Real-World Treatment Patterns and Effectiveness of Targeted and Immune Checkpoint Inhibitor-Based Systemic Therapy in BRAF Mutation-Positive NSCLC.

Introduction: BRAF mutations (present in 2%-3% of NSCLC) are a known oncogenic driver and emerging therapeutic target. There is a scarcity of real-world data describing the clinical characteristics, treatment patterns, and effectiveness of targeted BRAF-inhibiting and immune checkpoint inhibitor (ICI)-based systemic therapies, yet this is required for appropriate treatment decisions that optimize patient outcome. Methods: Demographic, clinical, treatment, and outcome data of patients with BRAF mutation-positive NSCLC diagnosed between 2018 and 2022 were identified from the Glans-Look Lung Cancer Research database and included in this analysis. Results: A total of 53 BRAF mutation-positive patients were identified (V600E, n = 35; non-V600E, n = 18). Furthermore, 46 patients (87%) were diagnosed with metastatic disease, of whom 61% were treated with systemic anticancer therapy, which significantly improved overall survival (34.1 versus 2.2 mo, p = 0.01). ICI-based regimens were found to have effectiveness in the first-line setting for both V600E and non-V600E cohorts (objective response rate: 38%-43%; real-world calculations of median progression-free survival: 10.5-10.8 mo, respectively). Dual-targeted BRAF/MEK inhibition was also found to have effectiveness in the first-line setting for V600E patients (objective response rate: 33%, real-world calculations of median progression-free survival: 15.2 mo). Conclusions: This study of real-world patients with BRAF mutations confirms the importance of effective systemic therapies. Both dual-targeted BRAF/MEK inhibition and ICI-based regimens have evidence of benefit in this population revealing that real-world populations can experience similar clinical response and outcome to clinical trial cohorts on these treatment regimens. Future studies to clarify the role of co-mutations on response to both dual-targeted BRAF/MEK inhibition and ICI-based regimens may be important to treatment selection and optimization of patient outcome.

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort.

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

Retrospective Real-World Outcomes for Patients With ALK-Rearranged Lung Cancer Receiving ALK Receptor Tyrosine Kinase Inhibitors.

INTRODUCTION: This study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada. METHODS: Demographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis. RESULTS: A total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04). CONCLUSIONS: Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.

Impact of Asian ethnicity on outcome in metastatic EGFR-mutant non-small cell lung cancer.

AIM: To determine factors associated with survival in de novo stage IV, non-small cell lung cancer (NSCLC) patients possessing epidermal growth factor receptor mutations (EGFRmut+ ) receiving tyrosine kinase inhibitors (TKI) in the first-line setting. METHODS: The Glans-Look Lung Cancer Database was used to retrospectively review stage IV EGFRmut+ NSCLC patients diagnosed 2010-2016 receiving first-line TKI. Patients with overall survival times in the upper quartile (≥34 months) were designated "long-term survivors" (LTS), the remaining deemed "average-term survivors" and characteristics between these groups were compared in univariate analysis, and multivariable models constructed to determine predictors of outcome. RESULTS: Of 170 eligible patients, median overall survival was 21 months. LTS were significantly more likely to be of Asian ethnicity, be never-smokers and not possess brain or bone metastases at diagnosis. Asian and non-Asian patients were comparable, save for an increased propensity of Asian patients to be never smokers and have normal-range BMI. Multivariable analysis revealed Asian ethnicity [hazard ratio (HR) = 0.65; P = 0.016] and never-smoking history (HR = 0.65; P = 0.034) as indicators of improved outcome, and presence of brain metastasis at diagnosis an indicator of poor outcome (HR = 2.21; P < 0.001). CONCLUSIONS: Analysis of this population-based cohort identifies never-smoking history and absence of brain metastasis along with Asian ethnicity as an independent prognosticators of favorable outcome, and reveals Asian patients to be clinicopathologically similar to non-Asian patients. These findings suggest Asian patients represent a unique subpopulation within EGFRmut+ NSCLC who may possess different biological underpinnings of NSCLC.

Factors associated with early mortality in non-small cell lung cancer patients following systemic anti-cancer therapy: A 10 year population-based study.

OBJECTIVES: To investigate how clinical, demographic and treatment-related factors in non-small cell lung cancer (NSCLC) patients impact the risk of mortality in the 30 days following receipt of systemic anti-cancer therapies (SACT), and undertake a comprehensive review of the treatment decisions and experiences of a real-world population. MATERIALS AND METHODS: We reviewed NSCLC patients receiving SACT from 2005 to 2014, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data. The 30-day post-SACT mortality rate was calculated, and regimen changes in the last 14 days of life were identified. Univariate analysis and multivariate logistic regression were used to identify demographic, tumor and treatment-related factors that correlated with mortality risk. RESULTS: 1044 patients receiving ≥ 1 cycle of SACT in 2005-2014 were identified. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt; 32 (13.7%) of which had new SACT regimens ≤ 14 days prior to death. Risk of 30-day mortality and regimen changes at the end of life increased in association with being male [OR: 1.48 (1.12-1.95), p = 0.005], advanced disease at diagnosis [OR: 1.85 (1.19-2.88), p = 0.006], palliative-intent treatment [OR: 6.75 (3.88-11.77), p < 0.001], and use of EGFR-targeting agents [OR: 4.5 (3.27-6.18) p < 0.001]. Risk of early mortality decreased for never-smokers [OR: 0.62 (0.41-0.95), p = 0.028], and those receiving SACT in more recent years (2010-2014) [OR: 0.65 (0.49-0.86), p = 0.002]. CONCLUSION: Our findings identified several factors that affected the risk of early mortality in NSCLC patients following SACT. These results from a representative population provide insights regarding the benefits and risks of SACT and can serve to inform clinical and palliative best practices.

Comparison of Clinical Characteristics and Outcomes in Relapsed Versus De Novo Metastatic Non-Small Cell Lung Cancer.

OBJECTIVES: To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed. RESULTS: A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, P<0.001). Relapsed patients demonstrated significant improvements in outcomes over time. In multivariate analysis, de novo metastatic disease continued to bode a worse prognosis (adjusted hazard ratio [HR], 1.4) as did male sex (HR, 1.2), never-smoking history (HR, 1.2), and presence of extrapulmonary metastases (HR, 1.3). Systemic therapy receipt conferred better outcome (HR, 0.4), although the impact of relapsed versus de novo disease on outcomes persisted regardless of systemic therapy receipt. CONCLUSIONS: Relapsed and de novo patients represent significantly different subpopulations within metastatic NSCLC with the latter exhibiting poorer survival. This information facilitates discussions about prognosis with patients and supports screening initiatives aimed at reducing de novo disease.