Outcomes for pembrolizumab stratified by pemetrexed maintenance post pembrolizumab-platinum-pemetrexed induction in metastatic non-small-cell lung cancer.

Aim: We assessed treatment patterns and outcomes in patients with metastatic nonsquamous non-small-cell lung cancer (mNSCLC) who initiated first-line pembrolizumab-platinum-pemetrexed (induction) in US community oncology settings. Methods: Patients initiating induction were retrospectively identified. Patients continuing pembrolizumab afterward underwent chart review. Clinical outcomes were described by maintenance pemetrexed exposure after inverse probability of treatment weighting (IPTW). Results: Median induction pembrolizumab and pemetrexed durations were 5.1 and 4.2 months. Among patients continuing pembrolizumab after induction, 64% received maintenance pemetrexed. Common discontinuation reasons for induction pemetrexed were completion of planned therapy (79%) and partial response (68%) and progressive disease (38%) and toxicity (29%) for maintenance pemetrexed. After IPTW, median overall survival and real-world progression-free survival were longer in patients continuing pembrolizumab with versus without maintenance pemetrexed (20.3 vs 12.0 months and 10.3 vs 5.8 months, respectively). Conclusion: Patient characteristics and planned treatment decisions affect maintenance pemetrexed utilization in the community oncology setting.

What is this summary about? Pembrolizumab is a drug that helps the lung cancer patient's immune system fight the cancer, even after the cancer has spread, or metastasized. After the patient gets better, the patient is treated with chemotherapy so the cancer will not come back. This is called 'maintenance treatment'. In KEYNOTE-189, a clinical trial, patients lived longer if they had pembrolizumab added to pemetrexed and platinum, which are chemotherapy drugs. If patients had maintenance treatment with pembrolizumab and pemetrexed, they also lived longer. However, do patients in community practices get those treatments? What were the results? We found that at cancer practices in the community instead of clinical trials, not all patients received pemetrexed in maintenance treatment. Many had finished their planned therapy and their tumors had shrunk. Also, some physicians chose not to give their patients pemetrexed. In addition, some women and some older and sicker patients did not get pemetrexed. Some patients had pemetrexed in maintenance but stopped because their cancer grew worse or because they had side effects. Those patients did not live as long as patients who did have maintenance pemetrexed. What do the results mean? Patients with metastatic non-small-cell lung cancer in the community practice do better on the treatments tested in clinical trials. However, certain patients do not get those treatments. The reasons need to be understood, to make sure that those patients get better treatments.

Healthcare Costs and Resource Utilisation of Italian Metastatic Non-Small Cell Lung Cancer Patients.

This study evaluated the economic burden of metastatic non-small cell lung cancer patients before and after the availability of an immuno-oncology (IO) regimen as a first-line (1L) treatment. Patients from 2014 to 2020 were categorized according to mutational status into mutation-positive and negative/unknown groups, which were further divided into pre-1L IO and post-1L IO sub-groups depending on the availability of pembrolizumab monotherapy in 1L. Healthcare costs and HCRU for a 1L treatment and overall follow-up were reported as the mean total and per-month cost per patient by groups. Of 644 patients, 125were mutation-positive and 519 negative/unknown (229 and 290 in pre- and post-1L IO, respectively). The mean total per-patient cost in 1L was lower in pre- (EUR 7804) and post-1L IO (EUR 19,301) than the mutation-positive group (EUR 45,247), persisting throughout overall disease follow-up. However, this difference was less when analyzing monthly costs. Therapy costs were the primary driver in 1L, while hospitalization costs rose during follow-up. In both mutation-positive and post-IO 1L groups, the 1L costs represented a significant portion (70.1% and 66.3%, respectively) of the total costs in the overall follow-up. Pembrolizumab introduction increased expenses but improved survival. Higher hospitalisation and emergency room occupation rates during follow-up reflected worsening clinical conditions of the negative/unknown group than the mutation-positive population.

Cytosolic bacterial pathogens activate TLR pathways in tumors that synergistically enhance STING agonist cancer therapies.

Bacterial pathogens that invade the eukaryotic cytosol are distinctive tools for fighting cancer, as they preferentially target tumors and can deliver cancer antigens to MHC-I. Cytosolic bacterial pathogens have undergone extensive preclinical development and human clinical trials, yet the molecular mechanisms by which they are detected by innate immunity in tumors is unclear. We report that intratumoral delivery of phylogenetically distinct cytosolic pathogens, including Listeria, Rickettsia, and Burkholderia species, elicited anti-tumor responses in established, poorly immunogenic melanoma and lymphoma in mice. We were surprised to observe that although the bacteria required entry to the cytosol, the anti-tumor responses were largely independent of the cytosolic sensors cGAS/STING and instead required TLR signaling. Combining pathogens with TLR agonists did not enhance anti-tumor efficacy, while combinations with STING agonists elicited profound, synergistic anti-tumor effects with complete responses in >80% of mice after a single dose. Small molecule TLR agonists also synergistically enhanced the anti-tumor activity of STING agonists. The anti-tumor effects were diminished in Rag2-deficient mice and upon CD8 T cell depletion. Mice cured from combination therapy developed immunity to cancer rechallenge that was superior to STING agonist monotherapy. Together, these data provide a framework for enhancing the efficacy of microbial cancer therapies and small molecule innate immune agonists, via the co-activation of STING and TLRs.

Health Care Resource Use Among Patients with Advanced Non-Small Cell Lung Cancer in Japan, 2017-2019.

Background: First-line immune checkpoint inhibitor (ICI) monotherapy for advanced non-small cell lung cancer (NSCLC) was introduced in Japan in February 2017. Limited information is available since that time regarding health care resource use for NSCLC in Japan, where the hospitalization burden is high. Objective: We evaluated health care resource use from first- through third-line systemic anticancer therapy for patients with advanced NSCLC included in a multicenter, retrospective chart review study. Methods: Eligible patients were aged 20 years or older with unresectable locally advanced/metastatic NSCLC with no known actionable genomic alteration who initiated first-line systemic anticancer therapy from July 1, 2017, to December 20, 2018, at 23 Japanese hospitals. We calculated the percentage of patients with a record of each resource used, the total number of each resource, and the resource use per 100 patient-weeks of follow-up from initiation of first-, second-, and third-line therapy, overall and by the 3 most common regimen categories, namely, ICI monotherapy, platinum-doublet chemotherapy (without concomitant ICI), and nonplatinum cytotoxic regimens (nonplatinum). Study follow-up ended September 30, 2019. Results: Among 1208 patients (median age = 70 years; 975 [81%] men), 463 patients (38%) received ICI monotherapy, 647 (54%) received platinum-doublet chemotherapy, and 98 (8%) received nonplatinum regimens as first-line therapy. During the study, 621 (51%) patients initiated second-line, and 281 (23%) initiated third-line therapy. The majority of patients experienced ≥1 hospitalization (76%-94%) and ≥1 outpatient visit (85%-90%) during each therapy line. The number of hospitalizations increased from 6.5 per 100 patient-weeks in first-line to 8.0 per 100 patient-weeks in third-line. During first-line therapy, the number of hospitalizations per 100 patient-weeks were 4.8, 8.4, and 6.5 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of hospitalizations categorized as attributable to NSCLC treatment administration (no surgery, procedure, treatment of metastasis, or palliative lung radiation) were 64%, 77%, and 73%, respectively. The number of outpatient visits increased from 43.0 per 100 patient-weeks in first-line to 51.4 per 100 patient-weeks in third-line therapy. During first-line therapy, outpatient visits per 100 patient-weeks were 41.0, 46.7, and 33.0 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of outpatient visits for infusion therapy were 48%, 34%, and 36%, respectively. Conclusions: The results of this study, although solely descriptive, showed differing patterns of health care resource use during first-line therapy among the 3 common systemic anticancer therapy regimens for advanced NSCLC in Japan and suggest that further research is needed to investigate these apparent differences by treatment regimen.

Pembrolizumab-combination therapy for previously untreated metastatic nonsquamous NSCLC: Real-world outcomes at US oncology practices.

Objectives: The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Methods: Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Results: Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). Conclusions: These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

First-Line Pembrolizumab Monotherapy for Advanced NSCLC With Programmed Death-Ligand 1 Expression Greater Than or Equal to 50%: Real-World Study Including Older Patients in Japan.

Introduction: Pembrolizumab became available in Japan in February 2017 for first-line monotherapy of unresectable advanced and metastatic NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. This retrospective chart review study aimed to describe real-world clinical outcomes of first-line pembrolizumab monotherapy, including for patients 75 years or older, who are under-represented in clinical trials. Methods: We identified patients (≥20 y old) at 23 sites initiating first-line pembrolizumab monotherapy from July 1, 2017, to December 20, 2018, for stages IIIB, IIIC, and IV NSCLC with PD-L1 TPS greater than or equal to 50% and Eastern Cooperative Oncology Group performance status of 0 to 2 or unknown. Patients with actionable genomic alterations (EGFR, ALK, ROS1, BRAF) and clinical trial participants were excluded. Time-to-event outcomes were estimated using Kaplan-Meier, with data cutoff on September 30, 2019. Results: Of 441 eligible patients (78% men), 303 (69%) were younger than 75 years and 138 (31%) were 75 years or older; median age was 70 years. With median follow-up of 13.5 months, median overall survival (OS) was not reached (NR); 12- and 24-month OS rates were 72% and 58%, respectively. For ages younger than 75 and 75 years or older, median OS was NR and 23.5 months (95% confidence interval: 16.2-NR), respectively; 12-month OS rates were 74% and 67% and 24-month OS rates were 62% and 48%, respectively. Median real-world progression-free survival was similar in the two age groups (10.1 and 9.5 mo, respectively), as was median real-world time on treatment with pembrolizumab (5.7 and 5.6 mo). Conclusions: These findings complement clinical trial results, adding real-world evidence supporting benefits of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 TPS greater than or equal to 50%, including for patients 75 years or older.

Real-World Outcomes and Treatments Patterns Prior and after the Introduction of First-Line Immunotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: This study provides insights into the treatment use and outcomes of metastatic non-small cell lung cancer (NSCLC) patients in a real-world setting prior to and after the availability of immuno-oncology (IO) regimens in the first line (1L). METHODS: Metastatic NSCLC patients, who initiated systemic 1L anticancer treatment from 2014 to 2020, were identified from health records. Patients were grouped into Pre-1L IO and Post-1L IO, according to the availability of pembrolizumab 1L monotherapy at the date of initiating 1L systemic anticancer treatment. Patient characteristics, treatment patterns and outcomes were assessed by the cohort. Overall survival (OS) and real-world progression-free survival (rwPFS) were calculated using the Kaplan-Meier method. RESULTS: The most common 1L treatment was platinum-based chemotherapy regimens in both groups (≥46%), followed by single-agent chemotherapy (27.0%) in Pre-1L IO and pembrolizumab (26.0%) in Post-1L IO. Median OS was 6.2 (95% CI 5.5-7.4) in Pre- and 8.9 months (95% CI 7.5-10.6) in Post-1L IO, while rwPFS was 3.7 (95% CI 3.3-4.2) and 4.7 months (95% CI 3.9-5.7), respectively. CONCLUSIONS: Even if a small proportion of patients received a 1L IO, the data showed an improved survival outcomes in the Post-1L IO group.

SARS-CoV-2 reinfection across a spectrum of immunological states.

Purpose: Several cases of symptomatic reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after full recovery from a prior episode have been reported. As reinfection has become an increasingly common phenomenon, an improved understanding of the risk factors for reinfection and the character and duration of the serological responses to infection and vaccination is critical for managing the coronavirus disease 2019 (COVID-19) pandemic. Methods: We described four cases of SARS-CoV-2 reinfection in individuals representing a spectrum of healthy and immunocompromised states, including (1) a healthy 41-year-old pediatrician, (2) an immunocompromised 31-year-old with granulomatosis with polyangiitis, (3) a healthy 26-year-old pregnant woman, and (4) a 50-year-old with hypertension and hyperlipidemia. We performed confirmatory quantitative reverse transcription-polymerase chain reaction and qualitative immunoglobulin M and quantitative IgG testing on all available patient samples to confirm the presence of infection and serological response to infection. Results: Our analysis showed that patients 1 and 2, a healthy and an immunocompromised patient, both failed to mount a robust serologic response to the initial infection. In contrast, patients 3 and 4, with minimal comorbid disease, both mounted a strong serological response to their initial infection, but were still susceptible to reinfection. Conclusion: Repeat episodes of COVID-19 are capable of occurring in patients regardless of the presence of known risk factors for infection or level of serological response to infection, although this did not trigger critical illness in any instance.

Real-World Treatments and Clinical Outcomes in Advanced NSCLC without Actionable Mutations after Introduction of Immunotherapy in Japan.

The aims of this study were to describe systemic treatment patterns and clinical outcomes for unresectable advanced/metastatic non-small-cell lung cancer (NSCLC) by first-line regimen type in real-world clinical settings in Japan after the introduction of first-line immune checkpoint inhibitor (ICI) monotherapy in 2017. Using retrospective chart review at 23 study sites, we identified patients ≥20 years old initiating first-line systemic therapy from 1 July 2017 to 20 December 2018, for unresectable stage IIIB/C or IV NSCLC; the data cutoff was 30 September 2019. Eligible patients had recorded programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) and no known actionable EGFR/ALK/ROS1/BRAF genomic alteration. Kaplan-Meier method was used to determine time-to-event endpoints. Of 1208 patients, 647 patients (54%) received platinum doublet, 463 (38%) received ICI monotherapy, and 98 (8%) received nonplatinum cytotoxic regimen as first-line therapy. PD-L1 TPS was ≥50%, 1−49% and <1% for 44%, 30%, and 25% of patients, respectively. Most patients with PD-L1 TPS ≥50% received ICI monotherapy (453/529; 86%). Excluding 26 patients with ECOG performance status of 3−4 from outcome analyses, the median patient follow-up was 11.3 months. With first-line platinum doublet, ICI monotherapy, and nonplatinum cytotoxic regimens, median overall survival (OS) was 16.3 months (95% CI, 14.0−20.1 months), not reached, and 14.4 months (95% CI, 10.3−21.2 months), respectively; 24-month OS was 40%, 58%, and 31%, respectively. Differences in OS relative to historical cohort data reported in Japan are consistent with improvement over time in real-world clinical outcomes for advanced NSCLC.

Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic Non-Small Cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1.

Objectives: Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status. Methods: This retrospective two-cohort study used technology-enabled abstraction of deidentified electronic health records (EHR cohort) plus enhanced manual chart review (spotlight cohort) to study adult patients with stage IV NSCLC, PD-L1 expression ≥50%, no documented EGFR/ALK/ROS1 genomic aberration, and ECOG performance status 0-1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR). Results: The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0-52.7) and 38.4 months (range, 33.1-44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6-24.3) and 21.1 months (95% CI, 16.2-28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7-9.2); 88 patients (38.6%; 95% CI, 32.2-45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]). Conclusions: Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ): Measurement Properties and Estimated Clinically Meaningful Thresholds From a Phase 3 Study.

Introduction: The NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to assess NSCLC symptom severity in accordance with Food and Drug Administration evidentiary expectations leading to Food and Drug Administration qualification in 2018. This study evaluated the NSCLC-SAQ's measurement properties within a clinical trial. Methods: The KEYNOTE-598 phase 3 study of participants with stage IV metastatic NSCLC with programmed death-ligand 1 tumor proportion score greater than or equal to 50% was used to assess the NSCLC-SAQ's reliability, construct validity, responsiveness, and estimate clinically meaningful within-person change. Other patient-reported outcome measures included patient global impression items of severity and change in lung cancer symptoms, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and lung cancer module, LC13. Results: Participants (N = 560) were mostly men (70%), had a mean age of 64 years, and had Eastern Cooperative Oncology Group performance status of 1 (64%) or 0 (36%). Internal consistency at baseline (Cronbach's α = 0.74) and test-retest reliability after 3 weeks (intraclass correlation coefficient = 0.79) were satisfactory. NSCLC-SAQ items, domains, and total score correlated moderately to highly with patient-reported outcome measures capturing similar content, and the total score differentiated among patient global impression of severity groups (p < 0.001). The total score detected improvement over time and the estimated clinically meaningful within-person change threshold for improvement ranged from three to five points on the 0 to 20 scale. Few participants exhibited symptom worsening (n = 38), limiting inferences in this group. Conclusions: The NSCLC-SAQ was found to be reliable, valid, responsive, and interpretable for assessing symptom improvement in NSCLC. Further evaluation is recommended in trial participants whose symptoms worsen over time.

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship. Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI. Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc. Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection. Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Charting a Path Forward: Assessing the Science of Chemical Risk Evaluations under the Toxic Substances Control Act in the Context of Recent National Academies Recommendations.

BACKGROUND: In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations. OBJECTIVES: We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods. DISCUSSION: Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.

Real-World Time on Treatment with First-Line Pembrolizumab Monotherapy for Advanced NSCLC with PD-L1 Expression ≥ 50%: 3-Year Follow-Up Data.

Our aim was to evaluate real-world time on treatment (rwToT), overall and by KRAS mutation status, with first-line pembrolizumab monotherapy for advanced non-small cell lung cancer (NSCLC) in real-world oncology practice in the US. rwToT is a readily available, intermediate-range endpoint that is moderately to highly correlated with overall survival in clinical trials and real-world data. Using deidentified electronic medical record data, we studied patients with ECOG performance status (PS) of 0-2 who initiated pembrolizumab (1 November 2016 to 31 March 2020) for advanced NSCLC with programmed death-ligand 1 (PD-L1) expression ≥ 50% and without EGFR/ALK/ROS1 genomic alterations. The data cutoff was 31 March 2021, and the median study follow-up was 34 months. The Kaplan-Meier median rwToT with first-line pembrolizumab monotherapy was 7.4 months (95% CI, 6.3-8.1) for 807 patients with PS 0-1, which was consistent with the median treatment duration in the KEYNOTE-024 trial (7.9 months). The median rwToT for 237 patients with PS 2 was 2.1 months (95% CI, 1.4-2.8). For those with KRAS-mutated and KRAS wild-type nonsquamous NSCLC and PS 0-1, the median rwToT was 7.6 months and 7.0 months, respectively. Our findings suggest long-term benefit of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 expression ≥ 50% in real-world settings in the US, particularly for patients with good performance status at the start of therapy, irrespective of KRAS status.

Indirect comparison of pembrolizumab monotherapy versus nivolumab + ipilimumab in first-line metastatic lung cancer.

Aim: This study indirectly compared the effectiveness of pembrolizumab monotherapy versus nivolumab + ipilimumab in metastatic non-small-cell lung cancer. Materials and methods: A matching-adjusted indirect comparison was conducted using pooled individual patient data from KEYNOTE-024 and KEYNOTE-042 and published aggregate data from CheckMate 227 Part 1A, with platinum doublet chemotherapy as the anchor. Results: After matching, estimated hazard ratios (95% CI) of pembrolizumab monotherapy versus nivolumab + ipilimumab for overall survival and progression-free survival were 1.07 (0.82, 1.39) and 1.16 (0.93, 1.45), respectively. For objective response rate, the estimated risk ratio (95% CI) was 0.93 (0.71, 1.22) and the risk difference (95% CI) was -2.86%(-11.38, 5.67). Conclusion: Matching-adjusted indirect comparison results demonstrated comparable effectiveness between pembrolizumab monotherapy and nivolumab + ipilimumab as first-line therapies for metastatic non-small-cell lung cancer with PD-L1 tumor-proportion score ≥1%.

A ketamine package for use in emergency cesarean delivery when no anesthetist is available: An analysis of 401 consecutive operations.

OBJECTIVE: To evaluate the safety and effectiveness of a ketamine-based anesthesia package to support emergency cesarean section when no anesthetist is available. METHODS: A prospective case-series was conducted between December 11, 2013 and September 30, 2021 across nine sub-county hospitals in Kenya. Non-anesthetist healthcare providers undertook an evidence-based five-day training course. A structured instrument was used to collect preoperative, intraoperative, and postoperative data, and patients were contacted 6 months following the surgery to collect outcomes. The primary outcome measures were maternal and newborn survival and the ability of the ketamine package (ESM-Ketamine) to safely support cesarean deliveries. RESULTS: A total of 401 emergency cesarean sections were performed using ketamine, administered by 54 non-anesthetist providers. All mothers survived to discharge. Brief oxygen desaturations were recorded among 33 (8.2%) mothers, and agitation and hallucinations occurred among 13 (3.2%). There were no maternal serious adverse events. At 6-month follow-up, 94.2% of mothers who could be reached reported no complaints. Additionally, 402 (92.4%) of the 435 operative births survived to discharge. CONCLUSION: The ESM-Ketamine package can be used by trained non-anesthetist providers to support emergency cesarean sections when no anesthetist is available. Ketamine has significant potential to increase access to emergency cesarean deliveries in resource-limited settings.

A comparison of host response strategies to distinguish bacterial and viral infection.

OBJECTIVES: Compare three host response strategies to distinguish bacterial and viral etiologies of acute respiratory illness (ARI). METHODS: In this observational cohort study, procalcitonin, a 3-protein panel (CRP, IP-10, TRAIL), and a host gene expression mRNA panel were measured in 286 subjects with ARI from four emergency departments. Multinomial logistic regression and leave-one-out cross validation were used to evaluate the protein and mRNA tests. RESULTS: The mRNA panel performed better than alternative strategies to identify bacterial infection: AUC 0.93 vs. 0.83 for the protein panel and 0.84 for procalcitonin (P<0.02 for each comparison). This corresponded to a sensitivity and specificity of 92% and 83% for the mRNA panel, 81% and 73% for the protein panel, and 68% and 87% for procalcitonin, respectively. A model utilizing all three strategies was the same as mRNA alone. For the diagnosis of viral infection, the AUC was 0.93 for mRNA and 0.84 for the protein panel (p<0.05). This corresponded to a sensitivity and specificity of 89% and 82% for the mRNA panel, and 85% and 62% for the protein panel, respectively. CONCLUSIONS: A gene expression signature was the most accurate host response strategy for classifying subjects with bacterial, viral, or non-infectious ARI.

The Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood.

Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.

Assessment of the Feasibility of Using Noninvasive Wearable Biometric Monitoring Sensors to Detect Influenza and the Common Cold Before Symptom Onset.

Importance: Currently, there are no presymptomatic screening methods to identify individuals infected with a respiratory virus to prevent disease spread and to predict their trajectory for resource allocation. Objective: To evaluate the feasibility of using noninvasive, wrist-worn wearable biometric monitoring sensors to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus. Design, Setting, and Participants: The cohort H1N1 viral challenge study was conducted during 2018; data were collected from September 11, 2017, to May 4, 2018. The cohort rhinovirus challenge study was conducted during 2015; data were collected from September 14 to 21, 2015. A total of 39 adult participants were recruited for the H1N1 challenge study, and 24 adult participants were recruited for the rhinovirus challenge study. Exclusion criteria for both challenges included chronic respiratory illness and high levels of serum antibodies. Participants in the H1N1 challenge study were isolated in a clinic for a minimum of 8 days after inoculation. The rhinovirus challenge took place on a college campus, and participants were not isolated. Exposures: Participants in the H1N1 challenge study were inoculated via intranasal drops of diluted influenza A/California/03/09 (H1N1) virus with a mean count of 106 using the median tissue culture infectious dose (TCID50) assay. Participants in the rhinovirus challenge study were inoculated via intranasal drops of diluted human rhinovirus strain type 16 with a count of 100 using the TCID50 assay. Main Outcomes and Measures: The primary outcome measures included cross-validated performance metrics of random forest models to screen for presymptomatic infection and predict infection severity, including accuracy, precision, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC). Results: A total of 31 participants with H1N1 (24 men [77.4%]; mean [SD] age, 34.7 [12.3] years) and 18 participants with rhinovirus (11 men [61.1%]; mean [SD] age, 21.7 [3.1] years) were included in the analysis after data preprocessing. Separate H1N1 and rhinovirus detection models, using only data on wearble devices as input, were able to distinguish between infection and noninfection with accuracies of up to 92% for H1N1 (90% precision, 90% sensitivity, 93% specificity, and 90% F1 score, 0.85 [95% CI, 0.70-1.00] AUC) and 88% for rhinovirus (100% precision, 78% sensitivity, 100% specificity, 88% F1 score, and 0.96 [95% CI, 0.85-1.00] AUC). The infection severity prediction model was able to distinguish between mild and moderate infection 24 hours prior to symptom onset with an accuracy of 90% for H1N1 (88% precision, 88% sensitivity, 92% specificity, 88% F1 score, and 0.88 [95% CI, 0.72-1.00] AUC) and 89% for rhinovirus (100% precision, 75% sensitivity, 100% specificity, 86% F1 score, and 0.95 [95% CI, 0.79-1.00] AUC). Conclusions and Relevance: This cohort study suggests that the use of a noninvasive, wrist-worn wearable device to predict an individual's response to viral exposure prior to symptoms is feasible. Harnessing this technology would support early interventions to limit presymptomatic spread of viral respiratory infections, which is timely in the era of COVID-19.

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab.

PURPOSE: To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non-small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy. METHODS: Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment. RESULTS: At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. CONCLUSION: Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis.