Recent treatment patterns and real-world survival following first-line anti-PD-L1 treatment for extensive-stage small cell lung cancer.

BACKGROUND: The landscape of small cell lung cancer (SCLC) has changed since the 2019 and 2020 approvals of anti-PD-L1 atezolizumab and durvalumab for first-line (1L) treatment in combination with chemotherapy. We studied treatment patterns and real-world overall survival (rwOS) following 1L-3L therapy. PATIENTS AND METHODS: A nationwide electronic health record (EHR)-derived de-identified database was used to describe treatment patterns, characteristics, and survival of patients with extensive-stage (ES)-SCLC by 1L anti-PD-L1 treatment. Patients with ES-SCLC who initiated ≥1 line of systemic therapy from 2013 to 2021, with potential follow-up through 2022, were included. RESULTS: Among 9952 patients with SCLC, there were 4308 patients with ES-SCLC treated during the study period who met eligibility criteria. Etoposide + platinum (EP) chemotherapy was most common in the 1L, with addition of anti-PD-L1 therapy to most regimens by 2019. Second-line regimens varied by platinum sensitivity status and shifted from topotecan to lurbinectedin over time. Median rwOS following 1L therapy was 8.3 months (95% CI, 7.9-8.8) in those treated with 1L anti-PD-L1 and 8.0 months (95% CI, 7.8-8.2) in those who were not. Following 2L and 3L, median rwOS was 5.6 (95% CI, 4.9-6.3) and 4.9 months (95% CI, 3.4-6.0), respectively, among 1L anti-PD-L1-treated, and 4.5 (95% CI, 4.2-4.9) and 4.0 months (95% CI, 3.7-4.5), respectively, among those who were not. CONCLUSION: Despite the introduction of frontline anti-PD-L1 therapy, survival remains dismal among patients with ES-SCLC treated in the real-world setting.

Correction: Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. This has now been corrected in both the PDF and HTML versions of the Article.

Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

BACKGROUND: Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells. METHODS: We analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability. RESULTS: IC50 values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC50 for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death. CONCLUSIONS: Patients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.

Development of an algorithm to identify small cell lung cancer patients in claims databases.

Introduction: The treatment landscape of small cell lung cancer (SCLC) is evolving. Evidence generated from administrative claims is needed to characterize real-world SCLC patients. However, the current ICD-10 coding system cannot distinguish SCLC from non-small cell lung cancer (NSCLC). We developed and estimated the accuracy of an algorithm to identify SCLC in claims-only databases. Methods: We performed a cross-sectional study of lung cancer patients diagnosed from 2016-2017 using the Surveillance, Epidemiology and End Results (SEER), linked with Medicare database. The analysis included two phases - data exploration (utilizing a 25% random sample) and data validation (remaining 75% sample). The SEER definition of SCLC and NSCLC were used as the gold standard. Claims-based algorithms were identified and evaluated for their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: The eligible cohort included 31,912 lung cancer patients. The mean age was 76.3 years, 44.6% were male, with 9.4% having SCLC and 90.6% identified as NSCLC using SEER. The exploration analysis identified potential algorithms based on treatment data. In the validation analysis of 7,438 lung cancer patients who received systemic treatment in the outpatient setting, an etoposide-based algorithm (etoposide use in 180 days following lung cancer diagnosis) to identify SCLC showed: sensitivity 95%, specificity 95%, PPV 82% and NPV 99%. Discussion: An etoposide treatment-based algorithm showed good accuracy in identifying SCLC patients. Such algorithms can facilitate analyses of treatment patterns, outcomes, healthcare resource and costs among treated SCLC patients, thereby bolstering the evidence-base for best patient care.

Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Symptoms and Experiences with Small Cell Lung Cancer: A Mixed Methods Study of Patients and Caregivers.

INTRODUCTION: Understanding of the patient-perceived symptom burden of small cell lung cancer (SCLC) is limited. The objective of this study was to explore patients' experiences with SCLC, identify which treatment-/disease-related symptoms have the greatest impact on their well-being, and gain caregiver perspectives. METHODS: A noninterventional, cross-sectional, multimodal, mixed methods study was conducted from April-June 2021. Adult patients with SCLC and unpaid caregivers were eligible to participate. Patients' experiences, captured via 5-day video diaries and follow-up interviews, were scored 1-10 on how bothersome the patients perceived each symptom/symptomatic adverse event. Patients indicated if they believed a symptom was disease or treatment related. Caregivers participated in an online community board. RESULTS: The study included nine patients (five with extensive-stage [ES] disease, four with limited-stage [LS] disease) and nine caregivers. Except for one patient/caregiver pairing, patients and caregivers were unmatched. The most common impactful symptoms in patients with ES-SCLC were shortness of breath, fatigue, coughing, chest pain, and nausea/vomiting; in LS-SCLC, these were fatigue and shortness of breath. Among patients with ES disease, SCLC had a high impact on physical (leisure/hobbies, work, sleep, ability to do household chores and errands/responsibilities outside home), social (family dynamics, extrafamilial social interaction), and emotional (mental health) aspects. Patients with LS-SCLC faced the long-term physical effects of treatment, financial implications, and emotional toll of an uncertain prognosis. SCLC had a high personal and psychologic burden among caregivers, whose duties consumed much of their time. Caregivers observed similar symptoms and impacts of SCLC as those reported by patients. CONCLUSIONS: This study provides valuable insight into patient- and caregiver-perceived burden of SCLC and can inform the design of prospective studies. Clinicians should seek to understand patients' opinions and priorities before making treatment decisions.

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.

A Real-World Evaluation of Atezolizumab Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC in Canada.

INTRODUCTION: The real-world data evaluating treatment outcomes of atezolizumab plus carboplatin-etoposide chemotherapy (atezolizumab) for extensive-stage SCLC (ESCLC) are lacking. Our objective was to evaluate real-world outcomes of ESCLC treated with atezolizumab. METHODS: A retrospective analysis of provincial patients with ESCLC who started first-line (1L) systemic treatment was conducted. We primarily evaluated the progression-free survival (PFS) and overall survival (OS) outcomes in association with atezolizumab compared with platinum-etoposide chemotherapy (chemotherapy) while adjusting for relevant demographic and clinical factors. Adverse events (AEs) during 1L were evaluated. RESULTS: A total of 67 patients were identified. Of the 34 patients who received atezolizumab, 24% had Eastern Cooperative Oncology Group performance status greater than or equal to 2, approximately 50% were more than or equal to 65 years, 21% received cisplatin-etoposide chemotherapy before atezolizumab, and 12% had thoracic radiation (tRT).Within the atezolizumab versus chemotherapy group, the median PFS equals to 6.0 versus 4.3 months (p = 0.03) whereas OS = 12.8 versus 7.1 months (p = 0.01). Relative to chemotherapy, the hazard ratio (95% confidence interval) for PFS was 0.53 (0.28-1.02) and OS was 0.42 (0.20-0.88) with atezolizumab. tRT compared with no tRT receipt correlated with reduced death risk (hazard ratio [95% confidence interval] = 0.33 [0.13-0.88]).AE-related treatment withdrawal with atezolizumab was 32% and 15% with chemotherapy (p = 0.02). Within the tRT subgroup, 25% versus 20% in atezolizumab versus chemotherapy group, respectively, discontinued 1L owing to AE. CONCLUSIONS: This is the first real-world study revealing comparable survival with that in the IMpower133 trial. Treatment discontinuation from AEs was higher with atezolizumab among Canadian patients with ESCLC. Our data suggest safe use of tRT and chemoimmunotherapy, but its efficacy for ESCLC warrants further study.

CXCR4 expression in lung carcinogenesis: Evaluating gender-specific differences in survival outcomes based on CXCR4 expression in early stage non-small cell lung cancer patients.

INTRODUCTION: Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. METHODS: Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). RESULTS: 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. CONCLUSIONS: CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.