Approaches for Enhanced Extrapolation of Long-Term Survival Outcomes Using Electronic Health Records of Patients With Cancer.

OBJECTIVES: This study aimed to demonstrate enhanced survival extrapolation methods using electronic health record-derived real-world data (RWD). METHODS: The study population included patients diagnosed of ER+/HER2- metastatic breast cancer who started first-line treatment with anastrozole or letrozole between November 18, 2014, and November 18, 2015. Two patient cohorts were constructed: a clinical trial cohort from digitized MONARCH-3 clinical trial results and a RWD cohort from a deidentified electronic health record-derived database. RWD patients were weighted to trial baseline covariate distributions. Standard parametric approaches were applied to trial data and a "best-fit" model was selected. We demonstrate traditional and enhanced hybrid (pooling with weighted RWD at start, 75%, or end of trial) extrapolation approaches. RESULTS: Observed and estimated 5-year progression-free survival (PFS) rates in extrapolating the trial control arm (n = 165) were comparable across all methods. Compared with the observed 5-year mean PFS in the RWD cohort (n = 118) of 20.4 months (95% confidence interval [CI] 16.9-23.8), there was some variation among studied methods. Best-fit standard parametric model (log-normal) had 5-year mean PFS of 21.3 months (95% CI 18.2-24.9), and for the hybrid methods in order of estimate conservativeness was start of trial (20.8 months; 95% CI 18.5-23.2), 75% of trial (21.3 months; 95% CI 18.1-24.5), and end of trial (21.8 months; 95% CI 18.8-25.2). CONCLUSIONS: Our study leverages RWD to enhance long-term survival extrapolation. Future use cases should include applying patient eligibility criteria, weighting on baseline characteristics, and choice of time window to add RWD to trial data.

Differential frequency in imaging-based outcome measurement: Bias in real-world oncology comparative-effectiveness studies.

BACKGROUND: Comparative-effectiveness studies using real-world data (RWD) can be susceptible to surveillance bias. In solid tumor oncology studies, analyses of endpoints such as progression-free survival (PFS) are based on progression events detected by imaging assessments. This study aimed to evaluate the potential bias introduced by differential imaging assessment frequency when using electronic health record (EHR)-derived data to investigate the comparative effectiveness of cancer therapies. METHODS: Using a nationwide de-identified EHR-derived database, we first analyzed imaging assessment frequency patterns in patients diagnosed with advanced non-small cell lung cancer (aNSCLC). We used those RWD inputs to develop a discrete event simulation model of two treatments where disease progression was the outcome and PFS was the endpoint. Using this model, we induced bias with differential imaging assessment timing and quantified its effect on observed versus true treatment effectiveness. We assessed percent bias in the estimated hazard ratio (HR). RESULTS: The frequency of assessments differed by cancer treatment types. In simulated comparative-effectiveness studies, PFS HRs estimated using real-world imaging assessment frequencies differed from the true HR by less than 10% in all scenarios (range: 0.4% to -9.6%). The greatest risk of biased effect estimates was found comparing treatments with widely different imaging frequencies, most exaggerated in disease settings where time to progression is very short. CONCLUSIONS: This study provided evidence that the frequency of imaging assessments to detect disease progression can differ by treatment type in real-world patients with cancer and may induce some bias in comparative-effectiveness studies in some situations.

Finding and treating early-stage HIV infections: A cost-effectiveness analysis of the Sabes study in Lima, Peru.

Background: Sabes, a treatment-as-prevention intervention among men who have sex with men and transgender women in Lima, Peru, was developed to identify HIV during early primary infection (<3 months from acquisition) through monthly serologic assays and HIV RNA tests. Newly diagnosed individuals were rapidly linked to care and offered to initiate ART. In this study we sought to study the cost-effectiveness of Sabes compared to the standard of care (SOC) for HIV testing and initiation of treatment. Methods: We adapted a compartmental model of HIV transmission to evaluate the cost-effectiveness of the Sabes approach compared to the SOC using a government health care perspective, 20-year time horizon, and 3% annual discounting. We estimated the proportion of cases of HIV detected during early primary infection, reduction in HIV incidence and prevalence, incremental cost-effectiveness ratio (ICER), and net monetary benefit. We analyzed costs using data from the Sabes study, the Peruvian Ministry of Health, published literature, and expert consultation. Findings: The Sabes intervention is projected to identify 9294 early primary HIV infections in Lima, Peru over 20 years. The intervention costs $6,896 per early primary infection diagnosed and by 2038 is expected to decrease the fraction of early infections among prevalent infections by 62%. Sabes is expected to improve health, resulting in greater total discounted QALYs per person than the SOC (16·7 vs 16·4, respectively). Sabes had an ICER of $1431 (22% per capita GDP in Peru) per QALY compared to SOC. Interpretation: Our analysis suggests that in Lima, Peru the Sabes intervention could be a cost-effective approach to reduce the burden of HIV even under stringent cost-effectiveness criteria. This finding suggests that programs that use frequent HIV testing, rapid linkage to care and initiation of ART should be considered as part of a comprehensive HIV prevention strategy. Funding: National Institutes of Health.

ACA Medicaid expansion association with racial disparity reductions in timely cancer treatment.

OBJECTIVES: Racial disparities in cancer care and outcomes remain a societal challenge. Medicaid expansion through the Affordable Care Act was intended to improve health care access and equity. This study aimed to assess whether state Medicaid expansions were associated with a reduction in racial disparities in timely treatment among patients diagnosed with advanced cancer. STUDY DESIGN: This difference-in-differences study analyzed deidentified electronic health record-derived data. Patients aged 18 to 64 years with advanced or metastatic cancers diagnosed between January 1, 2011, and January 31, 2019, and receiving systemic therapy were included. METHODS: The primary end point was receipt of timely treatment, defined as first-line systemic therapy starting within 30 days after diagnosis of advanced or metastatic disease. Racial disparity was defined as adjusted percentage-point (PP) difference for Black vs White patients, adjusted for age, sex, practice setting, cancer type, stage, insurance marketplace, and area unemployment rate, with time and state fixed effects. RESULTS: The study included 30,310 patients (12.3% Black race). Without Medicaid expansion, Black patients were less likely to receive timely treatment than White patients (43.7% vs 48.4%; adjusted difference, -4.8 PP; P < .001). With Medicaid expansion, this disparity was diminished and lost significance (49.7% vs 50.5%; adjusted difference, -0.8 PP; P = .605). The adjusted difference-in-differences estimate was a 3.9 PP reduction in racial disparity (95% CI, 0.1-7.7 PP; P = .045). CONCLUSIONS: Medicaid expansion was associated with reduced Black-White racial disparities in receipt of timely systemic treatment for patients with advanced or metastatic cancers.

Using electronic health record data to identify comparator populations for comparative effectiveness research.

Electronic health records (EHRs) can define real world patient populations with high levels of clinical specificity, potentially addressing some of the shortcomings of other types of real world data (RWD) when informing decisions about the comparative effectiveness of medical technologies. An important but under-recognized concern for EHR-derived RWD, however, is that the rich clinical data permits creation of very homogenous subpopulations from the larger group of eligible patients, thereby reducing the representativeness of the cohort relative to clinical practice. In this article, we discuss the tradeoffs between choosing clinical specificity versus representativeness in population sampling for comparative effectiveness research. Using EHR-derived RWD, we provide an example in non-small cell lung cancer to illustrate the concepts, showing wide variation in outcomes among potential comparator cohorts. We close with several recommendations for selecting comparator populations from EHRs that address the balance between matching clinical guidelines and capturing practice variability in comparative effectiveness research.

Adoption of Immune Checkpoint Inhibitors and Patterns of Care at the End of Life.

PURPOSE: As immune checkpoint inhibitors (ICIs) have transformed the care of patients with cancer, it is unclear whether treatment at the end of life (EOL) has changed. Because aggressive therapy at the EOL is associated with increased costs and patient distress, we explored the association between the Food and Drug Administration (FDA) approvals of ICIs and treatment patterns at the EOL. METHODS: We conducted a retrospective, observational study using patient-level data from a nationwide electronic health record-derived database. Patients had advanced melanoma, non-small-cell lung cancer (NSCLC; cancer types with an ICI indication), or microsatellite stable (MSS) colon cancer (a cancer type without an ICI indication) and died between 2013 and 2017. We calculated annual proportions of decedents who received systemic cancer therapy in the final 30 days of life, using logistic regression to model the association between the post-ICI FDA approval time and use of systemic therapy at the EOL, adjusting for patient characteristics. We assessed the use of chemotherapy or targeted/biologic therapies at the EOL, before and after FDA approval of ICIs using Pearson chi-square test. RESULTS: There was an increase in use of EOL systemic cancer therapy in the post-ICI approval period for both melanoma (33.9% to 43.2%; P < .001) and NSCLC (37.4% to 40.3%; P < .001), with no significant change in use of systemic therapy in MSS colon cancer. After FDA approval of ICIs, patients with NSCLC and melanoma had a decrease in the use of chemotherapy, with a concomitant increase in use of ICIs at the EOL. CONCLUSION: The adoption of ICIs was associated with a substantive increase in the use of systemic therapy at the EOL in melanoma and a smaller yet significant increase in NSCLC.

Evaluating the Impact of Oncology Care Model Reporting Requirements on Biomarker Testing and Treatment.

PURPOSE: The Oncology Care Model (OCM) is Medicare's first alternative payment model program for patients with cancer. As of October 2017, participating practices were required to report biomarker testing of patients with advanced non-small-cell lung cancer (aNSCLC). Our objective was to evaluate the effect of this OCM reporting requirement on quality of care. METHODS: We selected patients with aNSCLC receiving care in practices in a nationwide de-identified electronic health record-derived database. We used an adjusted difference-in-differences (DID) logistic regression model to compare changes in biomarker testing rates (EGFR, ROS1, and ALK) and receipt of biomarker-guided therapy between patients in OCM versus non-OCM practices, before and after OCM implementation. RESULTS: The analysis included 14,048 patients from 45 OCM practices (n = 8,151) and 105 non-OCM practices (n = 5,897). The overall unadjusted rates for biomarker testing and receipt of biomarker-guided therapy increased over the study period (2011-2018) in both OCM (55.5% v 71.6%; 89.8% v 94.6%, respectively) and non-OCM (55.2% v 69.7%; 90.1% v 95.2%, respectively) practices. In the adjusted DID model, the rates of biomarker testing (odds ratio [OR], 1.09 [95% CI, 0.88 to 1.34]; P = .45) and receipt of biomarker-guided therapy (OR, 0.87 [95% CI, 0.52 to 1.45]; P = .58) were similar between OCM and non-OCM practices. CONCLUSION: OCM biomarker documentation and reporting requirements did not appear to increase the proportions of patients with aNSCLC who underwent testing or who received biomarker-guided therapy in OCM versus non-OCM practices.

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

BACKGROUND: Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown. OBJECTIVE: To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness. RESULTS AND LIMITATIONS: IPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding. CONCLUSIONS: In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy. PATIENT SUMMARY: To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.

Trends in Checkpoint Inhibitor Therapy for Advanced Urothelial Cell Carcinoma at the End of Life: Insights from Real-World Practice.

Several immune checkpoint inhibitor therapies (CPIs) have been approved to treat metastatic urothelial cell carcinoma (mUC). Because of the favorable toxicity profile of CPI compared with chemotherapy, oncologists may have a low threshold to prescribe CPI to patients near the end of life. We evaluated trends in initiation of end-of-life systemic therapy in 1,637 individuals in the Flatiron Health Database who were diagnosed with mUC between 2015 and 2017 and who died. Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated CPI within 60 days of death increased from 1.0% to 23% during the study period (p trend < .001). After CPI approval, end-of-life CPI initiation significantly increased among patients with poor performance status (p trend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.

Targeting and vaccine durability are key for population-level impact and cost-effectiveness of a pox-protein HIV vaccine regimen in South Africa.

BACKGROUND: RV144 is to date the only HIV vaccine trial to demonstrate efficacy, albeit rapidly waning over time. The HVTN 702 trial is currently evaluating in South Africa a similar vaccine formulation to that of RV144 for subtype C HIV with additional boosters (pox-protein regimen). Using a detailed stochastic individual-based network model of disease transmission calibrated to the HIV epidemic, we investigate population-level impact and maximum cost of an HIV vaccine to remain cost-effective. METHODS: Consistent with the original pox-protein regimen, we model a primary series of five vaccinations meeting the goal of 50% cumulative efficacy 24 months after the first dose and include two-yearly boosters that maintain durable efficacy over 10 years. We simulate vaccination programs in South Africa starting in 2027 under various vaccine targeting and HIV treatment and prevention assumptions. RESULTS: Our analysis shows that this partially effective vaccine could prevent, at catch-up vaccination with 60% coverage, up to 941,000 (15.6%) new infections between 2027 and 2047 assuming current trends of antiretroviral treatment. An impact of up to 697,000 (11.5%) infections prevented could be achieved by targeting age cohorts of highest incidence. Economic evaluation indicates that, if treatment scale-up was achieved, vaccination could be cost-effective at a total cost of less than $385 and $62 per 10-year series (cost-effectiveness thresholds of $5,691 and $750). CONCLUSIONS: While a partially effective, rapidly waning vaccine could help to prevent HIV infections, it will not eliminate HIV as a public health priority in sub-Saharan Africa. Vaccination is expected to be most effective under targeted delivery to age groups of highest HIV incidence. Awaiting results of trial, the introduction of vaccination should go in parallel with continued innovation in HIV prevention, including studies to determine the costs of delivery and feasibility and further research into products with greater efficacy and durability.

Disease Control With FOLFIRI Plus Ziv-aflibercept (zFOLFIRI) Beyond FOLFIRI Plus Bevacizumab: Case Series in Metastatic Colorectal Cancer (mCRC).

Background: The prognosis of patients with metastatic colorectal cancer (mCRC) is poor, especially after failure of initial systemic therapy. The VELOUR study showed modestly prolonged overall survival (OS) with ziv-aflibercept plus 5-fluorouracil, leucovorin, and irinotecan (zFOLFIRI) vs. placebo+FOLFIRI after progression on 5-fluoruracil, leucovorin, and oxaliplatin (FOLFOX) ± bevacizumab. The utility of zFOLFIRI after bevacizumab+FOLFIRI is unknown and not recommended in NCCN guidelines. We explored whether zFOLFIRI may be active beyond progression on bevacizumab+FOLFIRI. Methods: We undertook a retrospective analysis of patients treated in routine clinical practice. A chart review was conducted for a cohort (N = 19) of advanced cancer patients (18 mCRC) who received zFOLFIRI from 2014 to 2018 at Fox Chase Cancer Center (FCCC). Analysis included time on zFOLFIRI, PFS, OS, CEA trends and adverse events. A second mCRC cohort (N = 26) from the Flatiron Health EHR-derived database treated with zFOLFIRI after prior bevacizumab+FOLFOX and bevacizumab+FOLFIRI was analyzed for time-on-treatment and overall survival. Results: Median age of mCRC cohort at zFOLFIRI treatment was 54 (FCCC; N = 18) and 62 (Flatiron Health-cohort; N = 26). Of 18 FCCC mCRC patients, 1 patient had prior bevacizumab+FOLFOX and ramucirumab+irinotecan prior to zFOLFIRI for 8.5 months. Of 17 FCCC mCRC patients with prior bevacizumab+FOLFIRI who received zFOLFIRI, 13 had mutant-KRAS, 3 WT-KRAS, and one BRAF-V600E. The patient with BRAF-V600E mutation achieved stable disease on zFOLFIRI after multiple BRAF-targeted therapies. One patient (WT-KRAS mCRC) remained on zFOLFIRI for 14 months. Of 14 patients with mutated-KRAS, 8 remained on zFOLFIRI for >5 months including 3 for >15 months. The rate-of-change in CEA measures on zFOLFIRI was significantly different (p = 0.004) between rapid progressors and those with PFS>4 months. For mCRC patients treated with zFOLFIRI in the 3rd line or greater (N = 18), median PFS was 7.1 months (214 days) and median OS was 13.8 months (416 days). Median time-on-treatment with zFOLFIRI in the Flatiron Health cohort was 4.4 months, median OS was 7.8 months, and longest time-on-treatment with zFOLFIRI was 266 days. Conclusions: In these small real-world cohorts, clinical meaningful stable disease and overall survival on zFOLFIRI beyond progression on bevacizumab+FOLFIRI was observed in patients with mCRC. Further exploration of this approach is warranted.

Projected effectiveness and added value of HIV vaccination campaigns in South Africa: A modeling study.

Promising multi-dose HIV vaccine regimens are being tested in trials in South Africa. We estimated the potential epidemiological and economic impact of HIV vaccine campaigns compared to continuous vaccination, assuming that vaccine efficacy is transient and dependent on immune response. We used a dynamic economic mathematical model of HIV transmission calibrated to 2012 epidemiological data to simulate vaccination with anticipated antiretroviral treatment scale-up in South Africa. We estimate that biennial vaccination with a 70% efficacious vaccine reaching 20% of the sexually active population could prevent 480,000-650,000 HIV infections (13.8-15.3% of all infections) over 10 years. Assuming a launch price of $15 per dose, vaccination was found to be cost-effective, with an incremental cost-effectiveness ratio of $13,746 per quality-adjusted life-year as compared to no vaccination. Increasing vaccination coverage to 50% will prevent more infections but is less likely to achieve cost-effectiveness. Campaign vaccination is consistently more effective and costs less than continuous vaccination across scenarios. Results suggest that a partially effective HIV vaccine will have substantial impact on the HIV epidemic in South Africa and offer good value if priced less than $105 for a five-dose series. Vaccination campaigns every two years may offer greater value for money than continuous vaccination reaching the same coverage level.

The Potential Cost-Effectiveness of Pre-Exposure Prophylaxis Combined with HIV Vaccines in the United States.

This economic evaluation aims to support policy-making on the combined use of pre-exposure prophylaxis (PrEP) with HIV vaccines in development by evaluating the potential cost-effectiveness of implementation that would support the design of clinical trials for the assessment of combined product safety and efficacy. The target study population is a cohort of men who have sex with men (MSM) in the United States. Policy strategies considered include standard HIV prevention, daily oral PrEP, HIV vaccine, and their combination. We constructed a Markov model based on clinical trial data and the published literature. We used a payer perspective, monthly cycle length, a lifetime horizon, and a 3% discount rate. We assumed a price of $500 per HIV vaccine series in the base case. HIV vaccines dominated standard care and PrEP. At current prices, PrEP was not cost-effective alone or in combination. A combination strategy had the greatest health benefit but was not cost-effective (ICER = $463,448/QALY) as compared to vaccination alone. Sensitivity analyses suggest a combination may be valuable for higher-risk men with good adherence. Vaccine durability and PrEP drug prices were key drivers of cost-effectiveness. The results suggest that boosting potential may be key to HIV vaccine value.

A new model for catalyzing translational science: the early stage investigator mentored research scholar program in HIV vaccines.

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large-scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.