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.

Principal investigators over-optimistically forecast scientific and operational outcomes for clinical trials.

OBJECTIVE: To assess the accuracy of principal investigators' (PIs) predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful recruitment and timely trial completion. STUDY DESIGN AND SETTING: A short, electronic survey was used to elicit subjective probabilities within seven months of trial registration. When trial results became available, prediction skill was calculated using Brier scores (BS) and compared against uninformative prediction (i.e. predicting 50% all of the time). RESULTS: 740 PIs returned surveys (16.7% response rate). Predictions on all three events tended to exceed observed event frequency. Averaged PI skill did not surpass uninformative predictions (e.g., BS = 0.25) for primary outcomes (BS = 0.25, 95% CI 0.20, 0.30) and were significantly worse for recruitment and timeline predictions (BS 0.38, 95% CI 0.33, 0.42; BS = 0.52, 95% CI 0.50, 0.55, respectively). PIs showed poor calibration for primary outcome, recruitment, and timelines (calibration index = 0.064, 0.150 and 0.406, respectively), modest discrimination in primary outcome predictions (AUC = 0.76, 95% CI 0.65, 0.85) but minimal discrimination in the other two outcomes (AUC = 0.64, 95% CI 0.57, 0.70; and 0.55, 95% CI 0.47, 0.62, respectively). CONCLUSION: PIs showed overconfidence in favorable outcomes and exhibited limited skill in predicting scientific or operational outcomes for their own trials. They nevertheless showed modest ability to discriminate between positive and non-positive trial outcomes. Low survey response rates may limit generalizability.

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.

Impact of Precision Medicine on Efficiencies of Novel Drug Development in Cancer.

Precision medicine (PM) offers opportunities for reducing the costs, burdens, and time associated with drug development. We examined time, number of trials, indications tested, and patient burden needed to achieve first U.S. Food and Drug Administration license for all five novel anticancer PM drugs and all 10 novel non-PM drugs receiving U.S. Food and Drug Administration approval during 2010-2014. The 15 drug portfolios encompassed 242 trials: 87 for PM drugs and 155 for non-PM drugs. Embase and MEDLINE databases were searched for all prelicensure clinical trials, and data on time, patient numbers, indications tested, and total treatment-emergent grade 3-5 adverse events were measured from the first trial of each drug. We did not find patterns suggesting greater efficiencies in PM compared with non-PM. Gains in efficiency for PM drug development may be offset by challenges with recruitment.