With regards to conflicts of interest, Yulin Li, Anita Appius, and Andrea Feyereislova are Roche employees; Thirupathi Pattipaka and Adrian Cassidy were employees of Roche at the time the analyses were conducted; Apar Kishor Ganti has no conflicts of interest to disclose. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
‡ Affiliation correct at the time of the study.
Randomized phase III trials have established the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line treatment for
Data were extracted from the US Flatiron Electronic Health Record-derived database. Adult patients with stage IIIB/IV
Of the 22,258 patients with advanced NSCLC in the database, 961 met the inclusion criteria. Median age was 69.0 years (range: 61–78) and the majority were female (68.0%), with stage IV (93.9%), non-squamous cell carcinoma (97.4%). EGFR tyrosine kinase inhibitors were the most widely prescribed first-line therapy (72.8%). The likelihood of receiving an EGFR tyrosine kinase inhibitor or chemotherapy was unaffected by the type of medical insurance patients had. Patients treated with an EGFR tyrosine kinase inhibitor had significantly longer time to next treatment than those given other first-line systemic therapies (p < 0.0001). There were no significant differences in overall survival according to treatment type.
Results from this large US cohort study reflect those obtained in randomized trials of patients with advanced
Non–small-cell lung cancer (NSCLC) comprises up to 80% of all newly diagnosed lung cancer cases, and more than half of all patients (57%) are diagnosed with metastatic disease [
The superiority of EGFR TKIs over platinum-doublet chemotherapy has been demonstrated in a number of randomized, phase III studies in treatment-naïve advanced
Despite the wealth of published clinical trial data, information concerning the use of EGFR TKIs in a real-world setting is limited. Real-world data complement results from randomized clinical trials and generate evidence on the effectiveness and use of medical products in daily practice [
This study used data extracted from the Flatiron Health Cloud-based Oncology Electronic Health Record (EHR)-derived database. The longitudinal database represents one of the most comprehensive sources of real-world evidence in oncology. At the data cut-off date of August 31, 2017, the Flatiron Health database included data from more than 265 cancer clinics (~800 sites of care) representing more than 2 million active US cancer patients available for analysis. This database captures data from both structured and unstructured EHR fields using a technology-enabled abstraction process and multi-pronged quality assurance approaches. Data are refreshed monthly to provide near real-time research-ready datasets [
Approval of the study protocol was obtained from Copernicus Group Independent Review Board (CGIRB) prior to study conduct, and included a waiver of informed consent. Data provided to third parties were de-identified and provisions were in place to prevent re-identification in order to protect patients’ confidentiality.
This retrospective study examined treatment patterns, demographic and disease characteristics, and clinical outcomes of patients with locally advanced unresectable or metastatic,
The selection criteria for this study included: age ≥18 years at diagnosis, histologically confirmed stage IIIB/IV NSCLC (American Joint Committee on Cancer [AJCC], 7th edition), documented
Demographic variables evaluated were age, gender, race, and smoking status. Disease clinical characteristics included tumor histology, stage at diagnosis, absence or presence of brain metastases, Eastern Cooperative Oncology Group performance status, and
Time to next treatment (TTNT) was used as a surrogate for PFS and was defined as the time from the start of first-line treatment for advanced
The predefined variable of line of therapy in the Flatiron database was used to define the first-line setting. However, since this variable was derived from administrative or prescription dates, and name and dosage of regimens, rather than date of disease progression, line of therapy described in the study should be interpreted as a surrogate to line of therapy in a clinical trial.
Baseline patient and clinical characteristics were described at the start of the first-line treatment in the overall study cohort and by treatment subgroups. Categorical variables were described as frequency and percentages. For continuous variables, means, standard deviations, medians, range and percentiles (25th and 75th) were reported when appropriate. Comparisons between treatment subgroups were made using chi-square tests for categorical variables and Wilcoxon rank-sum test for continuous variables (two-sided test, p-value threshold ≤ 0.05). No formal hypotheses were tested and p-values were reported purely for descriptive purposes. All analyses were performed in the overall study cohort and by treatment subgroups (e.g., TKIs, erlotinib, afatinib, chemotherapy, or other non-TKI target therapy in the first-line). A Kaplan–Meier analysis was conducted to estimate median TTNT and OS with 95% CIs; HRs and 95% CIs with p-values were calculated using a Cox-proportional hazards model after adjusting for patient age, gender, race, smoking status, and histology. All statistical analyses were conducted using SAS software (SAS Institute, Cary, NC) or R.
In total, 22,258 patients aged ≥18 years with stage IIIB/IV NSCLC were identified from the Flatiron advanced NSCLC cohort (
Patients were older than the median age observed in clinical trials of
All NSCLC |
EGFR TKIs |
Afatinib |
Erlotinib |
Gefitinib |
Chemotherapy only (n = 169) | Chemotherapy + non-TKI targeted therapy (n = 85) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
n | % | n | % | n | % | n | % | n | % | n | % | n | % | |
Age at advanced diagnosis, years | ||||||||||||||
18–64 | 341 | 35.5 | 236 | 33.7 | 24 | 27.6 | 207 | 34.9 | 1 | 7.7 | 62 | 36.7 | 40 | 47.1 |
65–74 | 309 | 32.2 | 208 | 29.7 | 25 | 28.7 | 179 | 30.2 | 3 | 23.1 | 68 | 40.2 | 29 | 34.1 |
75+ | 311 | 32.4 | 256 | 36.6 | 38 | 43.7 | 207 | 34.9 | 9 | 69.2 | 39 | 23.1 | 16 | 18.8 |
Median ( |
69 (61–78) | 69 (62–79) | 69 (62–81) | 69 (62–78) | 79 (74–84) | 68 (59–74) | 65 (60–72) | |||||||
Gender | ||||||||||||||
Female | 653 | 68.0 | 488 | 69.7 | 62 | 71.3 | 410 | 69.1 | 12 | 92.3 | 103 | 61.0 | 58 | 68.2 |
Male | 308 | 32.1 | 212 | 30.3 | 25 | 28.7 | 183 | 30.9 | 1 | 7.7 | 66 | 39.1 | 27 | 31.8 |
Race | ||||||||||||||
Asian | 122 | 12.7 | 102 | 14.6 | 10 | 11.5 | 89 | 15.0 | 2 | 15.4 | 16 | 19.5 | 3 | 3.5 |
Black / African American | 55 | 5.7 | 38 | 5.4 | 4 | 4.6 | 33 | 5.6 | 1 | 7.7 | 11 | 6.5 | 6 | 7.1 |
Hispanic or Latino | 6 | 0.6 | 6 | 0.9 | 3 | 3.5 | 2 | 0.3 | 0 | 0 | 0 | 0 | 0 | 0 |
Other race | 117 | 12.2 | 89 | 12.7 | 12 | 13.8 | 73 | 12.3 | 4 | 30.8 | 14 | 8.3 | 14 | 16.5 |
White | 532 | 55.4 | 371 | 53.0 | 43 | 49.4 | 321 | 54.1 | 4 | 30.8 | 106 | 62.7 | 50 | 58.8 |
Missing | 129 | 13.4 | 94 | 13.4 | 15 | 17.2 | 75 | 12.7 | 2 | 15.4 | 22 | 13.0 | 12 | 14.1 |
Smoking status | ||||||||||||||
History of smoking | 423 | 44.0 | 289 | 41.3 | 37 | 42.5 | 245 | 41.3 | 5 | 38.5 | 92 | 54.4 | 42 | 49.4 |
No history of smoking | 525 | 54.6 | 404 | 57.7 | 50 | 57.5 | 341 | 57.5 | 8 | 61.5 | 74 | 43.8 | 41 | 48.2 |
Unknown/ not documented | 13 | 1.4 | 7 | 1.0 | 0 | 0 | 7 | 1.2 | 0 | 0 | 3 | 1.8 | 2 | 2.4 |
Histology | ||||||||||||||
NSCLC histology NOS | 12 | 1.3 | 4 | 0.6 | 0 | 0 | 4 | 0.7 | 0 | 0 | 6 | 3.6 | 1 | 1.2 |
Non-squamous NSCLC | 936 | 97.4 | 692 | 98.9 | 86 | 98.9 | 586 | 98.8 | 13 | 100 | 154 | 91.1 | 84 | 98.8 |
Squamous cell carcinoma | 13 | 1.4 | 4 | 0.6 | 1 | 1.2 | 3 | 0.5 | 0 | 0 | 9 | 5.3 | 0 | 0 |
Clinical stage | ||||||||||||||
IIIB | 59 | 6.1 | 2 | 2.9 | 2 | 2.3 | 18 | 3.0 | 0 | 0 | 36 | 21.3 | 3 | 3.5 |
IV | 902 | 93.9 | 680 | 97.1 | 85 | 97.7 | 575 | 97.0 | 13 | 100 | 133 | 78.7 | 82 | 96.5 |
Brain metastases | ||||||||||||||
Absent |
804 | 83.7 | 586 | 83.7 | 72 | 82.8 | 498 | 84.0 | 11 | 84.6 | 136 | 80.5 | 76 | 89.4 |
Diagnosed after treatment | 81 | 8.4 | 54 | 7.7 | 7 | 8.1 | 46 | 7.8 | 1 | 7.7 | 18 | 10.7 | 8 | 9.4 |
Diagnosed before treatment | 76 | 7.9 | 60 | 8.6 | 8 | 9.2 | 49 | 8.3 | 1 | 7.7 | 15 | 8.9 | 1 | 1.2 |
ECOG PS (± 90 days of diagnosis) | ||||||||||||||
0–1 | 342 | 35.6 | 263 | 37.6 | 31 | 35.6 | 221 | 37.3 | 6 | 46.2 | 49 | 29.0 | 29 | 34.1 |
2+ | 85 | 8.8 | 68 | 9.7 | 10 | 11.5 | 55 | 9.3 | 3 | 23.1 | 11 | 6.5 | 6 | 7.1 |
Unknown | 534 | 55.6 | 369 | 52.7 | 46 | 52.9 | 317 | 53.5 | 4 | 30.8 | 109 | 64.5 | 50 | 58.8 |
Practice type | ||||||||||||||
Academic | 84 | 8.7 | 71 | 10.1 | 6 | 6.9 | 65 | 11.0 | 0 | 0 | 9 | 5.3 | 1 | 1.2 |
Community | 877 | 91.3 | 629 | 89.9 | 81 | 93.1 | 528 | 89.0 | 13 | 100 | 160 | 94.7 | 84 | 98.8 |
Insurance type | ||||||||||||||
Commercial health plan | 367 | 38.2 | 258 | 36.9 | 29 | 33.3 | 221 | 37.3 | 3 | 23.1 | 69 | 40.8 | 35 | 41.2 |
Medicaid | 29 | 3.0 | 24 | 3.4 | 2 | 2.3 | 22 | 3.7 | 0 | 0 | 3 | 1.8 | 2 | 2.4 |
Medicare | 145 | 15.1 | 109 | 15.6 | 21 | 24.1 | 84 | 14.2 | 4 | 30.8 | 23 | 13.6 | 12 | 14.1 |
Missing | 167 | 17.4 | 115 | 16.4 | 14 | 16.1 | 97 | 16.4 | 4 | 30.8 | 32 | 18.9 | 20 | 23.5 |
Other government program | 24 | 2.5 | 8 | 2.6 | 1 | 1.2 | 17 | 2.9 | 0 | 0 | 3 | 1.8 | 3 | 3.5 |
Other payer–type unknown | 190 | 19.8 | 151 | 21.6 | 17 | 19.5 | 130 | 21.9 | 2 | 15.4 | 30 | 17.8 | 8 | 9.4 |
Patient-assistance program | 37 | 3.9 | 23 | 3.3 | 3 | 3.5 | 20 | 3.4 | 0 | 0 | 9 | 5.3 | 5 | 5.9 |
Self-pay | 2 | 0.2 | 2 | 0.3 | 0 | 0 | 2 | 0.3 | 0 | 0 | 0 | 0 | 0 | 0 |
a Data for patients who received gefitinib were removed from all analyses due to the small sample size (n = 13).
b No secondary malignant brain, spinal cord, or nervous system neoplasm present during the study period.
CTX, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small-cell lung cancer; NOS, not otherwise specified; EGFR TKIs, epidermal growth factor receptor tyrosine kinase inhibitors
Rates of
Year | Patients diagnosed |
Testing rate |
---|---|---|
n | % | |
2010 | – | – |
2011 | 2,650 | 30.5 |
2012 | 3,420 | 48.0 |
2013 | 4,093 | 55.0 |
2014 | 4,599 | 60.5 |
2015 | 4,934 | 63.9 |
2016 |
2,562 | 78.4 |
a Patients may be tested in different years to their year of diagnosis.
b Testing was only undertaken for a 6-month period up to June 30, 2016.
Note: The patient cohort presented in this table is larger than the cohort described in the methods.
Of the 961 patients in the main analysis, EGFR TKIs (72.8%, n = 700) were the most widely prescribed first-line therapy (erlotinib 61.7% [n = 593], afatinib 9.1% [n = 87], gefitinib 1.4% [n = 13]). Seven patients received a combination of these TKIs. First-line chemotherapy was prescribed to 17.6% (n = 169) of patients and first-line chemotherapy ± non-EGFR TKI targeted therapy (either bevacizumab or cetuximab) to 8.8% of patients (n = 85) (
First-line regimen, n | Second-line regimen, n | ||||||||
---|---|---|---|---|---|---|---|---|---|
None | Erlotinib | Afatinib | Gefitinib | TKI combination | Chemotherapy | Targeted drug | Clinical study drug | Total, n (% |
|
Erlotinib | 365 | 23 | 57 | 9 | 4 | 91 | 38 | 6 | 593 (61.7) |
Afatinib | 67 | 7 | 1 | 0 | 1 | 4 | 7 | 0 | 87 (9.1) |
Gefitinib | 13 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 13 (1.4) |
TKI combination |
6 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 7 (0.7) |
Chemotherapy |
54 | 74 | 9 | 1 | 0 | 28 | 3 | 0 | 169 (17.6) |
Targeted drug |
29 | 32 | 1 | 1 | 0 | 13 | 9 | 0 | 85 (8.8) |
Clinical study drug | 5 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 7 (0.7) |
Total, |
539 | 138 (32.7) | 68 (16.1) | 11 (2.6) | 5 (1.2) | 137 (32.5) | 57 (0.1) | 6 (1.4) | 961 |
a Patients who received a combination of erlotinib or afatinib or gefitinib in the examined line.
b Patients who received chemotherapy without combination use of any EGFR TKI or non-EGFR TKI targeted treatments.
c Patients who received at least one non-EGFR TKI targeted treatment in the examined line.
d Denominator = 961 patients who received first-line treatment.
e Denominator = 442 patients who received second-line treatment.
TKI, tyrosine kinase inhibitor
Amongst patients receiving treatments other than EGFR TKIs (n = 261), carboplatin/pemetrexed (23.4%, n = 61), carboplatin/paclitaxel (20.3%, n = 53), and bevacizumab/carboplatin/pemetrexed (16.9%, n = 44) were the most frequently prescribed first-line therapies.
Fewer than half of all patients (43.9%, n = 422) received second-line treatment (
The likelihood of receiving an EGFR TKI was generally unaffected by the type of medical insurance patients had (
Patients who received erlotinib (n = 593) or afatinib (n = 87) as their first-line therapy had a significantly longer TTNT than patients receiving non-EGFR TKI therapy (n = 261) (both p < 0.0001;
Kaplan-Meier estimates of (A) TTNT, and (B) OS stratified by treatment group.
Among the 961 patients included in the main analysis, 549 patients (57.1%) had died at the time of the analysis. These included 40 (46% of 87), 338 (57% of 593), and 104 (61.5% of 169) patients treated with afatinib, erlotinib, and chemotherapy, respectively. Estimated median OS with erlotinib (median 23.2 months, 95% CI 21.2–24.9) and afatinib (median 20.7 months, 95% CI 16.2–35.1) was comparable to that seen with non-EGFR TKI targeted treatment (median 24.1 months, 95% CI 20.9–29.5) and chemotherapy (median 22.1 months, 95% CI 18.3–30.0) (
Similar results were seen in exploratory subgroup analyses in patients diagnosed with advanced
Exon 19 deletion was identified in 52 patients in the afatinib group and 326 patients in the erlotinib group, and exon 21 mutation was found in 35 and 268 patients, respectively. Median TTNT was similar between these treatment groups for both mutations; median TTNT was 12.6 months (95% CI 9.0–17.5) with afatinib and 14.0 months (95% CI 12.4–15.3) with erlotinib for patients with an exon 19 deletion, and 11.2 months (95% CI 8.7–16.2) and 12.1 months (95% CI 10.6–14.2), respectively, for those with an exon 21 mutation (
This retrospective study evaluated real-world treatment patterns of patients with advanced
The rate of
Treatment patterns were as expected, based on the mutation status of the patients’ tumors, with single-agent EGFR TKIs, predominantly erlotinib, having been the most widely prescribed first-line therapy. The type of medical insurance that patients had did not influence the likelihood of them receiving an EGFR TKI. There has been a lack of evidence supporting the efficacy of combining EGFR TKIs with chemotherapy, nevertheless, erlotinib and afatinib were used in combination with chemotherapy in a few patients (n = 32; 3.3% of the entire cohort). We speculate that a TKI was intercalated with chemotherapy rather than given concomitantly.
Approximately 27% of patients with
Patients who were given an EGFR TKI as first-line therapy had significantly longer TTNT, a surrogate for PFS, than those receiving other systemic treatments. Median TTNT was 13.1 months (95% CI 12.1–14.3) with erlotinib and 12.1 months (95% CI 9.7–14.9) with afatinib. Erlotinib and afatinib demonstrated comparable efficacy in this regard (both p < 0.0001 vs other systemic therapies). The slightly longer duration of TTNT in this study compared with PFS in clinical trials [
The results from this real-world study support the efficacy of the EGFR TKIs established in clinical trials. However, the population studied in the USA may not be representative of a global population, and additional analyses may be needed to evaluate real-world treatment patterns in other countries. In a retrospective chart review examining real-world practice patterns in 175 Japanese patients treated for stage IIB/IV NSCLC between 2011 and 2013, EGFR TKIs were the most commonly prescribed therapies for
Limitations of this analysis are reflective of the data source and collection. Flatiron data are generated from real-world clinical practice, and are subject to miscoding and errors. The data are mainly drawn from community oncology centers and therefore may not be representative of treatment patterns at academic medical centers. Since information about patients prior to the clinical oncology practice’s adoption of the EHR may not be available, particularly in the structured data, the extent to which historical data are entered into the EHR is a practice-specific decision and varies widely. An important strength of the present study over previous real-world data studies [
These real-world data reflect the results of randomized clinical trials of
(DOCX)
Third-party medical writing assistance, under the direction of the authors, was provided by Fiona Fernando, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.