Outcome Differences Between First- and Second-generation EGFR Inhibitors in Advanced EGFR Mutated NSCLC in a Large Population-based Cohort.

INTRODUCTION: Second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) appear superior to first-generation TKIs in clinical trials, but at the cost of greater toxicity. It is unclear whether real-world patients, who often suffer worse outcomes, experience similar survival benefits. Using population-based data, we aim to characterize outcome differences by type of treatment. PATIENTS AND METHODS: We reviewed all patients with advanced non-small-cell lung cancer who initiated treatment with an EGFR TKI at BC Cancer between 2010 and 2015. A propensity score was generated to account for imbalances in patient characteristics between treatment groups. A Cox proportional hazards model based on the propensity score was then used to estimate effects of treatment on survival. RESULTS: A total of 484 patients were identified for analysis. Patients in the second-generation cohort were younger (62 vs. 67 years), had less baseline central nervous system metastases (9% vs. 22%), and more uncommon EGFR mutations (13% vs. 7%). Patients receiving a second-generation TKI had an improved overall survival (hazard ratio, 0.69; P = .05), driven by the subgroup with an EGFR exon 19 deletion. Patients with a L858R mutation did not appear to derive benefit from a second-generation TKI (hazard ratio, 0.91; P = .74). Overall, 40% of patients receiving a second-generation TKI required a dose reduction, but only 1% required discontinuation. CONCLUSIONS: Second-generation TKIs tended to be chosen over first-generation TKIs as frontline therapy in younger patients with uncommon EGFR mutations and without central nervous system metastases. The survival benefit of a second-generation TKI seen in clinical trials appeared to be generalizable to real-world patients and is a reasonable first-line therapy.

Palliative thoracic radiotherapy near the end of life in lung cancer: A population-based analysis.

OBJECTIVES: Palliative thoracic radiotherapy (RT) can improve quality of life for patients with advanced lung cancer, but treatment can be associated with acute toxicity and symptomatic relief may take several weeks. The optimal fractionation schedule is not known. Delivery of RT near the end of life (EOL) is an emerging indicator of poor quality care. The aim of this study was to determine utilization of palliative thoracic RT in the last 4 weeks of life, and factors associated with its use, in patients with incurable lung cancer in a population-based healthcare system. MATERIALS AND METHODS: All patients with lung cancer in British Columbia treated with palliative thoracic RT in 2014 and 2015 were identified. Associations between starting a course of palliative thoracic RT within 4 weeks of death and patient/treatment characteristics were assessed using univariate and multivariate logistic regression analysis. RESULTS: 1676 courses of palliative thoracic RT were delivered to 1584 lung cancer patients. Median survival was 20 weeks. 12% of palliative thoracic RT courses were delivered in the last 4 weeks of life, with short fractionation schedules and simple RT planning techniques used more frequently near EOL. Of RT courses delivered in the last 4 weeks of life 89% were courses of 1 - 5 fractions, 75% were completed as prescribed and 94% involved simple 1-2 field RT techniques. Receipt of RT in the last 4 weeks of life was associated with male gender, younger age, poor performance status, metastatic disease, small cell carcinoma histology and no prior chemotherapy. CONCLUSION: Further study and standardization of quality indicators for palliative RT utilization near EOL is required. Whilst clarification occurs, physicians should consider the prognosis of patients with incurable lung cancer and the realistic expectation of benefit from palliative thoracic RT when considering treatment indications and fractionation schedules.

Clinical outcomes after whole-genome sequencing in patients with metastatic non-small-cell lung cancer.

The Personalized Onco-Genomics (POG) program at BC Cancer integrates whole-genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examined the subgroup of patients with metastatic non-small-cell lung cancer (NSCLC) and report the prevalence of actionable targets, treatments, and outcomes. We identified patients who were enrolled in the POG program between 2012 and 2016 who had a tumor biopsy and blood samples with comprehensive DNA (80×, 40× normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer drivers and actionable targets. In NSCLC cases, we compared the progression-free survival (PFS) of "POG-informed therapies" with the PFS of the last regimen prior to POG (PFS ratio). In 29 NSCLC cases, 11 were male (38%), the median age was 60.2 yr (range: 39.4-72.6), and histologies included were adenocarcinoma (93%) and squamous cell carcinoma (7%). Potential molecular targets (i.e., cancer drivers including TP53 mutations) were identified in 26 (90%), and 21 (72%) had actionable targets. Therapies based on standard-of-care mutation analysis, such as EGFR mutations, were not considered POG-informed therapies. Thirteen received POG-informed therapies, of which three had no therapy before POG; therefore a comparator PFS could not be obtained. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). Three (30%) had a PFS ratio ≥1.3, and three (30%) had a PFS ratio ≥0.8 and <1.3. In this small cohort of NSCLC, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole-genome analysis in clinical practice.

CNS Metastases in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: Impact on Health Resource Utilization.

PURPOSE: Patients with epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) non-small-cell lung cancer commonly experience disease progression in the CNS. Here, we assess the impact of CNS disease on resource utilization and outcomes in patients who are EGFRm. METHODS: We completed a retrospective review of all advanced patients who were EGFRm, referred to BC Cancer, and treated with a first- and/or second-generation EGFR tyrosine kinase inhibitor from 2010 to 2015. Baseline characteristics, systemic treatment, and CNS management were collected. We compared health resource utilization (HRU) between patients with CNS-negative disease and those with CNS metastases from the median time of CNS metastases diagnosis to death or last follow-up (9.1 months) and at 9 months preceding death or last follow-up for the CNS-negative group. RESULTS: Four hundred ninety-nine patients were referred, of which 68% were female; 51% were of Asian ethnicity; and 57%, 37%, and 6% were exon 19, 21, or other, respectively; with a median age of 66 years. Two hundred twenty-nine (46%) of 499 patients developed CNS metastases-39% at diagnosis and 61% over the course of disease. CNS metastases were managed with surgery with or without whole-brain radiotherapy (WBRT; 13%) WBRT alone (73%), stereotactic radiosurgery with or without WBRT (5%), or no CNS-directed therapy (9%). The median time from the development of CNS metastases diagnosis to death was 9.1 months. CNS-negative patients used less HRU versus patients that were CNS-positive in the 9 months preceding death or last follow-up-in the average number of clinic visits (8.53 v 12.71, respectively; P < .001), hospitalizations (0.43 v 0.76, respectively; P < .001), CNS imaging investigations (0.52 v 2.65, respectively; P < .001), emergency room visits (0.03 v 0.14, respectively; P = .001), palliative care unit admission (8% v 10%, respectively; P = .64), and hospice admission (3% v 19%, respectively; P < .001). CONCLUSION: The incidence of CNS metastases in patients with EGFRm is high and associated with increased HRU. Prevention or delay of CNS metastases with newer systemic therapy options may translate into lower resource utilization.