Biomarker Testing Rates in Patients with Advanced Non-Small Cell Lung Cancer Treated in the Community

Introduction: Over the past few years, molecular targeted therapies have been emerging for the treatment of metastatic non-small cell lung cancer (NSCLC). Targeted therapy is associated with improved outcomes in patients with identified gene alterations, and national guidelines recommend routine biomarker testing. This study evaluated real-world rates of documented epidermal growth factor receptor (EGFR) mutation and other biomarker testing in patients with advanced NSCLC over time. Methods: Adult patients with Stage IV NSCLC were identified between January 1, 2012 and May 31, 2017 from the US Oncology Network iKnowMed TM electronic health records. Patients were examined overall and by histology. Rates of documented EGFR mutation and other biomarker testing were calculated. Multivariable regression analyses were conducted to identify characteristics associated with documented biomarker testing. Results: A total of 14,461 patients were identified: median age was 69.3 years, 52.3% were male, 14.6% were nonsmokers, and 64.7% had non-squamous histology. EGFR mutation testing rates were 35.5% overall, with an increase in rates seen over time: 30.0% in 2012 to 44.0% in 2016 (p < 0.001). Anaplastic lymphoma for biomarkers in NSCLC.


Introduction
Lung cancer is the leading cause of cancer-related deaths in the USA. It is estimated that there will be 228,150 new cases and 142,670 deaths due to lung cancer in 2019 [1]. Approximately 85% of lung cancers are non-small cell lung cancers (NSCLC), and non-squamous histologies are the most common. The most common non-squamous histologies are adenocarcinoma (approximately 40%) and large cell (approximately 10% -15%) [2]. Over the past few years, molecular targeted therapies have been emerging for the treatment of metastatic NSCLC with identified gene alterations. Actionable targets that can impact treatment selection include epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, c-ros oncogene 1 (ROS1) rearrangements, B-Raf proto-oncogene (BRAF) mutations, programmed death-ligand 1 (PD-L1) expression, and neurotrophic tyrosine kinase (NTRK) gene fusions [3] [4]. The use of targeted therapy is associated with improved outcomes in patients with advanced disease with identified gene alterations, and national guidelines recommend routine biomarker testing in patients with NSCLC so that those with gene alterations can receive treatment with effective targeted therapies [3] [4].
EGFR mutations are observed in approximately 40% and 20% of patients with NSCLC in Asian and non-Asian populations, respectively [5]. Mutations in exons 18 -21 confer sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) such as afatinib, erlotinib, and gefitinib. In patients with known EGFR mutations, frontline treatment with EGFR-TKIs is recommended. However, in approximately 50% of patients with EGFR mutation-positive NSCLC, a secondary mutation, EGFR T790M, develops, conferring resistance to first-and second-generation EGFR-TKI treatments [6]- [11]. Osimertinib, a third-generation, irreversible, oral EGFR-TKI, potently and selectively inhibits both EGFR sensitizing mutations and EGFR T790M, and has demonstrated efficacy in NSCLC central nervous system metastases [12]- [17]. Thus, continued biomarker testing in EGFR mutation-positive patients after progression on an EGFR-TKI may help identify patients who can continue to benefit from additional targeted therapies.
The primary objective of this study was to examine the rate of documented biomarker testing, including EGFR, EGFR T790M, ALK, ROS1, PD-L1, and BRAF, for patients with advanced NSCLC being treated in a US community oncology setting during the study. The secondary objective was to examine patient, disease, and provider factors associated with documented biomarker testing in patients with NSCLC in a real-world setting.

Study Design and Data Sources
This was a retrospective observational study among patients who received care within a US Oncology Network clinic between January 1, 2012 and May 31, 2017. The US Oncology Network is affiliated with approximately 1400 physicians in more than 60 community oncology practices in over 450 sites of care across 25 states in the US. Patients were identified from practices using the iK-nowMed (iKM) electronic health record (EHR) system. iKM is an oncology-specific EHR system that captures outpatient practice encounter history. Within the EHR, many data elements, including specific tumor biomarkers (EGFR, ALK, ROS1, PD-L1, and BRAF), are documented within structured data fields. Demographic and disease characteristic data including age, sex, race, smoking history, Eastern Cooperative Oncology Group performance status, histology, tumor biomarker status, and year of diagnosis were collected via programmatic queries of the iKM database. Eligible patients were at least 18 years of age at diagnosis of NSCLC, with Stage IV disease, and with at least two visits during the study period (January 2012 to May 2017). Patients enrolled in clinical trials at any time during the study period, and patients with other documented primary cancer diagnoses during the study period were excluded. The index date was defined as the date of Stage IV NSCLC diagnosis. The US Oncology Institutional Review Board approval was obtained for the study.

Statistical Analysis
Standard descriptive statistics were used for continuous and categorical study variables. Characteristics were calculated and compared using standard significance testing, such as chi-squared/Fisher's exact test (for categorical variables), and t-test/Mann-Whitney U test/ANOVA/Kruskal-Wallis test (for the continuous variables). Patients were examined overall and by histology. Rates of documented biomarker testing were calculated, overall and by year. All patients who met the eligibility criteria and had results from documented biomarker testing were included. The actual testing date for each patient was also collected. Multivariable stepwise logistic regression analysis was conducted to identify characteristics associated with documented biomarker testing. The stepwise model building process used a type 3 p-value for entry of 0.20 and type 3 p-value for retention of 0.10. Odds ratios and 95% confidence intervals (CIs) were reported. For any significance testing, an alpha of 0.05 was used unless otherwise stated or requested. The analyses were conducted using SAS® (SAS Institute Inc., Version 9.4, Cary, NC, US).

Patient Characteristics
There were 14,461 patients with advanced NSCLC meeting eligibility during the 5-year study period. Table 1 describes the demographic and clinical characteristics

Testing Patterns
Less than half of patients overall and in all histology groups had documentation of EGFR testing ( Table 2). The lowest proportion of patients tested for a EGFR  (Figure 1(a), Figure 1

Predictors of Testing
In a multivariate logistic regression analysis, several parameters were strongly associated with higher documented EGFR mutation testing rates (  Unlike EGFR mutation testing rates, gender had no significant association with documented ALK mutation testing rates.
Testing rates for other biomarkers were low, therefore a predictive modelling was not performed.

Discussion
Although clinical practice guidelines recommend biomarker testing in all NSCLC patients, little is known about actual testing rates in the real-world setting, particularly in community settings. In our study, testing rates for EGFR mutations specifically were 35% overall, with an increase observed over time from 30% in 2012 to 41% in 2016. The testing rate for ALK rearrangements was 33% overall.
It was not unreasonable that testing rates for the other actionable biomarkers in our study were low, given the timeframe of this study in relation to the ap-   [19]. Therefore, other methods such as using circulating free tumorderived DNA from plasma have been tested. Additionally, the use of large-scale sequencing strategies, such as next-generation sequencing, allows for the detection of multiple molecular targets simultaneously. Targeted educational interventions are needed regarding how and when biomarker testing should be performed to optimize and support personalized treatment for NSCLC. We observed that non-squamous histology, larger practice size, and nonsmoking status were strongly associated with higher documented EGFR mutation testing rates in our study. This mutation is often found in nonsmoking women from East Asian decent with non-squamous histology [2]. Increased knowledge and education regarding patient and clinical characteristics associated with specific gene alterations may also improve testing rates.
One study reported an increase in EGFR testing after implementation of reflex testing, defined as a request for EGFR testing by the pathologist at the time of non-squamous NSCLC diagnosis [20]. ALK status was tested in 18% of patients in the international PIvOTAL observational study (n = 1440) [21] and in 17% of patients in a retrospective Japanese study (n = 175) [22]. The other biomarkers tested in this study have more recently been added to the advanced NSCLC guidelines so there are few studies analyzing testing rates to compare with our data. The recommended timing for when to conduct biomarker testing in NSCLC has also evolved over the years. At the time that this study was performed, biomarker testing was recommended for all patients with Stage IV NSCLC. Improved understanding and better dissemination of updates to guideline recommendations for testing timing and methods may also improve testing rates overall.
Limitations of this study include the retrospective observational nature of the study with data extracted from a database, and the potential for under-reported testing. Availability of biomarker testing required that results were directly entered into the specific structured EHR fields. Results available through scanned documents or progress notes may not have been entered into the specific fields in the EHR, and therefore reasons for not testing could not be investigated. The low rate of EGFR mutation testing (35%) was likely a consequence of this structured data extraction methodology, as well as a general lack of documentation.
Also, biomarker testing rates were captured when some therapies were not approved, thereby impacting what biomarkers were actionable for documentation as structured data in the EHR. Furthermore, at the time of the study, osimertinib was not approved as first-line treatment for EGFR mutated NSCLC patients which may have an impact on translating these data to current practice. Strengths of this study include the large sample size of over 14,000 advanced NSCLC patients evaluated in community oncology practices across the US, reflecting real-world community practice and testing patterns.

Conclusion
Between 2012 and 2016, EGFR mutation testing rates steadily increased over time in patients with Stage IV NSCLC but remained less than 50%. Testing rates for ALK, ROS1, PD-L1, and BRAF were lower, ranging from <1% to 33%. Our data, therefore, suggest that opportunities exist to improve biomarker testing