Faculty Bibliography

BACKGROUND:The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups. METHODS:In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use. RESULTS:Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression <1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006). CONCLUSIONS:This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.

BACKGROUND:Tobacco exposure contributes to over 80 % of lung cancer cases. Smoking is associated with programmed death-ligand 1 (PD-L1) tumor expression and better outcomes from anti-programmed cell death protein 1 (anti-PD-1) therapy in patients with advanced non-small cell lung cancer (NSCLC). PD-L1 tumor expression is now routinely used to predict benefit from anti-PD-1 therapy in patients with advanced NSCLC. In this study, we explored the impact of smoking status on patient outcomes with anti-PD-1 therapy in addition to PD-L1 tumor expression. METHODS:A prospective real-world cohort of 268 patients with advanced NSCLC treated with anti-PD-1 monotherapy at the Princess Margaret Cancer Centre (PMCC) was used for this analysis. Logistic regression was performed to test factors associated with treatment response (RECIST v1.1), including PD-L1 tumour proportion score (TPS) and smoking status. RESULTS:Overall response rates (ORR) to immunotherapy were significantly higher in current and former smokers than never smokers (36 % vs 26 % vs 14 %; p = 0.02). In patients with PD-L1 tumour proportion score (TPS) ≥50 %, current smokers continued to experience better ORR to anti-PD-1 therapy than never smokers (58 % vs 19 %; p = 0.03). Current smoking was associated with higher response even after adjusting for level of PD-L1 TPS expression (adjusted odds ratio 5.9, 95 % CI 1.6-25.0, p = 0.03). Exploratory analysis demonstrated higher 1-year survival rates in smokers compared to never smokers (p = 0.003). CONCLUSIONS:Smoking remains an important factor associated with response to anti-PD-1 monotherapy. Advanced NSCLC patients with positive PD-L1 expression are more likely to respond to anti-PD-1 monotherapy if they are current smokers compared to never smokers.

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.

INTRODUCTION:Financial distress has been established as a clinically relevant patient-reported outcome associated with worse mortality and quality of life. Our goal was to define factors associated with financial burden (FB) in a public health care system. MATERIALS AND METHODS:Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FB was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-item survey scored from 0 to 44, with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP), and private insurance coverage were collected. Multivariable logistic regression models were fit for COST score and each variable, to determine factors associated with greater FB (COST < 21). RESULTS:Of 251 patients approached, 200 (80%) participated. The median age of the cohort was 65 years; 56% were female. The median total OOP ranged between $1000 and $5000 CAD. The median COST score was 21 (range, 0-44). FB was associated with age, with patients < 65 years reporting greater FB than older patients (COST, 18.0 vs. 24.0; P < .0001). In multivariable logistic regression analysis, younger age was associated with greater FB, when adjusting for income, employment status, OOP, and private insurance coverage (odds ratio, 3.6; 95% confidence interval, 1.5-9.1; P < .0001). CONCLUSION:Age is significantly associated with FB in the Canadian (Ontario) public health care system, with younger patients with lung cancer reporting greater financial distress. This study highlights priority patient populations where FB should be routinely assessed and appropriate resources for support offered.

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.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent a heterogeneous group of tumors that is associated with an indolent course. Octreotide has a positive effect on disease stabilization in well-differentiated midgut NETs, but a meaningful survival analysis was not possible due to insufficient events. Higher doses of octreotide long-acting release (LAR) are often used in clinical practice for control of carcinoid symptoms and our objective was to determine if dose of octreotide correlates with survival. We reviewed all patients with advanced GEP NETs who initiated treatment with octreotide LAR between 2000 and 2013 in a large, representative Canadian province. We compared overall survival in patients who received low (< 30 mg) compared to high (≥ 30 mg) doses of octreotide. A total of 170 patients were identified. Baseline characteristics in the low- and high-dose groups were similar: median age 62/63 years, 50/58% were male, 46/48% originated from the small bowel, and 74/66% had liver metastases at diagnosis. The median time from diagnosis to treatment initiation was 5.5 and 6.0 months. Octreotide LAR was initiated with the intent of symptom management (71%), disease stabilization (23%), or biomarker control (6%). Median overall survival (OS) was better in the high-dose group, 66 months compared to 22 months (multivariate HR 0.5, p < 0.01). Age ≥ 65 (HR 1.9, p < 0.01), ECOG ≥ 2 (HR 2.7, p < 0.01), and pancreatic NETs (HR 1.7, p = 0.03) were all predictors of worse survival. Our findings suggest that octreotide may confer survival benefits in GEP NETs. Further prospective studies are warranted to validate the impact of high-dose octreotide on outcomes.