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Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n = 94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n = 65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9–17.4) months for entrectinib; 8.2 (6.2–9.9) months for crizotinib (weighted hazard ratio: 0.72 [0.51–1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1–47.2) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.

Background: Huntington’s disease (HD) is a rare, genetic, neurodegenerative disease. Obtaining population-level data on epidemiology and disease management is challenging. Objective: To investigate the epidemiology, clinical manifestations, treatment, and healthcare utilization of patients with HD in Israel. Methods: Retrospective population-based cohort study, including 20 years of routinely collected data from Maccabi Healthcare Services, an insurer and healthcare provider for one-quarter of the Israeli population. Results: The study cohort included 109 adult patients (aged ≥18 years) diagnosed with HD, with mean age of 49.9 years and 56%females. The most common HD-related conditions were anxiety (40%), behavioral problems (34%), sleep disorders (21%), and falls (13%). Annual incidence rates for HD ranged from 0.17 to 1.34 per 100,000 from 2000 to 2018; the 2018 crude prevalence in adults was 4.36 per 100,000. Median survival from diagnosis was approximately 12 years (95%CI: 10.4–15.3). The most frequent symptomatic treatments were antidepressants (69%), antipsychotics (63%), and tetrabenazine (63%), the only drug approved for the treatment of HD chorea in Israel during the examined period. Patterns of healthcare utilization changed as disease duration increased, reflected by increased frequency of emergency department visits and home visits. Conclusion: This retrospective population-based study provides insights into the prevalence, incidence, clinical profile, survival, and resource utilization of patients with HD in ethnically diverse Israel. The findings in this study are generally consistent with the international literature and demonstrate the value of routinely collected healthcare data as a complementary resource in HD research.

Objective The FlywheelMS study will explore the use of a real-world health record data set generated by PicnicHealth, a patient-centric health records platform, to improve understanding of disease course and patterns of care for patients with multiple sclerosis (MS). Materials and Methods The FlywheelMS study aims to enroll 5000 adults with MS in the United States to create a large, deidentified, longitudinal data set for clinical research. PicnicHealth obtains health records, including paper charts, electronic health records, and radiology imaging files from any healthcare site. Using a large-scale health record processing pipeline, PicnicHealth abstracts standard and condition-specific data elements from structured (eg, laboratory test results) and unstructured (eg, narrative) text and maps these to standardized medical vocabularies. Researchers can use the resulting data set to answer empirical questions and study participants can access and share their harmonized health records using PicnicHealth’s web application. Results As of November 24, 2020, more than 4176 participants from 49 of 50 US states have enrolled in the FlywheelMS study. A median of 200 pages of records have been collected from 14 different doctors over 8 years per participant. Abstraction precision, established through inter-abstractor agreement, is as high as 97.8% when identifying and mapping data elements to a standard ontology. Conclusion Using a commercial health records platform, the FlywheelMS study is generating a real-world, multimodal data set that could provide valuable insights about patients with MS. This approach to data collection and abstraction is disease-agnostic and could be used to address other clinical research questions in the future.

Summary There is an increasing expectation that computational approaches may supplement existing human decision-making. Frontloading of models for cardiac safety prediction is no exception to this trend, and ongoing regulatory initiatives propose use of high-throughput in vitro data combined with computational models for calculating proarrhythmic risk. Evaluation of these models requires robust assessment of the outcomes. Using FDA Adverse Event Reporting System reports and electronic healthcare claims data from the Truven-MarketScan US claims database, we quantify the incidence rate of arrhythmia in patients and how this changes depending on patient characteristics. First, we propose that such datasets are a complementary resource for determining relative drug risk and assessing the performance of cardiac safety models for regulatory use. Second, the results suggest important determinants for appropriate stratification of patients and evaluation of additional drug risk in prescribing and clinical support algorithms and for precision health., Graphical Abstract, Highlights In vitro data and computational models can assist with calculating pro-arrhythmic risk We use patient health records and FDA Adverse Event Reporting System reports Use of such datasets helps assess relative drug risk and cardiac safety models We quantify how patient characteristics can affect arrhythmia incidence, Davies et al. analyze patient health records and FDA Adverse Event Reporting System reports to demonstrate how patient subtypes affect the incidence of drug-related arrhythmia. Using such real-world data to understand background arrhythmia can further validate cardiac risk models for regulatory use and help stratify patients when evaluating drug risk.

Background: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed. Methods: This retrospective US cohort study used Flatiron Health’s longitudinal electronic health record (EHR)-derived database. Patients (≥ 18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016. Patients enrolled on a clinical trial or exposed to ALK inhibitors other than crizotinib or ceritinib were excluded. Treatment patterns, time and type of biomarker testing, and overall survival (OS) were analyzed. Results: Median age (n = 300) was 62.5 years; 55% female; 48% non-smokers; 8.7% central nervous system (CNS) metastases at diagnosis. Overall, 73% and 86% received their first ALK biomarker test before/at diagnosis, or before/during first-line treatment, respectively. In total, 90.0%, 78.1%, and 74.7% received first-, second-, and third-line therapy, respectively. Most patients received ALK-targeted treatment; 62% received crizotinib, of which 21% reported a dose reduction. Progression was the most common reason for crizotinib (78%) and ceritinib (41%) discontinuation. Median OS was 29.4 months (95% CI =24.7–39.6) overall; 27.1 months (95% CI =22.0–35.0) in patients with CNS metastases, and 36.9 months (95% CI =25.1–not reached) without. Conclusions: Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors.

Aim: To compare the overall survival of anaplastic lymphoma kinase -positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib. Materials & methods: Two treatment arms (alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan–Meier and multivariate Cox regression were conducted. Results: After propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (alectinib = 24.3 months and ceritinib = 15.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48–0.88). Conclusion: Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

Background As new targeted therapies with CNS penetration and activity for non-small cell lung cancer (NSCLC) with ROS1 gene fusions (ROS1+) emerge, there is a need to characterize the disease course of patients (pts) receiving current treatment, especially in relation to CNS metastases (met). Methods We evaluated an anonymized cohort of ROS1+ NSCLC pts from the Flatiron Health electronic health record (EHR)-derived database of US cancer centers (2011–2018). Descriptive statistics were used for clinical and treatment pattern characterization. Kaplan-Meier curves estimated median overall survival (OS), real-world progression-free survival (rwPFS, using physician documentation in the EHR) and rwPFS in the CNS, from 1st-line treatment (1L) after diagnosis of advanced/metastatic NSCLC (aNSCLC Dx). Due to low numbers of pts in some groups, 95% CI are not reported. Results We identified 129 ROS1+ aNSCLC pts who received 1L treatment including crizotinib (n = 52, 40.3%), chemotherapy (n = 34, 26.4%), combination systemic therapy (n = 25, 19.4%), clinical study drug (n = 4, 3.1%), or no treatment (n = 14, 10.9%). For 1L crizotinib (the only approved therapy for ROS1+ NSCLC) after aNSCLC Dx median rwPFS: 8.6 m (95% CI: 6.2–12.1); OS: 19.9 m (95% CI: 15.1–NR). For pts receiving other 1L drugs median rwPFS: 5.9 m (95% CI: 4.1–7.2); OS: 18.1 m (95% CI: 12.9–34.6). There were 24 pts (18%) with CNS met at diagnosis and 20 pts (19%) at follow-up. Most pts with CNS met at or after diagnosis received surgery/radiotherapy (37/44, 84.1%). For CNS met pts who received 1L crizotinib after local treatment (6/11), median rwPFS: 8.0 m; OS: 27 m. From 1L crizotinib, pts with CNS met at follow-up only (10/21 pts with CNS mets who received 1L crizotinib), median rwPFS: 7.2 m; rwPFS-CNS: 9.1 m; OS: 15.1 m. For pts with no CNS mets anytime median rwPFS: 10.0 m; OS: 21.5 m from 1L crizotinib (34/55 pts). Conclusions In the US, ROS1+ NSCLC pts receive various 1L treatments after aNSCLC Dx. CNS was a site of metastasis in 44/129 ROS1+ NSCLC pts. Surgery/radiotherapy for CNS mets prior to systemic therapy appeared to result in favorable outcomes, however conclusions on the natural history of cancers with rare mutations rely on very small patient numbers. Editorial acknowledgement Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications, funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffmann-La Roche. Funding F. Hoffmann-La Roche. Disclosure M.G. Krebs: Advisory / Consultancy, Officer / Board of Directors: Roche, Achilles Therapeutics, Octimet, Janssen; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca, Bayer, BerGenBio, Blueprint, Carrick, Immutep, Incyte, Janssen, Merck, Octimet, Roche; Travel / Accommodation / Expenses: AstraZeneca, BerGenBio. L. Perez: Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Roche. A. Surinach: Full / Part-time employment: Genesis Research. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain Therapeutics; Research grant / Funding (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. M. Martinec: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche/Genentech. N.J. Meropol: Shareholder / Stockholder / Stock options: Roche; Shareholder / Stockholder / Stock options, Full / Part-time employment: Flatiron Health, Inc. W. Wong: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. G. Crane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. All other authors have declared no conflicts of interest.

9113 Background: We recently established the ability of broad-panel clinical sequencing data to stratify overall survival of patients with advanced lung adenocarcinomas in a single institutional experience (Shen, Riely et al., JCO Precision Oncology 2019). Here we sought to assess its generalizability to a broader range of patients (including patients from multiple community and academic sites) using a different sequencing panel, with an integrated electronic health record and genomic database. Methods: We identified 2,779 next-generation sequencing-tested patients with advanced lung adenocarcinomas from the Flatiron-Foundation Medicine Clinico-Genomic database. A genomic risk model developed from the initial discovery cohort (n=1,054) was used to calculate a risk score for each patient in the validation cohort, scaled between 0 and 10, indicating the risk of cancer specific mortality. Results: Patients in the validation cohort were classified into four risk categories with median survival ranging from 37.6 months (95% CI: 32.9-43.8) in the low risk group (n=534) to 10.9 months (95% CI: 8.0-16.5) in the highest risk group (n=75), representing a hazard ratio of 3.0 (95% CI: 2.2-4.1) and closely matching the discovery cohort observations. A smaller proportion of patients were deemed high risk in the validation cohort (2.7% vs 10% in the discovery cohort). There were some differences in the frequencies of the most common genomic alterations between the validation and discovery cohorts, including TP53 (57.3% vs 55.1%) , KRAS (32.8% vs 30%), EGFR (18.6% vs 29.4%) as well as overlapping STK11 and KEAP1 co-mutations (2.4% vs 10%). Conclusions: We demonstrate that a clinical tumor sequencing-based genomic risk stratification strategy can be applied broadly across cohorts and different sequencing panels and platforms, to improve the understanding of heterogeneity in clinical outcome for patients with metastatic lung adenocarcinomas and the mutation and co-mutational patterns that underlie such heterogeneity.

9070 Background: Entrectinib is an oral tyrosine kinase inhibitor for ROS1+ NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ pts generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC pts from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials. Methods: Crizotinib-treated pts with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database ( > 2.1 million cancer pts from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: TTD, adapted from Gong (ASCO 2018); rwPFS (physician/scan report) and OS were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors. Results: We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC pts. Median weighted TTD: entrectinib, 14.6 mo (95% CI: 8.3–23.8); crizotinib, 8.8 mo (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 mo); weighted median OS with crizotinib was 18.5 mo (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses. Conclusions: Entrectinib was associated with longer TTD and PFS in ROS1+ NSCLC pts vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.