Impact of Performance Status on Survival Outcomes and Health Care Utilization in Patients With Advanced NSCLC Treated With Immune Checkpoint Inhibitors.

Introduction: Landmark trials testing immune checkpoint inhibitors (ICIs) in advanced NSCLC are difficult to extrapolate to real-world practice given the exclusion of patients with poor (i.e., ≥2) Eastern Cooperative Oncology Group performance status (ECOG PS). We sought to evaluate the impact of ECOG PS on clinical outcomes and health care utilization in patients with NSCLC treated with ICIs in real-world practice. Methods: Patients with advanced NSCLC who received at least one dose of pembrolizumab or nivolumab were retrospectively identified from the Alberta Immunotherapy Database. The primary outcome was median overall survival, as stratified by ECOG PS. Secondary outcomes included median time-to-treatment failure and metrics of health care utilization, including emergency department visits, hospitalizations, and death in hospital. Results: A total of 790 patients were included, with 29.2% having poor ECOG PS at initiation of ICI. These patients had significantly lower median overall survival (3.3 versus 13.4 mo) and median time-to-treatment failure (1.4 versus 4.9 mo) compared with those with favorable ECOG PS (p < 0.0001 for both outcomes). Patients with poor ECOG PS were also more likely to present to the emergency department, be admitted to the hospital, and die in the hospital during their first admission (risk ratio = 1.6, 2.3-2.7, p < 0.001). Conclusions: Patients with NSCLC with poor ECOG PS treated with ICI had significantly worse survival outcomes and were significantly more likely to use health care services than those with favorable ECOG PS. The large proportion of patients with poor ECOG PS further justifies the urgent need for randomized trials evaluating the efficacy of ICI in this high-risk population.

Lung Immune Therapy Evaluation (LITE) Risk, a Novel Prognostic Model for Patients With Advanced Non-Small Cell Lung Cancer Treated With Immune Checkpoint Blockade.

INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized non-small cell lung cancer (NSCLC). We aimed to identify baseline characteristics, that are prognostic factors for overall survival (OS) in patients with NSCLC treated with ICI monotherapy, in order to derive the Lung Immune Therapy Evaluation (LITE) risk, a prognostic model. MATERIALS AND METHODS: Multi-center observational cohort study of patients with advanced NSCLC that received ≥1 dose of ICI monotherapy. The training set (n=342) consisted of patients with NSCLC who received first line ICI. The test set (n=153) used for external validation was a discrete cohort of patients who received second line ICI. 20 candidate prognostic factors were examined. Penalized Cox regression was used for variable selection. Multiple imputation was used to address missingness. RESULTS: Three baseline characteristics populated the final model: ECOG (0, 1 or ≥2), lactate dehydrogenase>upper limit of normal, and derived neutrophil to lymphocyte ratio ≥3. Patients were parsed into 3 risk groups; favorable (n=146, risk score 0-1), intermediate (n=101, risk score 2) and poor (n=95, risk score ≥3). The c-statistic of the training cohort was 0.702 and 0.694 after bootstrapping. The test cohort c-statistic was 0.664. The median OS for favorable, intermediate and poor LITE risk were; 28.3 months, 9.1 months and 2.1 months respectively. Improving LITE risk group was associated with improved OS, intermediate vs favorable HR 2.08 (95%CI 1.46-2.97, P < .001); poor vs favorable HR 5.21 (95%CI 3.69-7.34, P < .001). CONCLUSION: A simple prognostic model, utilizing accessible clinical data, can discriminate survival outcomes in patients with advanced NSCLC.

Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection.

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified. Using confocal intravital microscopy in a mouse model of IAV infection, we observed profound neutrophil recruitment, platelet aggregation, neutrophil extracellular trap (NET) production and thrombin activation within the lung microvasculature in vivo. Importantly, deficiency or antagonism of the protease-activated receptor 4 (PAR4) reduced platelet aggregation, NET production, and neutrophil recruitment. Critically, inhibition of thrombin or PAR4 protected mice from virus-induced lung tissue damage and edema. Together, these data imply thrombin-stimulated platelets play a critical role in the activation/recruitment of neutrophils, NET release and directly contribute to IAV pathogenesis in the lung.

Effectiveness and Safety of First-Line Pembrolizumab in Older Adults with PD-L1 Positive Non-Small Cell Lung Cancer: A Retrospective Cohort Study of the Alberta Immunotherapy Database.

The emergence of immunotherapy revolutionized the treatment of non-small-cell-lung cancer (NSCLC), with multiple landmark clinical trials establishing the efficacy of these agents. However, many patients who receive immunotherapy in clinical practice would be considered clinical trial ineligible. One such population that is often under-represented in clinical trials is older adults. In the current study, we evaluated clinical and safety outcomes in this population. Overall, older adults (>70 years of age) and younger adults had comparable clinical outcomes with an equivalent objective response rate (ORR), time to treatment failure (TTF), and median overall survival (p = 0.67, p = 0.98, and p = 0.91, respectively). Furthermore, the safety outcomes were equivalent between the cohorts with similar rates of immune-related adverse events (irAEs), irAE-related hospitalizations, and all-cause hospitalization (p = 0.99, p = 0.63, and p = 0.74, respectively). While older age was not found to impact overall survival, multivariant analysis revealed that a poor Eastern Cooperative Oncology Group (ECOG) status, low body-mass-index (BMI), and poor/intermediate lung immune prognostic index (LIPI) were all associated with worse survival. In conclusion, age does not impact the efficacy or safety of pembrolizumab in NSCLC, and therefore advanced age should not be a deterrent for treating these patients with pembrolizumab. Physicians and care providers can thus focus on other factors that may influence therapeutic outcomes.

Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

BACKGROUND: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy. PATIENTS AND METHODS: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT). RESULTS: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively.. CONCLUSIONS: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.

Acetylsalicylic acid inhibits intravascular coagulation during Staphylococcus aureus-induced sepsis in mice.

Antiplatelet therapies have been proposed for the treatment of sepsis, a syndrome resulting from a dysregulated immune response and inappropriate activation of coagulation. Acetylsalicylic acid (ASA) may serve as a potential therapeutic strategy to prevent infection-induced coagulopathy and associated tissue damage. Using intravital microscopy, we found that Staphylococcus aureus infection induced neutrophil recruitment, platelet aggregation, and neutrophil extracellular trap (NET) release in the liver. Mice pretreated with ASA, or animals receiving ASA 3 hours postinfection, had significantly reduced platelet aggregation and NET release. Additionally, ASA-treated mice had reduced intravascular thrombin activity and microvascular occlusion as compared with untreated S aureus-infected mice. This inhibition of coagulation was accompanied by decreased levels of alanine aminotransferase and aspartate aminotransferase in the plasma, indicating less liver damage. Finally, bacterial loads (colony-forming units per milliliter) in liver, lung, and spleen were not different between groups, and the phagocytic capacity of Kupffer cells was preserved following ASA treatment. These results suggest that ASA may serve as a therapeutic approach to sepsis through its ability to reduce the deleterious action of immunothrombi while maintaining innate immune functions.