Clinical Impact of Adherence to NCCN Guidelines for Biomarker Testing and First-Line Treatment in Advanced Non-Small Cell Lung Cancer (aNSCLC) Using Real-World Electronic Health Record Data

This study aimed to assess the association between adherence to NCCN guidelines and clinical outcomes among adult patients with NSCLC in the advanced setting (stage IIIB or higher), based on the most recent 2019 NCCN guidelines (V.7) available at the time of analysis [4]. We conducted two analyses within this study. For the first analysis, we assessed the association between adherence to guideline-recommended biomarker testing and OS. For the second analysis, we assessed the association between adherence to guideline-recommended first-line therapy and TTD.

This was a retrospective cohort study of adult patients with aNSCLC (stages IIIB, IIIC, IVA, and IVB) from the Flatiron Health database. Flatiron Health is a nationwide longitudinal, de-identified database derived from electronic health record (EHR) data. During the study period, the de-identified data originated from approximately 280 US cancer clinics (~ 800 sites of care). Structured data include data on diagnosis, laboratory values, and medication administrations, and unstructured data include clinic notes, both curated via technology-enabled abstraction [14, 15]. This database provides longitudinal data that allow individual patients to be followed over several years after their date of advanced cancer diagnosis.

No ethics committee or IRB approval is required for this study using de-identified retrospective data.

Adult patients, aged 18 years or older, diagnosed with non-squamous or not otherwise specified (NOS) aNSCLC from January 1, 2011 through July 31, 2019 were included in this analysis. To minimize bias, patients must have had recorded medical activity within 90 days following aNSCLC diagnosis, and at least a 90-day follow-up period after diagnosis. Patients were excluded if age and sex were unknown. Further, patients with evidence of a biomarker test in their EHR record, but without a biomarker result date recorded, were excluded from this study.

An additional set of exclusion criteria were applied for the first-line therapy analysis. Firstly, patients must have had a recorded first-line therapy within 90 days of aNSCLC diagnosis, and at least 90 days of follow-up following initiation of the first-line therapy. Patients who received a clinical study drug as part of the first-line therapy were excluded. Further, patients who received a biomarker-driven targeted or immunotherapy as first-line without evidence of a positive biomarker test result were excluded, as testing information may be incomplete or missing in these patients’ records or in the database.

These analyses found that there was strong evidence supporting adherence to NCCN biomarker testing guidelines: approximately two-thirds (68.7%) of patients received a recommended biomarker test, highlighting the need for improvement in the utilization of biomarker testing as an integral component of routine practice. There may be several reasons for lack of adherence to guideline-recommended biomarker testing, including slow clinician uptake of tests, difficulties assessing samples, and payer coverage [17]. Only recently has the US Centers for Medicare and Medicaid Services approved a national coverage decision for Next-generation Sequencing (NGS) in patients with aNSCLC [18]. Additionally, the US Food and Drug Administration has recently approved several NGS-based platforms for biomarker testing [17]. As such, in the coming years, it is expected that adherence to testing guidelines will be increased. This is already observable in this study, as patients in the biomarker testing-adherent group were more likely to be diagnosed in recent years. Mason et al. published a similar study in 2018 using a smaller patient sample size (n = 379) across seven academic and community centers, and found higher rates of biomarker testing ranging from 85 to 100%, including ALK, EGFR, and ROS1, but lower rates of PD-L1 testing (~ 57%) [19]. This study demonstrates that adherence to biomarker testing may vary drastically based on the type of biomarker. While Mason et al. used data from primarily large, academic and community institutions, our study collected data across ~ 800 national sites, varying in size, affiliations, and regions. Regardless, our study finds relatively high overall adherence to biomarker testing given a non-homogenous sample.

Adherence to NCCN-recommended biomarker testing was associated with 10% reduced risk of mortality for patients with advanced diagnosis in this analysis. Furthermore, in a subset of patients with a more advanced initial diagnosis (initial stage IV diagnosis), where biomarker testing is well-specified in the guidelines, the risk of mortality was reduced by 20% compared to non-adherent patients. These results reaffirmed findings from various studies reporting the benefits of individual biomarkers and associated treatment [9, 12, 13, 20‐22].

This analysis assessed the association between adherence to NCCN-recommended first-line therapy and TTD in adult patients with aNSCLC. The majority of patients in this analysis were adherent to NCCN-recommended first-line therapy. Of the patients included in this analysis, 69.9% were treated with NCCN-recommended first-line therapy based on their biomarker test results, agnostic of mutation. Mason et al. reported varying adherence to first-line treatment dependent on mutation: 96.8% adherence to recommended first-line treatment among patients with ALK, EGFR, or ROS1 mutations and 9.6% among patients with PD-L1 mutations [19].

There may be several reasons for treatment non-adherence that are not captured in this study, including physician preference, patient safety profile, and therapy availability. We believe that non-adherence may not necessarily be intentional and may be related to many unmeasured factors such as patient’s underlying health, safety reasons, patient and/or physician preference, compliance, access to testing or treatment, reimbursement barriers, and other healthcare system-related factors (clinical pathways), etc. Access to biomarker testing and the appropriate therapy may also serve as a barrier to adherence across non-homogenous US sites included in the database; certain biomarker tests and therapies may be more widely available in some regions or institutions versus others. Because data on the availability of each biomarker test and therapy at the contributing institutions were not captured, the authors cannot conclude that all patients in the present study had equal access to NCCN-recommended biomarker tests and therapies. These may be a few of the reasons for a lower observed adherence in this study, given the general understanding of guideline importance. Further studies are needed to better understand why patients may not receive NCCN-recommended biomarker tests or first-line therapy.

Overall, our study found that patients who were adherent to first-line recommendations had a 40% lower probability of discontinuing treatment, and were more likely to remain on their treatment for about a month longer than non-adherent patients. Wang et al. [9] similarly found that patients who received guideline-recommended first-line therapy had significantly longer follow-up periods on first-line therapy than patients who were not administered guideline-recommended therapy [9]. In a study conducted in Spain, patients with guideline-recommended diagnosis and treatment had improved survival, with 1- and 2-year relative survival of 51% and 28.2% versus 34.1% and 17.5%, respectively, in patients who did not receive guideline-recommended diagnosis and treatment, and non-adherence may have been due to bad performance status, advanced age, exitus, and patient preference [12]. These may also be contributing factors in our study. In addition to OS, adherence to guideline-recommended precision medicine has been shown to improve progression-free survival in patients with advanced-stage cancer [20].

In this study, there was significant heterogeneity by the types of treatment for both groups, and this effect was seen for risk of and time to discontinuation. More than half of the patients received chemotherapy alone as their first-line treatment; however, the difference in risk for patients receiving chemotherapy alone was null. Among patients who received immunotherapy or targeted therapy (as monotherapy or in combination with chemotherapy) as first-line treatment, adherence was associated with more than 50% reduced risk of discontinuation. Chemotherapy had the shortest treatment duration of just over 2 months, followed by targeted therapy with 4 months and immunotherapy with about 9 months.

Despite the heterogeneity of treatment, these findings suggest that patients who are adherent to guidelines had more favorable overall outcomes, especially if initiating treatment on immunotherapy or targeted therapy, adding to the growing body of literature outlining improved outcomes based on individual biomarker-driven treatment [9, 12, 13, 20‐22].

This real-world study assessed adherence to guidelines using a holistic approach, agnostic of biomarkers and treatments. This study comprised a large cohort of patients with aNSCLC who were treated primarily in a community-based setting, reflecting clinical practice in the real world. Moreover, the use of EHR data captured as part of routine care enabled extended follow-up periods and the ability to include additional variables as potential confounders.

Despite the large sample size and availability of longitudinal data, there are several limitations associated with the use of real-world data; therefore, our study findings should be interpreted within the context of these noted limitations (e.g., missingness, unmeasured confounders, misclassification). For example, patients may have undergone biomarker testing or received guideline-recommended treatment outside of the Flatiron Health network; however, as this study was conducted only with data from this EHR system, these patients may have been inaccurately placed in the non-adherent cohorts and hence may potentially bias the estimation. One limitation of selecting OS as the outcome of interest for this analysis is the number of potential factors intervening between the exposure of interest (in this case, biomarker testing) and the outcome (OS) over time. Several clinical factors, including choice of first-line therapy, tolerance to therapy, switching, discontinuation, etc. that occur after initial biomarker testing, may have a significant impact on OS; however, it is likely that both groups would be subject to this limitation. Another limitation of this study was our inability to account for the changes to NCCN guidelines that likely occurred over the 8.5-year timeframe. For instance, many more new biomarkers emerged over time, or immunotherapies as a class were not introduced to the market until 2015. Therefore, adherence in patients recruited from earlier in the study time frame (e.g., 2011–2015) may be underestimated as the options within the guidelines were not as fully developed as they are today. This limitation may explain why patients diagnosed in earlier years were more likely to be classified as non-adherent. Finally, rationale for non-adherence was not available; these may be related to underlying patient health, safety, or cancer progression characteristics, patient and physician preference, compliance, physician, reimbursement, and other healthcare system-related factors, etc.