Background
Lung cancer is the leading cause of cancer-related death in the United States.1,2 Approximately 84% of all lung cancer cases are non–small cell lung cancers (NSCLCs).1,3 Most patients have advanced or metastatic NSCLC (a/mNSCLC) at diagnosis, with 5-year survival rates ranging from 8% to 37%.4 The treatment paradigm in patients with a/mNSCLC has evolved considerably over the past decade with the identification of several actionable genes and the availability of associated targeted therapies. Novel FDA-approved targeted therapies have shown superior efficacy compared with chemotherapy in several pivotal clinical trials.5–14 Genomic alterations that can be targeted with these therapies include ALK (observed in 5%–7% of patients),15 EGFR (10%–20%),15 BRAF (2%–5%),15 METex14 (3%),16 RET (1%–2%),17,18 KRAS G12C (13%),19 ROS1 (1%–3%),15 ERBB (HER2) (1%–4%),20,21 and NTRK1/2/3 (0.2%).22 In patients without actionable alterations, the standard of care includes treatment with standard platinum doublet chemotherapy with or without immune checkpoint inhibitors.23
National treatment guidelines in the United States recommend broad molecular profiling to determine the presence or absence of actionable alterations in patients with squamous or nonsquamous a/mNSCLC before initiating first-line treatment.18,24 Despite recommendations that biomarker testing be conducted to guide first-line treatment selection, many patients do not have broad molecular testing performed on their tumor tissue as reported in multiple studies.25–29 Data from the MYLUNG study reported changes in rates of molecular testing from April 2018 to March 2020 for genes including EGFR (71%→71%), BRAF (51%→59%), ROS1 (69%→67%), and ALK (71%→70%), and reported an overall increase of 33% to 45% in the use of next-generation sequencing (NGS)–based testing in patients with a/mNSCLC.28 In another study, despite a reported increase in the use of NGS-based testing from 28% (2015) to 68% (2020) in patients with a/mNSCLC in the United States, approximately 33% of patients did not receive testing for all guideline-recommended biomarkers.27
Moreover, patients who had a positive test for an actionable biomarker might not be treated in a way concordant with their test result and treatment guidelines, and a limited number of studies have investigated this in association with eventual survival outcomes. A study based on administrative claims data from 2010 to 2014 showed that 42% of patients with a/mNSCLC received molecular testing and only 9% received a matched targeted therapy; however, the number of patients who tested positive and the number of those who did not receive targeted therapy after testing positive are unclear.30 Another study using a clinicogenomic database of patients with a/mNSCLC found that only 48% with an actionable genomic alteration received a guideline-concordant therapy after diagnosis.26 This study also reported a median survival of 18.6 months from diagnosis of a/mNSCLC in patients with actionable alterations who received guideline-concordant targeted therapy, compared with 11.4 months among those who did not, regardless of line of treatment.26 However, this finding was based on an unadjusted, exploratory analysis and should be considered hypothesis-generating.
Therefore, little is known about the impact of up-front biomarker testing on long-term outcomes in this patient population. To fill this gap, this study was designed to compare overall survival (OS) among patients who did not receive biomarker testing versus those who did receive biomarker testing (for EGFR, BRAF, ROS1, and ALK) at 2 different timepoints. This study compared survival outcomes among patients whose disease tested positive for an actionable biomarker and received guideline-recommended therapy in the first-line setting versus those who did not. It was hypothesized that patients who underwent biomarker testing and those who received concordant therapy would have improved survival outcomes compared with those who did not receive biomarker testing or did not receive concordant therapy.
Patients and Methods
Research Design and Data Source
This retrospective cohort study used the nationwide de-identified Flatiron Health electronic health record–derived NSCLC database from January 2015 to June 2021. These data are comprised of de-identified patient-level structured and unstructured data curated via technology-enabled abstractions.31,32 During the study period, the de-identified data originated from approximately 280 US cancer clinics (∼800 sites of care). Patient-level information included demographics, diagnoses, dates and types of visit, laboratory tests, ordered and administered medications, performance status, stage at initial diagnosis, histology, biomarker testing and status, and month and year of death. In this database, gender information likely reflected patient’s sex at birth and was captured based on structured data in the medical records. Patients included in this database were predominantly those receiving treatments at community-based clinics ranging in size from small practices to large, multilocation practices, and several hospital-affiliated clinics.31,32
Study Population
Patients included in this study (1) had nonsquamous a/mNSCLC as the primary cancer, (2) initiated first-line systemic anticancer therapy on or after January 1, 2015, with evidence of initiation of systemic therapy within 90 days of the a/mNSCLC diagnosis, and (3) were aged ≥18 years at diagnosis. The start of first-line (1L) therapy was defined as the index date.
Study Measures
Biomarker Testing
Testing for actionable biomarkers (ie, EGFR, BRAF, ROS1, and ALK) recommended in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC (Version 3.2020)19 at the time of analysis was described in this study (supplemental eTable 1, available with this article at JNCCN.org).
Patients were categorized as those who (1) received (“ever tested”) or did not receive (“never tested”) biomarker testing for at least one of the biomarkers included in the study at any time in the database during the study period; and (2) received (“tested”) or did not receive (“not tested”) biomarker testing for at least one of the biomarkers included in the study prior to/on initiation of 1L therapy. For the latter cohort, biomarker testing occurred between diagnosis and initiation of 1L therapy.
Concordant and Discordant Treatments
The proportions of patients testing positive for a biomarker who subsequently received or did not receive targeted therapy based on the NCCN Guidelines19 were reported. Patients categorized as concordant were those who had a positive biomarker testing result prior to/on initiation of 1L treatment and received guideline-concordant 1L targeted therapy. Patients categorized as discordant were those who had positive biomarker testing results but did not receive the guideline-recommended targeted therapy in the 1L setting.
Overall Survival
OS was measured as the number of months from initiation of 1L therapy to the date of death. Patients without a death event were censored at the end of the database or last observation in the database if this occurred >90 days before the end of the database.
Statistical Analyses
Baseline characteristics used descriptive statistics and were compared using Student t test or chi-square test as appropriate. Missing data were not imputed and not included in statistical testing. Statistical significance was defined by a 2-sided alpha level of 0.05 or by using a 2-sided 95% confidence interval. OS was described by using Kaplan-Meier analysis, and log-rank tests were conducted to perform unadjusted comparison between groups. Multivariable Cox proportional hazard modeling was conducted to compare OS between groups adjusting for baseline covariates, including age, sex, race, region, body mass index, smoking status, ECOG performance status, academic or community practice, cancer stage at initial diagnosis, and year of advanced or metastatic diagnosis. OS comparisons were made between (1) patients who were ever tested versus never tested; (2) patients who were tested versus not tested prior to/on initiation of 1L therapy; and (3) patients who received concordant versus those who received discordant treatment in the 1L setting after testing positive for a biomarker prior to/on initiation of 1L therapy. All analyses were conducted using SAS 9.4 (SAS Institute Inc.).
Results
Patient Characteristics
A total of 21,572 patients with nonsquamous a/mNSCLC (supplemental eFigure 1) with a median age of 69 years (IQR, 61–76 years) and follow-up of 9.5 months (IQR, 3.5–21.5 months) were included in the analysis. Most patients were white (67%), overweight or obese (52%), had a history of smoking (83%), a documented ECOG performance status of 0 or 1 (56%), and were diagnosed with stage IV NSCLC at initial diagnosis (70%). Patients were treated predominantly in community-based oncology practices (88%) and in the southern region of the United States (41%). Overall, the median time from advanced diagnosis to initiation of 1L therapy was 1.1 months (IQR, 0.7–1.5 months; Table 1).
Patient Sociodemographic and Clinical Characteristics
A total of 69% of patients had a record of receiving testing for at least 1 biomarker prior to/on initiation of 1L treatment (Table 1). Patients who received testing were more likely to be female and older, have a history of smoking, and be initially diagnosed with stage IV disease. These patients were more likely to be diagnosed with an advanced disease in more recent years compared with those who did not receive testing prior to/on initiation of 1L therapy. Among those who received testing, 48% underwent testing for 4 biomarkers, with EGFR (94%) and ALK (89%) having the highest rates of testing. Mean [SD] number of months from advanced diagnosis to initiation of 1L treatment was longer in those who received testing compared with those who did not (1.3 [0.6] vs 0.9 [0.6]; P<.0001; Table 1).
Biomarker Testing and Concordant and Discordant Treatments
Of patients who received testing for ALK, 3% (443/13,233) tested positive, and of those, 83% (366/443) received concordant therapy in the 1L setting, whereas 17% (77/443) received discordant therapy (Table 2). Of those who received testing for BRAF, 5% (422/8,180) tested positive, and of those, 18% (78/422) received concordant therapy in the 1L setting, whereas 82% (344/422) received discordant therapy (Table 2). Of those who received testing for EGFR, 18% (2,569/14,010) tested positive, and of those, 82% (2,112/2,569) received concordant therapy, whereas 18% (457/2,569) received discordant therapy (Table 2). Lastly, of those who received testing for ROS1, 1% (112/10,640) tested positive, and of those, 77% (86/112) received concordant therapy, whereas 23% (26/112) received discordant therapy (Table 2). The proportion of discordant 1L therapy was highest in patients with BRAF-positive disease relative to the other biomarkers.
Biomarker Test Result and Concordance and Discordance of 1L Treatment
Overall Survival
A total of 88% of patients (19,041/21,572) received testing for at least 1 biomarker in the database (“ever tested”). The estimated median OS from the initiation of 1L treatment of those ever tested (14.9 months; 95% CI, 14.5–15.3 months) was significantly longer compared with those who never received biomarker testing (“never tested”) in unadjusted analyses (9.0 months; 95% CI, 8.4–10.0 months; P<.0001; Figure 1A). After adjusting for baseline covariates, the hazard of death was 30% higher in patients never tested compared with those ever tested (hazard ratio [HR], 1.30; 95% CI, 1.24–1.37; Table 3).
OS for (A) patients with ≥1 biomarker test versus never tested for biomarkers in the database, and (B) patients tested versus not tested for biomarkers prior to/on initiation of 1L treatment.
Abbreviations: 1L, first-line; OS, overall survival.
Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7039
Analysis of Hazard of Death
The estimated median OS from the initiation of 1L treatment for patients who received biomarker testing prior to/on initiation of 1L treatment (“tested”) was significantly longer in unadjusted analyses compared with those who did not receive testing (“not tested”) (15.3 months [95% CI, 14.8–15.8 months] vs 11.6 [95% CI, 11.2–12.1 months]; P<.0001; Figure 1B). The adjusted hazard of death was 12% higher in patients not tested compared with those tested prior to/on initiation of 1L treatment (HR, 1.12; 95% CI, 1.08–1.16; Table 3).
The estimated median OS from the initiation of 1L treatment of patients whose disease tested positive for a biomarker prior to/on initiation of 1L treatment and received concordant 1L therapy (27.7 months; 95% CI, 26.2–29.4 months) was significantly longer in unadjusted analyses compared with those whose disease tested positive for a biomarker but received discordant 1L therapy (19.5 months; 95% CI, 17.2–20.7 months; P<.0001; Figure 2). The adjusted hazard of death was 25% higher in patients in the discordant group compared with those in the concordant group (HR, 1.25; 95% CI, 1.13–1.39; Table 3).
OS for patients receiving concordant versus discordant 1L treatment after testing positive for a biomarker prior to/on initiation of 1L treatment.
Abbreviations: 1L, first-line; OS, overall survival.
Citation: Journal of the National Comprehensive Cancer Network 21, 9; 10.6004/jnccn.2023.7039
Discussion
This large, real-world retrospective database study demonstrates that among patients with a/mNSCLC who ever (vs never) received biomarker testing, received testing for biomarker(s) prior to/on initiation of 1L treatment (vs not received), and received (vs not received) guideline-concordant therapy after a positive actionable biomarker test result are each significantly associated with longer survival outcomes. The significant improvement in survival observed for guideline-concordant therapy in this study is consistent with a previously reported hypothesis-generating association based on an exploratory analysis.26 These studies together provide real-world evidence that supports the importance of testing for actionable biomarkers to inform 1L treatment selection.
Also consistent with other work,28,33 this study found that only 69% of patients received testing for at least 1 actionable biomarker prior to/on initiation of 1L treatment, and more than half of those who underwent testing did not receive testing for all 4 biomarkers evaluated in this study prior to/on initiation of 1L treatment. Collectively, this body of evidence shows that despite recommendations from treatment guidelines, the overall rate of testing for all guideline-recommended actionable biomarkers among patients with a/mNSCLC is inadequate.27,28 Although reasons for why patients did not undergo biomarker testing or underwent inadequate testing are not documented in the database used in this study, this behavior of not testing or inadequate testing could serve as a proxy for lower-quality oncology care or inadequate oncologic knowledge of optimal patient management, among other factors. This could potentially contribute to suboptimal health outcomes in this patient population. Therefore, there is an urgent need to implement novel approaches to improve up-front biomarker testing in this patient population.
In addition to the gaps in biomarker testing, evidence from this study also suggests discrepancy between results of biomarker testing and receipt of subsequent treatments, and that there are additional challenges that may impact patients’ ability to access and potentially benefit from the 1L targeted therapy. Similar to previous work,33 in this study, many patients with biomarker-positive disease across all 4 biomarkers did not receive concordant 1L therapy, and the proportion of discordant 1L therapy was highest in patients with BRAF-positive disease relative to other biomarkers. Overall, receipt of discordant 1L therapy was associated with significantly worse survival outcomes. The reasons for the noted discrepancy between results of biomarker testing and receipt of subsequent 1L treatment could not be evaluated in this study because this information is not recorded in the database used. However, literature suggests that these reasons could include lack of physician awareness regarding available targeted therapy options for each biomarker, lack of insurance coverage, cost concerns, other social determinants of health, or comorbid conditions that preclude the use of these therapies.34 Patients ever (vs never) undergoing biomarker testing and receiving biomarker testing prior to/on initiation of 1L therapy (vs not testing) were also associated with improved OS. However, biomarker testing informs the selection of guideline-recommended treatment, which impacts survival outcomes; therefore, the receipt of testing alone cannot be interpreted as the causal element for the survival outcomes observed in this study. To identify a targeted agent for 1L therapy, a patient should undergo biomarker testing as a part of their initial diagnostic workup. However, given the availability of FDA-approved targeted therapies for several actionable alterations5–14 and to achieve biomarker testing in an efficient manner, treatment guidelines18,24 recommend using broad molecular profiling in this patient population. Therefore, it is important to ensure that any barriers related to comprehensive biomarker testing and/or access to targeted therapies are identified and addressed.
Strengths of this study include the evaluation of both the (1) timing of biomarker testing and the 1L treatments received and (2) quantification of their relationship with OS. In the clinical landscape of a/mNSCLC, which is rapidly evolving with a growing list of FDA-approved targeted therapies,35 the up-front use of comprehensive biomarker testing is critical to improving long-term survival.
The database used in this study is not nationally representative of the US population, although it captures data for approximately 15% of patients with cancer in the United States and is geographically and demographically diverse. However, the findings are limited in terms of generalizability because the study cohort received treatment predominantly in community oncology settings. The data used in this study were based on structured electronic health records, which are not primarily collected for research purposes, resulting in gaps and errors, potentially affecting study findings. Additionally, this study was limited to positive results for 4 genomic biomarkers in a/mNSCLC (ALK, BRAF, EGFR, and ROS1), and did not include rare biomarkers because those biomarkers were not included in the Flatiron Health database at the time of analysis. Future work should evaluate the study objectives using an expanded patient population including those with rare and emerging biomarkers. In addition, although the multivariable Cox proportional models implemented in this study accounted for observed differences between analyzed patient groups, given the retrospective nature of this study, the potential for unobserved confounders (such as duration and extent of smoking history, disease severity, reasons for or against biomarker testing, and reasons for or against treatment initiation) and their effect on the analysis presented in this article cannot be eliminated. Finally, there are many clinically appropriate reasons why concordant versus discordant treatment may be selected that could not be evaluated in this study. A positive result on a biomarker test does not indicate the appropriateness of targeted therapy for those who may otherwise have contraindications to these treatments. Therefore, the terms “concordant” and “discordant” used in this study should be interpreted as measures of consistency with guidelines and should not necessarily be interpreted as quality care (or lack thereof).
Conclusions
This study compared survival outcomes by biomarker testing status and by receipt of guideline-concordant therapy in a large real-world cohort of patients with a/mNSCLC in the United States. The findings suggest that receipt of 1L treatment that is concordant with biomarker testing results and national treatment guidelines is associated with improved survival outcomes in patients with a/mNSCLC.
Acknowledgments
The authors thank Yajun Emily Zhu, previously employed at Eli Lilly and Company, for her initial contributions to this work.
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