Association of Sociodemographic Factors With Immunotherapy Receipt for Metastatic Melanoma in the US

Key Points Question Are sociodemographic factors associated with likelihood of receiving immunotherapy for patients diagnosed with metastatic melanoma in the US? Findings In this cohort study of 9512 metastatic melanoma cases diagnosed between 2013 and 2016 in the National Cancer Database, factors associated with receiving immunotherapy included diagnosis in Medicaid expansion states, residence in areas with high rates of high school graduation, and treatment at academic cancer centers or integrated cancer networks. Meaning This study found that patients with metastatic melanoma diagnosed in Medicaid expansion states, treated at academic or integrated cancer centers, and living in high graduation–rate areas were more likely to receive immunotherapy.


Introduction
The mainstay treatment for unresectable or metastatic melanoma is systemic therapy. Before the introduction of immune checkpoint inhibitors (ICIs), the standard of care for most patients with metastatic melanoma was dacarbazine administered as single-agent therapy or part of combination therapy. 1,2 Immunotherapy with high-dose interleukin 2 showed durable response in a few patients but was associated with significant toxic effects 2,3 ; however, immunotherapeutic agents in the form of ICIs, including ipilimumab, nivolumab, and pembrolizumab, have substantially improved outcomes and become the standard of care for metastatic melanoma during the past decade. 4 After the landmark study of the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab by Hodi et al, 5 ipilimumab became the first ICI approved for metastatic melanoma in 2011. 6 Subsequently, single-agent anti-programmed cell death protein 1 10,11 Combination therapy with nivolumab and ipilimumab also showed improved overall survival, [12][13][14] leading to approval of the combination in the first-line setting. 11,15 Despite the improvement in outcomes with ICIs for metastatic melanoma, previous studies 16,17 have found that sociodemographic health disparities are associated with limited access to effective therapies for melanoma, including immunotherapy. Underinsurance may be associated with delays in surgery and treatment at low-volume centers. Insurance status is also associated with stage of diagnosis, with uninsured patients presenting at more advanced disease stages compared with privately insured patients. 18 Use of systemic therapy has been administered more frequently to those who were living in high-income areas, younger individuals, and married individuals. 19 Recently, the Patient Protection and Affordable Care Act (ACA) has included policies to reduce the socioeconomic and racial/ethnic disparities in health care access. When President Obama signed the ACA in 2010, a new patient's bill of rights was implemented to protect individuals with preexisting conditions, improve choice of physicians, and end insurance limits on care. This new bill of rights has allowed many patients with a new cancer diagnosis to gain and keep coverage. 20 The Medicaid expansion provision of the ACA encouraged states to expand Medicaid coverage by covering 100% of the expansion in the first 3 years and 90% afterward. 21 In 2013, the Medicaid expansion open enrollment period for states commenced, and by the beginning of 2017, 32 states had implemented expansion (eFigure 1 in Supplement). 22 In addition, the ACA established insurance marketplaces that provide access to more affordable private insurance plans and government subsidies. 23 Key dates for implementation of ACA and approval of immunotherapeutic agents are summarized in Figure 1.
Since enactment of the ACA, an estimated 20 million people have gained health insurance coverage through Medicaid expansion and health care insurance marketplaces. 25 The uninsured rate of the population younger than 65 years in the US decreased from 17% to 10% between 2013 and 2016, and the uninsured rate reduction in the Medicaid expansion states was 50% compared with 31% in the nonexpansion states. 26 With improved access to health care, patients with metastatic melanoma may have increased opportunity for treatment with immunotherapy.

Data Source
This cohort study used data from the NCDB, which was established in 1989 and is a nationwide, facility-based, comprehensive clinical surveillance resource oncology data set that currently captures 52% of all melanoma cases and 72% of all newly diagnosed malignant tumors in the US annually. 28 The NCDB is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. By waiver of determination, Loma Linda University did not require institutional review board approval of this study. The data were deidentified by the NCDB. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Population
This retrospective cohort study used melanoma cases registered in the NCDB that were diagnosed from January 1, 2013, to December 31, 2016, with follow-up through 2018. Data were analyzed from July 1, 2019, to December 15, 2019. We queried the database to identify patients with stage IV melanoma, also referred to as metastatic melanoma in this article. The primary outcome was the association of receipt of immunotherapy as first-line therapy with sociodemographic factors. Patients were divided into groups that received immunotherapy or that did not receive immunotherapy; cases without documentation of either were excluded. The secondary outcome was overall survival in the group that received immunotherapy vs the group that did not receive this therapy. Cases diagnosed in 2016 do not have survival data recorded and could not be included in the survival analysis.

Statistical Analysis
Covariates examined in the treatment groups included age, sex, year of diagnosis, Charlson-Deyo comorbidity index, primary payer, state Medicaid expansion status, treatment region, metropolitan vs suburban residence, facility type, educational level, and income level. Community type was

Survival and Time-to-Event Analysis
Median overall survival among all patients regardless of treatment was 10.1 months (95% CI, 9.6-10.6 months) (Figure 2A). Improved median overall survival was observed for patients who received

Discussion
Previous studies [29][30][31][32][33] have analyzed the NCDB cohort before our analysis of the 2016 participant user file. These analyses evaluated the disparity in use of immunotherapy for all stages of melanoma in diagnosis years before 2013, 29 before 2014, 30,31 and in 2015 32 and for stage III disease. 33 These prior studies [29][30][31][32][33] indicated the presence of comorbidities, older age, government or no insurance, lower educational and income levels, and treatment at a community practice as factors associated with decreased receipt of immunotherapy. Our study further supports that many of these prior demographic factors may be associated with receipt of immunotherapy with the addition of cases

JAMA Network Open | Health Policy
Association of Sociodemographic Factors With Immunotherapy Receipt for Metastatic Melanoma pembrolizumab, 7 and more than 60 months for the combination of nivolumab and ipilimumab. 14 Although all 4 of these treatment regimens were approved for use during this study's timeframe, surveys on community practice treatment trends favored ipilimumab use with subsequent adoption of the other regimens in the community. 43 The median overall survival of 18.4 months in this study is similar to that associated with ipilimumab treatment in the aforementioned trials but less than that of single-agent anti-programmed cell death protein 1 or combination checkpoint inhibition. Our finding further supports increasing evidence that real-world treatment outcomes are similar to those in clinical trials as has already been seen in non-small cell lung cancer. 44

Limitations
This study has limitations. The NCDB is a retrospective database that does not cover the entire population. Furthermore, only first-line systemic therapy is recorded. Immunotherapy given as second-line treatment may be associated with improved survival, 45 but receipt would not be recorded in the database. Because the insurance status and Medicaid expansion status are suppressed for patients younger than 40 years and cannot be evaluated, generalizability of results to patients younger than 40 years cannot be made. The specific agent or agents used as immunotherapy are not recorded and could include ICIs, vaccine therapy, interleukins, or other biologic response-modifying agents. In addition, disease-specific survival is not recorded. 46 The data used in the study are derived from a deidentified NCDB file.

Conclusions
Using the NCDB, we found that immunotherapy use for metastatic melanoma has increased since approval of ICIs by the US Food and Drug Administration. Nearly 50% of patients with metastatic melanoma were receiving first-line immunotherapy in 2016. An improvement in survival by more than 10 months was found in the population of the NCDB who received immunotherapy. Furthermore, patients with residence in Medicaid expansion states, younger age, low Charlson-Deyo comorbidity index, treatment at academic medical centers or integrated network cancer programs, and zip codes within the highest quartile of high school graduation were more likely to receive immunotherapy.