis. Thirteen studies were included in the SLR and 1539 pooled patients from 10 studies were included in the base-case meta-analysis. The pooled incidence of ≥ grade 3 pneumonitis was 3.28% (95% confidence interval [CI]: 1.52%-5.04%) in RCTs, and 6.34% (95% CI: 3.64%-9.04%) in non-RCTs. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% (95% CI: 0.00%-0.62%) in RCTs and 0.88% (95% CI: 0.02%-1.74%) in non-RCT. Results from sensitivity analyses were consistent with the base-case analysis. The results from this analysis show that the incidence of ≥ grade 3 pneumonitis in patients with LS-SCLC was 3.28% to 6.34%. The incidence of pneumonitis was higher in studies conducted in non-RCTs compared to RCTs. These results can be used to understand the safety, with regard to pneumonitis, of novel therapeutic agents when administered with CCRT to treat patients with LS-SCLC. To summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT, a systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines.

Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: A systematic literature review and meta-analysis.

INTRODUCTION: High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients. METHODS: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis. RESULTS: Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies. CONCLUSION: These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

Reducing Uninformative IND Safety Reports: A List of Serious Adverse Events anticipated to Occur in Patients with Lung Cancer.

Expedited reporting of unexpected serious adverse reactions that occur during clinical trials conducted under an IND is a critical component of the clinical trial process designed to protect patients by identifying potential safety issues with new agents. However, in recent years, the US FDA has presented extensive data about the problem of uninformative IND safety reporting. Despite published guidance documents aimed at clarifying requirements for submission of IND safety reports for individual events, there continues to be significant over-reporting of these events by many sponsors. This leads to excessive burden for the sponsors, the investigators who conduct clinical trials, and the FDA reviewers, who must evaluate each individual report submitted by the sponsor. This trend has the potential to endanger patients by obscuring true safety signals. To address this problem, LUNGevity Foundation empaneled a multi-sector working group of its Scientific and Clinical Research Roundtable (SCRT) charged with identifying ways to reduce unnecessary distribution of serious adverse events (SAEs) reports. This paper outlines the working group's activities, including a brief list of serious adverse events "anticipated" to occur within the lung cancer population that are either related to the underlying disease or condition being studied, concomitant or background therapy, or events associated with a demographic parameter such as age. These "anticipated" events, while required to be reported by investigators to sponsors, in general, should not then be individually reported by sponsors to FDA and to individual investigators in an IND safety report because these events require aggregate analysis across the development program to determine if they occur more frequently in treated versus untreated patients. This paper also includes discussion of how the use of background threshold values, generated from real-world data, could serve as one potential tool to guide sponsors in making causality assessments. If sponsors and other key stakeholders within the clinical research ecosystem embrace this type of approach and refrain from reporting "anticipated" events as single IND safety reports to the FDA staff and to each participating investigator, it could significantly reduce the amount of unnecessary reporting and serve as a model for other disease areas.

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC.

INTRODUCTION: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. METHODS: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. RESULTS: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. CONCLUSIONS: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population.

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial.

BACKGROUND: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS: In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029). INTERPRETATION: Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING: Merck & Co.

Risk of severe acute liver injury among patients with brain cancer treated with temozolomide: a nested case-control study using the healthcore integrated research database.

Temozolomide (TMZ) is used to treat adult patients with glioblastoma multiforme (GBM). Cases of hepatotoxicity have been reported among patients using TMZ. The objective of the study was to assess the relation, if any, between exposure to TMZ and serious acute liver injury (SALI). We used the HealthCore Integrated Research Database to perform a case-control study nested within a retrospective cohort of adult patients aged 18-100 years with at least two diagnoses of brain cancer anytime between 2006 and 2014. Patients without continuous eligibility or with a SALI diagnosis within 6 months prior to the date of incident brain cancer diagnosis were excluded. Medical records were sought for potential SALI cases and reviewed by two hepatologists. Five controls were selected for each case using incidence density sampling, matched on age and calendar year of index date. The analysis included 61 confirmed SALI cases and 305 selected controls. Exposure to TMZ was classified according to dispensing date and days supply of medication dispensed. We estimated odds ratios using conditional logistic regression models. The odds ratio for any exposure to TMZ was 0.91 (95% CI 0.44-1.91), for recent exposure to TMZ was 0.62 (95% CI 0.21-1.85). There was no increased risk of SALI with increasing duration of exposure to TMZ. When patients with unconfirmed SALI were included in the analysis, results were similar (OR 1.04; 95% CI 0.70-1.54). In conclusion, this study did not find an association between TMZ and SALI risk among patients with brain cancer.

The prevalence and correlates of binge eating disorder in the World Health Organization World Mental Health Surveys.

BACKGROUND: Little population-based data exist outside the United States on the epidemiology of binge eating disorder (BED). Cross-national BED data are presented here and compared with bulimia nervosa (BN) data in the World Health Organization (WHO) World Mental Health Surveys. METHODS: Community surveys with 24,124 respondents (ages 18+) across 14 mostly upper-middle and high-income countries assessed lifetime and 12-month DSM-IV mental disorders with the WHO Composite International Diagnostic Interview. Physical disorders were assessed with a chronic conditions checklist. RESULTS: Country-specific lifetime prevalence estimates are consistently (median; interquartile range) higher for BED (1.4%; .8-1.9%) than BN (.8%; .4-1.0%). Median age of onset is in the late teens to early 20s for both disorders but slightly younger for BN. Persistence is slightly higher for BN (6.5 years; 2.2-15.4) than BED (4.3 years; 1.0-11.7). Lifetime risk of both disorders is elevated for women and recent cohorts. Retrospective reports suggest that comorbid DSM-IV disorders predict subsequent onset of BN somewhat more strongly than BED and that BN predicts subsequent comorbid disorders somewhat more strongly than does BED. Significant comorbidities with physical conditions are due almost entirely to BN and to a somewhat lesser degree BED predicting subsequent onset of these conditions. Role impairments are similar for BN and BED. Fewer than half of lifetime BN or BED cases receive treatment. CONCLUSIONS: Binge eating disorder represents a public health problem at least equal to BN. Low treatment rates highlight the clinical importance of questioning patients about eating problems even when not included among presenting complaints.

Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer.

INTRODUCTION: At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basal-like. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer. METHODS: We constructed tissue microarrays (TMAs) from breast cancers that developed in 2897 women enrolled in the Nurses' Health Study (1976 to 1996). TMA slides were immunostained for oestrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR). Using these immunostain results, cases were grouped into molecularly defined subtypes. RESULTS: The prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249). The luminal A phenotype was significantly more frequent among invasive cancers (73.4%) than among DCIS lesions (62.5%) (p = 0.0002). In contrast, luminal B and HER2 molecular phenotypes were both more frequent among DCIS (13.2% and 13.6%, respectively) as compared with invasive tumours (5.2% and 5.7%, respectively) (p < 0.0001). The basal-like phenotype was more frequent among the invasive cancers (10.9%) than DCIS (7.7%), although this difference was not statistically significant (p = 0.15). High-grade DCIS and invasive tumours were more likely to be HER2 type and basal-like than low- or intermediate-grade lesions. Among invasive tumours, basal-like and HER2 type tumours were more likely to be more than 2 cm in size, high-grade and have nodal involvement compared with luminal A tumours. CONCLUSION: The major molecular phenotypes previously identified among invasive breast cancers were also identified among cases of DCIS. However, the prevalence of the luminal A, luminal B and HER2 phenotypes differed significantly between DCIS and invasive breast cancers.

Impact of misclassification in genotype-exposure interaction studies: example of N-acetyltransferase 2 (NAT2), smoking, and bladder cancer.

Errors in genotype determination can lead to bias in the estimation of genotype effects and gene-environment interactions and increases in the sample size required for molecular epidemiologic studies. We evaluated the effect of genotype misclassification on odds ratio estimates and sample size requirements for a study of NAT2 acetylation status, smoking, and bladder cancer risk. Errors in the assignment of NAT2 acetylation status by a commonly used 3-single nucleotide polymorphism (SNP) genotyping assay, compared with an 11-SNP assay, were relatively small (sensitivity of 94% and specificity of 100%) and resulted in only slight biases of the interaction parameters. However, use of the 11-SNP assay resulted in a substantial decrease in sample size needs to detect a previously reported NAT2-smoking interaction for bladder cancer: 1,121 cases instead of 1,444 cases, assuming a 1:1 case-control ratio. This example illustrates how reducing genotype misclassification can result in substantial decreases in sample size requirements and possibly substantial decreases in the cost of studies to evaluate interactions.