Organ Dysfunction in Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Real-world data enables evaluation of immune checkpoint inhibitor (ICI) use in advanced melanoma management. We examined characteristics and outcomes of ICI-treated patients with advanced melanoma and organ dysfunction (baseline and emergent). MATERIALS AND METHODS: This retrospective observational study used electronic health records derived from a nationwide data set to examine advanced melanoma patients treated with first-line ICIs (2011-2018). Clinical characteristics, real-world time to treatment discontinuation (rwTTD), and overall survival (OS) were analyzed for patients with normal organ function and those with organ dysfunction prior to ICI initiation. Patients with emergent dysfunction in the 90 days following ICI initiation were identified, and potentially associated characteristics were explored. RESULTS: Of 2,407 patients included, 1,884 and 1,717 had evaluable renal and hepatic laboratory values, respectively. Patients with baseline renal dysfunction (2.4%) were older and more frequently male, and less frequently treated with ICI combinations, than patients with normal renal function. Patients with baseline hepatic dysfunction (2.8%) were similar to patients with normal hepatic function regarding demographics and treatments received. Patients with baseline organ dysfunction displayed shorter rwTTD and OS. Among patients with normal baseline organ function, 4.6% and 7.4% developed renal and hepatic dysfunction within 90 days of ICI initiation, respectively; this was associated with combination ICI treatment. CONCLUSION: Patients with advanced melanoma and baseline organ dysfunction frequently receive ICI treatment but have poorer clinical outcomes than patients with normal organ function. Among patients with normal renal and hepatic function at ICI initiation, emergent organ dysfunction rates in this real-world cohort are similar to those reported in clinical trials. IMPLICATIONS FOR PRACTICE: Real-world data provide an opportunity to understand treatment patterns, toxicity, and clinical outcomes among patients treated outside of clinical trials. This study confirms that patients with advanced melanoma and baseline renal or hepatic dysfunction are being treated with ICI therapy more frequently as monotherapy than in combination therapy. For those real-world patients with normal baseline organ function, emergent renal and hepatic dysfunction are both more common in patients treated with combination versus ICI monotherapy.

Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non-small cell lung cancer.

BACKGROUND: Despite the rapid adoption of immunotherapies in advanced non-small cell lung cancer (advNSCLC), knowledge gaps remain about their real-world (rw) performance. METHODS: This retrospective, observational, multicenter analysis used the Flatiron Health deidentified electronic health record-derived database of rw patients with advNSCLC who received treatment with PD-1 and/or PD-L1 (PD-[L]1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow-up. The authors investigated PD-(L)1 line of treatment and PD-L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression-free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD). RESULTS: First-line PD-(L)1 inhibitor use increased from 0% (in the third quarter of 2014 [Q3 2014]) to 42% (Q2 2017) over the study period. PD-L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9-9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1-3.3 months). Longer OS and rwPFS were associated with ≥50% PD-L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73-0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57-0.63) for rwTTP, and, for treatment-based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56-0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80-0.82) for rwTTD. CONCLUSIONS: The use of first-line PD-(L)1 inhibitors and PD-L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD-L1 percentage staining. Intermediate rw tumor-dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials.

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

An evaluation of the impact of missing deaths on overall survival analyses of advanced non-small cell lung cancer patients conducted in an electronic health records database.

PURPOSE: The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR-derived database. METHODS: The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non-small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR-derived database, and "external control arm" analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR-derived database only. The hazard ratios (HRs) obtained within the EHR-derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. RESULTS: Bias in mOS ranged from modest (0.6-0.9 mos.) in the EHR-derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3-9.7 mos.). Overall, small differences were observed in the HRs for the EHR-derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. CONCLUSIONS: The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database.

Importance: Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine. Objective: To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non-small cell lung cancer (NSCLC). Design, Setting, and Participants: Clinical data from EHRs were linked with CGP results for 28 998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018. Exposures: Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs. Main Outcomes and Measures: Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy. Results: Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti-PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20. Conclusions and Relevance: Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.

Disparities in the Use of Programmed Death 1 Immune Checkpoint Inhibitors.

Amid growing excitement for immune checkpoint inhibitors of programmed death protein 1 (anti-PD1 agents), little is known about whether race- or sex-based disparities exist in their use. In this observational study, we constructed a large and mostly community-based cohort of patients with advanced stage cancers, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, to compare the odds of receiving systemic treatment with or without anti-PD1 agents by race and by sex. In multivariable models that adjusted for age, stage, and number of prior anticancer therapies, we found no significant race-based disparities in anti-PD1 treatment. However, among patients with NSCLC, males had significantly higher odds of receiving anti-PD1 treatment compared with females (odds ratio 1.13, 95% confidence interval 1.02-1.24, p = .02). This finding suggests that as anti-PD1 agents enter the market to transform patient care, it will be critical to monitor for disparities in the use of these drugs.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Comparison of Methods of Clinical Trial Emulation Utilizing Data From the Comparison of AMD Treatment Trial (CATT) and the IRIS® Registry.

Purpose: We used exact matching and inverse propensity score weighting (IPSW) using real-world data (RWD) from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) to emulate the 2 pro re nata (prn) treatment arms from the Comparison of AMD Treatment Trial (CATT) and to compare the outcomes of the RWD arms to the 2 monthly treatment arms from the clinical trial. Design: Retrospective cohort study utilizing deidentified electronic health record registry data and patient-level deidentified clinical trial data. Subjects: All treatment-naive patient eyes with neovascular age-related macular degeneration treated with ranibizumab or bevacizumab only for 1 year from either the CATT or the IRIS Registry. Methods: Patients were identified in the IRIS Registry between October 1, 2015 and December 31, 2019. After all nonimaging-based inclusion and exclusion criteria from the CATT were applied, patient eyes receiving bevacizumab or ranibizumab only on a prn basis were identified as the eligible cohort. Exact matching and ISPW was applied based on age, gender, and baseline visual acuity. Main Outcome Measures: Mean change in visual acuity, in approximated ETDRS letters, between baseline and 1 year for the IRIS Registry prn treatment arms generated by exact matching and IPSW. Results: We identified 427 eyes treated with ranibizumab prn and 771 eyes treated with bevacizumab prn. Using exact matching, 98% (n = 281) of CATT patient eyes in the bevacizumab monthly treatment arm and 87% (n = 261) of CATT patient eyes in the ranibizumab monthly treatment arm were matched to a patient eye in the IRIS Registry. For the ranibizumab prn treatment arm, patient eyes generated using exact matching gained 1.9 letters and those generated using IPSW gained 2.8 letters (exact matching: 1.9 letters ± 14.0 vs. IPSW: 2.8 letters ± 15.0 letters, P = 0.43). For the bevacizumab prn treatment arm, patient eyes generated using exact matching gained 2.4 letters and those generated using IPSW gained 2.1 letters (exact matching: 2.4 letters ± 15.4 vs. IPSW: 2.1 letters ± 16.0 letters, P = 0.79). Conclusions: Both exact matching and IPSW produced similar results in emulating the prn treatment arms of the CATT using IRIS Registry data and patient-level clinical trial data. Similar to prior real-world studies, the clinical outcomes were significantly worse in the IRIS Registry treatment arms compared with the clinical trial. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Multi-registry analysis of patients with multiple sclerosis and neuromyelitis optica to improve capture of demographic data and compare visual outcomes.

IMPORTANCE: The American Academy of Neurology Axon Registry® provides real-world data for patients with multiple sclerosis and neuro-myelitis optica. However, some data are incomplete (e.g. demographics) and some relevant outcomes are not systematically captured in neurology documentation (e.g. visual acuity). The American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) contains demographic and visual function data that may complement Axon Registry-derived data to enhance understanding of real-world visual outcomes in neurological disease. OBJECTIVE: To combine Axon Registry and IRIS Registry data to reduce missingness of demographic information and characterize visual outcomes in patients with multiple sclerosis and neuro-myelitis optica. DESIGN: Cross-sectional study. SETTING: Outpatient neurology and ophthalmology clinical practices. PARTICIPANTS: Patients participating in both registries between January 1, 2014 through December 10, 2021 were included if they had repeat ICD-9/10 codes for with multiple sclerosis or neuro-myelitis optica in the Axon registry. EXPOSURE: Diagnosis (multiple sclerosis or neuro-myelitis optica). MAIN OUTCOME AND MEASURE: Age, sex, race and ethnicity were assessed in the individual registries and classified as conflicting, missing, or not missing in the combined data set. The IRIS Registry contributed visual acuity data. RESULTS: Among 60,316 patients with multiple sclerosis and 1,068 patients with neuro-myelitis optica in the Axon Registry, 14,085 and 252 had temporal overlap in the IRIS Registry. Combining data reduced missing or conflicting data for race and ethnicity by 15-19 % (absolute reduction, all p ≤ 0.0005), but not age (p = 1.0) or gender (p = 0.08). 10,907 patients with MS and 142 with NMO had visual acuity data in the IRIS Registry. Visual acuity averaged between eyes was worse in patients with NMO after adjusting for age and gender (0.17 logMAR, 95 %CI 0.12,0.21, p < 0.0005). CONCLUSION AND RELEVANCE: Using data from two registries reduced missing data for race and ethnicity and enabled examination of outcomes captured in the IRIS Registry for conditions that are diagnosed more frequently in the Axon Registry, demonstrating the utility of a multi-registry analysis.

Emulating VIEW 1 and VIEW 2 Clinical Trial Outcome Data Using the American Academy of Ophthalmology IRIS Registry.

BACKGROUND AND OBJECTIVE: A retrospective, noninterventional cohort study of the American Academy of Ophthalmology IRIS Registry, an electronic health record (EHR)-based comprehensive eye disease and condition registry, intended to assess whether the IRIS® Registry (Intelligent Research in Sight) could emulate the VIEW randomized clinical trials (VIEW RCTs) eligibility criteria, treatment protocol regimen, and primary endpoint. PATIENTS AND METHODS: Deidentified patients having an anti-VEGF injection of aflibercept or ranibizumab between January 1, 2013, and December 31, 2018, from the IRIS Registry. Patients were treated in accordance with one of three treatment regimens from the VIEW RCT: monthly intravitreal aflibercept injection (IAI 2Q4), intravitreal aflibercept every 2 months after 3 initial monthly doses (IAI 2Q8), or monthly ranibizumab (RQ4) injection. The main outcome measures are the number and proportion of patients meeting VIEW RCT eligibility and treatment group criteria, demographic, and clinical differences between IRIS Registry treatment groups, mean change in best documented visual acuity at one year, and evaluation of the primary endpoint of the VIEW RCT: difference in the proportion of patients maintaining vision. RESULTS: Among the 90,900 patients who met VIEW RCT eligibility criteria, 4,457 (4.85%) met treatment group criteria. The percentage of patients maintaining vision at one year was over 90%. No statistically significant difference was observed when comparing the proportion of patients maintaining vision among the RQ4 treatment group to the IAI 2Q4 or IAI 2Q8 treatment group. CONCLUSIONS: A small percentage of real-world patients met VIEW RCT study eligibility criteria and treatment protocol regimen. Among patients meeting all available criteria, the primary endpoint interpretation yielded by an observational EHR-based dataset suggested comparable results to the VIEW RCT. [Ophthalmic Surg Lasers Imaging Retina 2023;54:6-14.].

Identifying the mechanism of missingness for unspecified diabetic retinopathy disease severity in the electronic health record: an IRIS® Registry analysis.

Observational studies of diabetic retinopathy (DR) using electronic health record data often determine disease severity using International Classification of Disease (ICD) codes. We investigated the mechanism of missingness for DR severity based on ICD coding using the American Academy of Ophthalmology IRIS® Registry. We included all patient encounters in the registry with a DR ICD-9 or ICD-10 code between January 1, 2014 and June 30, 2021. Demographic, clinical, and practice-level characteristics were compared between encounters with specified and unspecified disease severity. Practices were divided into quartiles based on the proportion of clinical encounters with unspecified DR severity. Encounters with unspecified disease severity were associated with significantly older patient age, better visual acuity, and lower utilization of ophthalmic procedures. Higher volume practices and retina specialist practices had lower proportions of clinical encounters with unspecified disease severity. Results strongly suggest that DR disease severity related to ICD coding is missing not at random.

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non-Small Cell Lung Cancer Treated With a PD-1/PD-L1 Blocking Antibody Using Real-World and Trial Data.

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan-Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

Analysis of a Real-World Progression Variable and Related Endpoints for Patients with Five Different Cancer Types.

INTRODUCTION: We previously demonstrated that real-world progression (rwP) can be ascertained from unstructured electronic health record (EHR)-derived documents using a novel abstraction approach for patients with advanced non-small cell lung cancer (base case). The objective of this methodological study was to assess the reliability, clinical relevance, and the need for disease-specific adjustments of this abstraction approach in five additional solid tumor types. METHODS: Patients with metastatic breast cancer (mBC), advanced melanoma (aMel), small cell lung cancer (SCLC), metastatic renal cell carcinoma (mRCC), and advanced gastric/esophageal cancer (aGEC) were selected from a real-world database. Disease-specific additions to the base case were implemented as needed. The resulting abstraction approach was applied to each disease cohort to capture rwP events and dates. To provide comprehensive clinical context, real-world progression-free survival (rwPFS) and time to progression (rwTTP) were compared to real-world overall survival (rwOS), time to next treatment (rwTTNT), and time to treatment discontinuation (rwTTD). Endpoint estimates were assessed using the Kaplan-Meier method. Correlations between real-world endpoints and rwOS were calculated using Spearman's ρ. RESULTS: Additions to the base-case rwP abstraction approach were required for mBC, aMel, and SCLC. Inter-abstractor agreement for rwP occurrence, irrespective of date, ranged from 88% to 97%. Occurrence of clinically relevant downstream events (new antineoplastic systemic therapy start, antineoplastic systemic therapy end, or death relative to the rwP event) ranged from 59% (aMel) to 72% (mBC). Median rwPFS ranged from 3.7 (aMel) to 7.7 (mBC) months, and median rwTTP ranged from 4.6 (aMel) to 8.3 (mRCC) months. Correlations between rwOS and rwPFS ranged from 0.52 (aMel) to 0.82 (SCLC). The correlation between rwOS and rwTTD was often lower relative to other comparisons (range 0.40-0.62). CONCLUSION: Derivation of a rwP variable from EHR documentation is feasible and reliable across the five solid tumors. Endpoint analyses show that rwP produces clinically meaningful information.

Exploring racial disparities in treatment patterns and outcomes for patients with multiple myeloma using real world data.

This retrospective observational study evaluated racial disparities among Black and White patients with multiple myeloma (MM). We included patients from a longitudinal de-identified EHR-derived database who had ≥2 visits recorded on or after 1/1/2011, documented treatment, and race listed as White or Black. Black patients (n = 1172) were more likely female (54.8%/42.9%) and younger (<65 years, 40.8%/30.8%) than White patients (n = 4637). Unadjusted median real-world overall survival (rwOS) indexed to first-line of therapy (LOT) was 64.6 months (95% CI: 57.8-74.0) for Blacks and 54.5 months (95% CI: 50.9-56.2) for Whites. Adjusted rwOS estimates (for sex, age at index date, and practice type) to either first- (aHR = 0.94; 95% CI: 0.84-1.06) or second-LOT (aHR = 0.90; 95% CI: 0.77-1.05) were similar. Unadjusted derived response rate (dRR) during first-LOT was 84.8% (95% CI: 80.7-88.1) for Blacks and 86.9% (95% CI: 85.0-88.5) for Whites (odds ratio [OR] = 0.78 [95% CI: 0.57-1.10]); in second-LOT, 67.2% (95% CI: 58.4-75.0) for Blacks and 72.4% (95% CI: 68.1-76.3) for Whites (OR = 0.72 [95% CI: 0.46-1.13]). High representation of Black patients enabled this robust analysis, albeit with limitations inherent to the observational data source, the retrospective design, and the analytic use of newly derived endpoints requiring further validation.

Best practices in the real-world data life cycle.

With increasing digitization of healthcare, real-world data (RWD) are available in greater quantity and scope than ever before. Since the 2016 United States 21st Century Cures Act, innovations in the RWD life cycle have taken tremendous strides forward, largely driven by demand for regulatory-grade real-world evidence from the biopharmaceutical sector. However, use cases for RWD continue to grow in number, moving beyond drug development, to population health and direct clinical applications pertinent to payors, providers, and health systems. Effective RWD utilization requires disparate data sources to be turned into high-quality datasets. To harness the potential of RWD for emerging use cases, providers and organizations must accelerate life cycle improvements that support this process. We build on examples obtained from the academic literature and author experience of data curation practices across a diverse range of sectors to describe a standardized RWD life cycle containing key steps in production of useful data for analysis and insights. We delineate best practices that will add value to current data pipelines. Seven themes are highlighted that ensure sustainability and scalability for RWD life cycles: data standards adherence, tailored quality assurance, data entry incentivization, deploying natural language processing, data platform solutions, RWD governance, and ensuring equity and representation in data.

Emulating Control Arms for Cancer Clinical Trials Using External Cohorts Created From Electronic Health Record-Derived Real-World Data.

Electronic health record (EHR)-derived real-world data (RWD) can be sourced to create external comparator cohorts to oncology clinical trials. This exploratory study assessed whether EHR-derived patient cohorts could emulate select clinical trial control arms across multiple tumor types. The impact of analytic decisions on emulation results was also evaluated. By digitizing Kaplan-Meier curves, we reconstructed published control arm results from 15 trials that supported drug approvals from January 1, 2016, to April 30, 2018. RWD cohorts were constructed using a nationwide EHR-derived de-identified database by aligning eligibility criteria and weighting to trial baseline characteristics. Trial data and RWD cohorts were compared using Kaplan-Meier and Cox proportional hazards regression models for progression-free survival (PFS) and overall survival (OS; individual cohorts) and multitumor random effects models of hazard ratios (HRs) for median endpoint correlations (across cohorts). Post hoc, the impact of specific analytic decisions on endpoints was assessed using a case study. Comparing trial data and weighted RWD cohorts, PFS results were more similar (HR range = 0.63-1.18, pooled HR = 0.84, correlation of median = 0.91) compared to OS (HR range = 0.36-1.09, pooled HR = 0.76, correlation of median = 0.85). OS HRs were more variable and trended toward worse for RWD cohorts. The post hoc case study had OS HR ranging from 0.67 (95% confidence interval (CI): 0.56-0.79) to 0.92 (95% CI: 0.78-1.09) depending on specific analytic decisions. EHR-derived RWD can emulate oncology clinical trial control arm results, although with variability. Visibility into clinical trial cohort characteristics may shape and refine analytic approaches.

Real-World Outcomes for Advanced Non-Small Cell Lung Cancer Patients Treated With a PD-L1 Inhibitor Beyond Progression.

BACKGROUND: Clinical trials of anti-programmed cell death ligand 1 (PD-L1) inhibitor to treat advanced non-small-cell lung cancer (aNSCLC) have permitted treatment beyond progression (TBP). However, the outcomes of patients receiving TBP in routine clinical care are unknown. MATERIALS AND METHODS: The present retrospective, observational, multicenter analysis evaluated de-identified electronic health record-derived data from community-based clinics in the United States. The patients had confirmed aNSCLC, had started anti-PD-L1 inhibitor therapy (nivolumab, pembrolizumab, or atezolizumab) before October 1, 2018, and had experienced a real-world progression (rwP) event. The study period ended March 31, 2019. The primary objective was to compare the overall survival (OS) of patients who had discontinued immunotherapy ≤ 30 days (non-TBP) compared with > 30 days after rwP (TBP). Descriptive analyses were performed. The Kaplan-Meier method and log-rank test were conducted for OS. An adjusted multivariable Cox proportional hazards regression model was also used. RESULTS: Overall, the data from 4223 patients were analyzed; 2555 (60.5%) and 1668 (39.5%) in the non-TBP and TBP cohorts, respectively. The median treatment duration for the non-TBP and TBP patients was 2.8 and 9.1 months (log-rank test, P < .001), respectively. The TBP group experienced longer unadjusted OS compared with the non-TBP group (11.5 vs. 5.1 months; log-rank test, P < .001). After adjusting for clinically relevant patient characteristics, the TBP OS benefit persisted (adjusted hazard ratio, 0.69; P < .001). CONCLUSIONS: TBP with PD-L1 inhibitor therapy is common in aNSCLC routine care and is potentially effective. These results support clinical trial observations likely to affect practice patterns.

Real-World Dosing Patterns and Outcomes of Patients With Metastatic Pancreatic Cancer Treated With a Liposomal Irinotecan Regimen in the United States.

OBJECTIVES: Liposomal irinotecan (nal-IRI) is a topoisomerase inhibitor proven to improve survival in metastatic pancreatic cancer (mPC). This study describes real-world characteristics of patients treated with nal-IRI for mPC. METHODS: Patients 18 years or older diagnosed with stage IV mPC and treated with nal-IRI were selected retrospectively from a deidentified electronic health record database of more than 2 million US cancer patients. Demographics, clinical and dosing characteristics, and treatment outcomes were collected. RESULTS: Of 257 total patients, 145 (57%) received nal-IRI as first- or second-line therapy. Median nal-IRI treatment duration was 51 days, longer when nal-IRI was used as first/second versus as third-line therapy or later (62 vs 44.5 days). Seventy patients (27.2%) experienced dose modification. Median time to treatment discontinuation was 2.3 versus 1.6 months for first-/second- versus third-line therapy or later, respectively. Median overall survival from nal-IRI initiation was 5.6 versus 4.1 months for first-/second- versus third-line therapy or later, respectively. Prior irinotecan treatment, baseline serum albumin less than 40 g/L, and baseline neutrophil-to-lymphocyte ratio greater than 5 were associated with reduced overall survival. CONCLUSIONS: This is the first large US study of real-world US mPC patients treated with nal-IRI. These results, comparable to the NAPOLI-1 trial, can help inform future studies and the efficacy of nal-IRI in mPC therapy.

Clinical and Genomic Characteristics of Small Cell Lung Cancer in Never Smokers: Results From a Retrospective Multicenter Cohort Study.

BACKGROUND: Small cell lung cancer (SCLC) has the strongest association with smoking among lung cancers. The characteristics of never smokers with SCLC is not known. RESEARCH QUESTION: Are the clinical characteristics, prognostic factors, survival, genomic alterations, and tumor mutational burdens of SCLC in patients who have never smoked different from those who have smoked? STUDY DESIGN AND METHODS: A retrospective multicenter cohort study of patients with clinician-confirmed SCLC was performed with the use of a longitudinal and nationally representative electronic medical records database. Smoking history was assessed through technology-enabled abstraction and confirmed for never smokers via chart review. Genomic characteristics of never smoker patients with SCLC were examined with the use of a next-generation sequencing-based gene panel and whole exome sequencing. RESULTS: One hundred of 5,632 patients (1.8%) with SCLC were never smokers. Relative to smokers, never smokers were more likely to be female (66.0% vs 52.4%; P = .009) and present with extensive stage (70.0% vs 62.2%; P = .028). Never smokers had a higher proportion of patients in age groups 35 to 49 years (7.0% vs 3.0%; P = .006) and ≥80 years (17.0% vs 8.2%; P = .006). Known risk factors for lung cancer were found in <20% of never smokers. There were no overall survival differences between never smokers and smokers. Among patients with available genomic data (n = 9), never smoker SCLC were characterized by lower tumor mutational burden, a lower frequency of TP53 mutations, and an absence of mutational signatures related to tobacco exposure. INTERPRETATION: The sex- and age-specific distribution of SCLC among never smokers, along with differences that were identified by genomic analyses, suggests a distinct biology of SCLC in never smokers compared with smokers.

Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting.

OBJECTIVES: In patients with non-squamous non-small-cell lung cancer (NSCLC), maintenance therapy regimens, including pemetrexed, have been shown to prolong overall survival (OS) and progression-free survival (PFS). The purpose of this study was to describe real-world maintenance use of pemetrexed and associated outcomes in patients with advanced NSCLC. METHODS: This was a retrospective, observational study that used longitudinal, demographically and geographically diverse electronic health record data in the United States. Eligible patients were adults with advanced non-squamous NSCLC who had received maintenance treatment with pemetrexed monotherapy or pemetrexed plus bevacizumab. Descriptive statistics were used to describe the patient population and multivariable logistic regression was used to identify the factors associated with duration of maintenance therapy. Kaplan-Meier curves and Cox regression models were used for time-to-event analysis. RESULTS: Patients receiving pemetrexed maintenance therapy were treated with either pemetrexed monotherapy (66.0%) or pemetrexed plus bevacizumab (34.0%). Carboplatin and pemetrexed (37.9%) or carboplatin, pemetrexed and bevacizumab (36.1%) were the most commonly used first-line therapies observed. The majority (84.9%) of these maintenance patients responded to first-line therapy. The median duration of maintenance therapy was 6.0 months for pemetrexed and bevacizumab and 4.1 months for pemetrexed monotherapy. The median OS from the start of first-line therapy of the total study cohort was 21.5 months (95% CI 20.0, 22.9). CONCLUSION: Real-world effectiveness of pemetrexed maintenance therapy is similar to that observed in published randomized controlled trials, confirming a role for pemetrexed maintenance in eligible patients in clinical practice.