Concordance of Clinician-Documented and Imaging Response in Patients With Stage IV Non-Small Cell Lung Cancer Treated With First-Line Therapy.

Importance: In observational oncology studies of solid tumors, response to treatment can be evaluated based on electronic health record (EHR) documentation (clinician-assessed response [CAR]), an approach different from standardized radiologist-measured response (Response Evaluation Criteria in Solid Tumours [RECIST] 1.1). Objective: To evaluate the feasibility of an imaging response based on RECIST (IRb-RECIST) and the concordance between CAR and imaging response based on RECIST assessments, and investigate discordance causes. Design, Setting, and Participants: This cohort study used an EHR-derived, deidentified database that included patients with stage IV non-small cell lung cancer (NSCLC) diagnosed between January 1, 2011, to June 30, 2019, selected from 3 study sites. Data analysis was conducted in August, 2020. Exposures: Undergoing first-line therapy and imaging assessments of response to treatment. Main Outcomes and Measures: In this study, CAR assessments (referred to in prior publications as "real-world response" [rwR]) were defined as clinician-documented changes in disease burden at radiologic evaluation time points; they were abstracted manually and assigned to response categories. The RECIST-based assessments accommodated routine practice patterns by using a modified version of RECIST 1.1 (IRb-RECIST), with independent radiology reads. Concordance was calculated as the percent agreement across all response categories and across a dichotomous stratification (response [complete or partial] vs no response), unconfirmed or confirmed. Results: This study found that, in 100 patients evaluated for concordance, agreement between CAR and IRb-RECIST was 71% (95% CI, 61%-80%), and 74% (95% CI, 64%-82%) for confirmed and unconfirmed response, respectively. There were more responders using CAR than IRb-RECIST (40 vs 29 with confirmation; 64 vs 43 without confirmation). The main sources of discordance were the different use of thresholds for tumor size changes by RECIST vs routine care, and unavailable baseline or follow-up scans resulting in inconsistent anatomic coverage over time. Conclusions and Relevance: In this cohort study of patients with stage IV NSCLC, we collected routine-care imaging, showing the feasibility of response evaluation using IRb-RECIST criteria with independent centralized review. Concordance between CAR and centralized IRb-RECIST was moderate. Future work is needed to evaluate the generalizability of these results to broader populations, and investigate concordance in other clinical settings.

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.

Characterization of a Real-World Response Variable and Comparison with RECIST-Based Response Rates from Clinical Trials in Advanced NSCLC.

INTRODUCTION: Effectiveness metrics for real-word research, analogous to clinical trial ones, are needed. This study aimed to develop a real-world response (rwR) variable applicable to solid tumors and to evaluate its clinical relevance and meaningfulness. METHODS: This retrospective study used patient cohorts with advanced non-small cell lung cancer from a nationwide, de-identified electronic health record (EHR)-derived database. Disease burden information abstracted manually was classified into response categories anchored to discrete therapy lines (per patient-line). In part 1, we quantified the feasibility and reliability of data capture, and estimated the association between rwR status and real-world progression-free survival (rwPFS) and real-world overall survival (rwOS). In part 2, we investigated the correlation between published clinical trial overall response rates (ORRs) and real-world response rates (rwRRs) from corresponding real-world patient cohorts. RESULTS: In part 1, 85.4% of patients (N = 3248) had at least one radiographic assessment documented. Median abstraction time per patient-line was 15.0 min (IQR 7.8-28.1). Inter-abstractor agreement on presence/absence of at least one assessment was 0.94 (95% CI 0.92-0.96; n = 503 patient-lines abstracted in duplicate); inter-abstractor agreement on best confirmed response category was 0.82 (95% CI 0.78-0.86; n = 384 with at least one captured assessment). Confirmed responders at a 3-month landmark showed significantly lower risk of death and progression in rwOS and rwPFS analyses across all line settings. In part 2, rwRRs (from 12 rw cohorts) showed a high correlation with trial ORRs (Spearman's ρ = 0.99). CONCLUSIONS: We developed a rwR variable generated from clinician assessments documented in EHRs following radiographic evaluations. This variable provides clinically meaningful information and may provide a real-world measure of treatment effectiveness.

A Pilot Study of a Multimodal Treatment Paradigm to Accelerate Drug Evaluations in Early-stage Metastatic Prostate Cancer.

OBJECTIVE: To evaluate a multimodal strategy aimed at treating all sites of disease that provides a rapid readout of success or failure in men presenting with non-castrate metastatic prostate cancers that are incurable with single modality therapy. MATERIALS AND METHODS: Twenty selected men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis were treated using a multimodal approach that included androgen deprivation, radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease or the primary site. Outcomes of each treatment were assessed sequentially. Androgen deprivation was discontinued in responding patients. The primary end point was an undetectable prostate-specific antigen (PSA) after testosterone recovery. The goal was to eliminate all detectable disease. RESULTS: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after androgen deprivation alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval: 3%-38%) achieved the primary end point, which persisted for 5, 6, 27+ , and 46+ months. All patients meeting the primary end point had been classified with M1b disease at presentation. CONCLUSION: A sequentially applied multimodal treatment strategy can eliminate detectable disease in selected patients with metastatic spread at diagnosis. The end point of undetectable PSA after testosterone recovery should be considered when evaluating new approaches to rapidly set priorities for large-scale testing in early metastatic disease states and to shift the paradigm from palliation to cure.