Real world comparison of immune-related adverse events with nivolumab-relatlimab versus ipilimumab-nivolumab in patients with advanced cutaneous melanoma

Abstract

Introduction

Frontline therapy for patients with advanced cutaneous melanoma often includes immune checkpoint inhibitors (ICIs). Although these agents have increased response rates, many patients will experience immune-related adverse events (irAEs). The difference in safety profiles of the current combinations available are not well established. Therefore, this study aimed to compare the incidence of severe irAEs of patients receiving ipilimumab-nivolumab versus nivolumab-relatlimab in a real-world setting.

Methods

A retrospective chart review was conducted on all patients who underwent treatment with either combination ICI for advanced cutaneous melanoma.

Results

A total of 47 patients who received either one or more doses of either combination ICI were included for analysis. Of these patients, 37 (78.2%) had at least one irAE of any grade. The baseline characteristics among the patients who received nivolumab-relatlimab and those who received ipilimumab-nivolumab were not significantly different. The severity of the 73 irAEs that occurred ranged from grade 1 to grade 3, with 16 (21.9%) irAEs occurring in the nivolumab-relatlimab, 3 (18.8%) of which were grade 3–4. Meanwhile, those receiving ipilimumab-nivolumab developed 57 (78.1%) irAEs, with 14 (24.6%) being grade 3–4. This study's findings show that nivolumab-relatlimab had a lower incidence of developing severe irAEs in comparison to ipilimumab-nivolumab.

Conclusions

Treatment with nivolumab-relatlimab could be preferred as a combination ICI given the lower incidence of severe irAEs, delayed onset of irAEs, and lower rate of treatment discontinuation.

Keywords

Cutaneous melanoma immune related adverse events immune checkpoint inhibitors ipilimumab-nivolumab nivolumab-relatlimab

Introduction

Mortality rates for melanoma have rapidly declined in recent years after the introduction of new therapy approvals for metastatic disease, which include immune checkpoint inhibitors.¹ Immune checkpoint inhibitors (ICIs) have allowed for tumor regression and long-term durable disease control in 50% of patients compared to 10% with traditional treatments utilized for melanoma, such as chemotherapy and IL-2 therapy.² The current US Food and Drug Administration (FDA) approved checkpoint inhibitor classes for metastatic melanoma include cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, programmed-death-1 (PD-1) inhibitors, programmed-death ligand-1 (PD-L1) inhibitors, and most recently, a lymphocyte-activation gene 3 (LAG-3) inhibitor.

In the United States, it is estimated that 100,000 new cases of melanoma will be diagnosed in 2023, therefore it is critical to understand the adverse events that can arise from these recently approved therapies.³ ICIs are often associated with a broad spectrum of toxicities called immune-related adverse events (irAEs) that are generally caused by off-target inflammatory reactions from uncontrolled activation of the immune system. Immune-related adverse events can occur anywhere in the body; however, the organ systems most impacted include the skin, gastrointestinal tract, and endocrine system.⁴ Treatment may continue with the development of lower grade irAEs if patients are closely monitored. Alternatively, for those who experience more severe irAEs, therapy is often discontinued. Durable response has been shown in patients with advanced melanoma after discontinuation of ICI due to severe irAEs.⁵ The frequency and severity of irAEs depend on a variety of factors such as the class of ICI, the administered dose, patient-specific factors, duration of therapy and use of combination agents.^6–8

Combination regimens have increased response rates in patients with advanced melanoma, but at the cost of increased toxicity.^4,6 The current FDA approved combinations for advanced cutaneous melanoma include ipilimumab-nivolumab and nivolumab-relatlimab, both of which are National Comprehensive Cancer Network (NCCN) category 1 recommended treatment options.^9,10 Nivolumab-relatlimab was recently approved in March of 2022 after the RELATIVITY-047 trial demonstrated those receiving the combination had a median progression free survival of 10.1 months compared to 4.6 months for those treated with nivolumab. When compared to nivolumab alone, the combination of nivolumab-relatlimab had a higher incidence of irAEs, with the most common irAEs being hypothyroidism, rash, and colitis. Grade 3 or 4 treatment related adverse events (TRAEs) occurred in 18.9% of patients treated with nivolumab-relatlimab compared to 9.7% in those treated with nivolumab alone, with hepatitis and adrenal insufficiency occurring more commonly in the combination group.¹¹

Similarly, when the combination of ipilimumab-nivolumab was compared to nivolumab alone in CheckMate067, ipilimumab-nivolumab had a higher risk of mild irAEs such as rash, colitis, and hypothyroidism. Patients who received the combination of ipilimumab-nivolumab experienced grade 3 or 4 TRAEs more than patients who were treated with nivolumab alone (59% vs 21%).¹² CheckMate511 compared two dosing strategies of ipilimumab-nivolumab to assess improvement in safety profile. These results showed fewer grade 3 or 4 TRAEs in patients treated with ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (33.9%) than those treated with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (47.8%).¹³

With no direct comparison of the current combinations available, health care providers have little information to guide clinical decisions regarding which combination product to use. This study characterizes irAEs in patients with advanced melanoma receiving ipilimumab-nivolumab versus nivolumab-relatlimab in a real-world setting by comparing the incidence of severe immune related adverse events. This study focuses on five types of immune-related adverse events including colitis, pneumonitis, hepatitis, dermatologic and endocrine toxicities. Previous literature demonstrates these toxicities represent five of the most clinically significant irAEs patients with melanoma experience.

The primary outcome was the incidence of severe irAEs that occur in patients with advanced melanoma who are treated with ipilimumab-nivolumab versus nivolumab-relatlimab. The secondary outcomes were to compare the type and grade of irAEs, number of hospital admissions, incidence of adverse effects based on body mass index, median time to onset, and discontinuation of therapy due to irAEs between groups.

Methods

This was an Institutional Review Board approved retrospective cohort study including patients who underwent treatment with either ipilimumab-nivolumab or nivolumab-relatlimab within WVU Medicine. Patients were included if they were ≥ 18 years old and had histologically confirmed stage III (unresectable) or stage IV melanoma per the American Joint Committee on Cancer v8 staging system. Patients must have also received at least one dose of nivolumab-relatlimab, ipilimumab 1 mg/kg plus nivolumab 3 mg/kg, or ipilimumab 3 mg/kg plus nivolumab 1 mg/kg. Patients were excluded if they had any of the following: uveal melanoma, active brain or leptomeningeal metastases, baseline autoimmune disease, and a history of transplant. Patients who were pregnant or breastfeeding were also excluded.

Chart reviews were conducted through the electronic medical record of the health system to assess if immune related adverse events occurred after receiving one or more doses of either combination ICI. Baseline data was collected from medical records at the time of ICI therapy initiation including age, body mass index, legal sex, performance status, stage, extent of disease, BRAF V600 mutation expression, lactate dehydrogenase, history of uveal melanoma, autoimmune disease, brain metastases, pregnancy status, transplant history, prior chemotherapy regimens and number of cycles received.

Immune related adverse event occurrence was based on documentation from healthcare providers. If a patient had more than one irAE, each irAE was counted. The collected data about the development of immune related adverse events included the date of onset, documented grade, and whether corticosteroid treatment was initiated. The severity of the irAEs was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). Other pertinent laboratory values and imaging results were obtained to further characterize these adverse events.

This study was carried out according to the ethical principles of the Belmont Report and the protocol of this retrospective study was approved by the ethics committee of the West Virginia University Office of Human Research Protections (WVU Protocol #:2309849638, approved on September 22, 2023). Given the retrospective nature of this study, no informed consents were obtained from individual patients and a WVU HIPAA Waiver of Research Authorization was obtained.

Statistical analysis

Statistical calculations were performed using statistical software R software, version R 3.6.3 (https://www.R-project.org/). Descriptive statistical analyses were utilized to summarize overall and specific toxicity rates, and to describe time to onset of immune related adverse events, including summary tables, scatterplots, boxplots, proportions, median, means, and standard deviation. Incidence and grade of immune related adverse events and the categorical variables were evaluated using Fischer's exact test between treatment groups. The continuous variables were assessed using Wilcoxon sum rank test. Kaplan-Meier curves and log-rank test were used in the statistical analysis of time-to-event data.

Results

Patients and clinical characteristics

A total of 47 patients with histologically confirmed unresectable cutaneous stage III or stage IV melanoma who met the inclusion criteria were included in the present analysis. Table 1 summarizes the patients’ baseline characteristics with no significant differences detected. The median age was 69 years (range 40 to 99), and more patients had stage IV disease (32, 68.1%) than stage III disease (15, 31.9%). Most patients were treated with ipilimumab-nivolumab 32 (68.1%) while 15 (31.9%) of patients were treated with nivolumab-relatlimab. In both treatment groups, a total of 16 (34%) patients were previously treated with one or more ICI therapy prior to initiation of ICI combination therapy. Of these 16 patients, 11 (68.8%) previously developed irAEs while on previous ICI therapy.

Table 1.

Baseline characteristics of patients treated with ICI combination therapy.

Characteristic	Nivolumab-relatlimab (n = 15)	Ipilimumab-nivolumab (n = 32)	Total	p-value
Sex
Male	11 (73.3)	20 (62.5)	31 (66)	0.465
ECOG PS
0	7 (46.7)	10 (31.3)	17 (36.2)	0.305
1	7 (46.7)	12 (37.5)	19 (40.4)	0.550
2	0 (0)	1 (3.1)	1 (2.1)	0.489
3	0 (0)	0 (0)	0 (0)
4	0 (0)	1 (3.1)	1 (2.1)	0.489
Unknown	1 (6.6)	8 (25)	9 (19.1)
Melanoma Stage
III	6 (40)	9 (28.1)	15 (31.9)	0.416
IV	9 (60)	23 (71.9)	32 (68.1)
Extent of Disease
M0	5 (33.3)	10 (31.3)	15 (31.9)	0.886
M1	10 (66.7)	22 (68.8)	32 (68.1)
BRAF V600 Mutation
Yes	8 (53.3)	13 (40.6)	21 (44.6)	0.414
Previous Therapy
BRAF/MEK Therapy	1 (6.7)	3 (9.4)	4 (8.5)	0.756
>1 ICI	3 (20)	2 (6.3)	5 (10.6)	0.154
PD-1	4 (16.7)	7 (21.9)	11 (23.4)	0.718
History of irAE development
Yes	6 (40)	5 (15.6)	11 (23.4)	0.07

Legend: Data presented as No. (%). Abbreviations: ECOG, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitor; PD-1, programmed death ligand; irAE, immune related adverse event.

Primary and secondary outcomes

A description and grading of the total 73 irAEs based on combination immunotherapy is in Table 2. The severity of adverse events ranged from grade 1 to grade 3, with no documented incidences of grade 4 irAEs. Of the 15 patients who received nivolumab-relatlimab there were 5 (31.3%) grade 1 irAEs, 8 (50%) grade 2, and 3 (18.8%) grade 3, for a total of 16 irAEs occurring in this group. Of the 32 patients who received ipilimumab-nivolumab there were 15 (26.3%) grade 1 irAEs, 18 (31.6%) grade 2, 14 (24.7%) grade 3, and 10 (17.5%) unknown grades, for a total of 57 irAEs occurring in this group. Overall, 3 (20%) patients in the nivolumab-relatlimab group developed grade 3 irAEs in comparison to 12 (37.5%) patients in the ipilimumab-nivolumab group. When comparing the use of steroids for treatment for irAEs between the two groups, the nivolumab-relatlimab group had 7 (46.7%) patients treated with steroids, meanwhile 22 (68.8%) of patients in the ipilimumab-nivolumab group were treated with steroids. A similar trend was observed with subsequent therapy following treatment with steroids with 1 (6.7%) of patients in the nivolumab-relatlimab group and 5 (15.6%) in the ipilimumab-nivolumab group.

Table 2.

Summary of irAEs occurring in patients treated with ICI combination therapy.

	Nivolumab-relatlimab(n = 15)		Ipilimumab-nivolumab(n = 32)
	Any Grade	Grade 3 and 4	Any Grade	Grade 3 and 4	Unknown
Any immune-related adverse event	16		57
Rash	6 (37.5)	1 (6.3)	15 (26.3)	1 (1.8)
Bullous Pemphigus	1 (6.3)	0	0	0
Colitis	3 (18.8)	0	14 (24.6)	5 (8.8)	3 (5.3)
Pneumonitis	0	0	2 (3.5)	1 (1.8)
Hepatitis	1 (6.3)	0	4 (7.0)	2 (3.5)
Hypothyroidism	2 (12.5)	0	8 (14.0)	0	1 (1.8)
Hypophysitis / Adrenal insufficiency	0	0	4 (7.0)	2 (3.5)
Aphthae	0	0	1 (1.8)	0
Arthralgias	1 (6.3)	0	4 (7.0)	0	4 (7.0)
Guillain-Barré syndrome	1 (6.3)	1 (6.3)	0	0
Myasthenia gravis	0	0	2 (3.5)	1 (1.8)	1 (1.8)
Myocarditis	0	0	1 (1.8)	0	1 (1.8)
Myositis	0	0	1 (1.8)	1 (1.8)
Nephritis	1 (6.3)	1 (6.3)	0	0
Pancreatitis	0	0	1 (1.8)	1 (1.8)

Legend: Number of any immune related adverse event in any patient after starting treatment with ICI combination therapy for advanced melanoma is shown. Data presented as No. (%).

Overall, there were 31 (66%) patients who were hospitalized for any cause after starting combination therapy, 9 (60%) of patients in the nivolumab-relatlimab compared to 22 (68.8%) of patients in the ipilimumab-nivolumab group (Figure 1) (p = 0.742). When comparing the number of patients hospitalized due to irAEs, there were 3 (20%) patients of the nivolumab-relatlimab group versus 17 (53.1%) patients in the ipilimumab-nivolumab (Figure 1) (p = 0.056).

Of the 73 immune related adverse events that occurred, 44 (60%) of those occurred in patients with a body mass index (BMI) ≤ 30, meanwhile 29 (40%) of those occurred in those with a BMI >30. The median number of irAEs in nivolumab-relatlimab and ipilimumab-nivolumab groups was 1. Figure 2 characterizes the 73 irAEs and details their incidence based on BMI. There were 10 dermatologic irAEs, 12 of colitis, three of hepatitis, 2 of pneumonitis, 11 endocrine-related irAEs, and six of other irAEs in those with a BMI ≤ 30. For those with a BMI > 30, there were 12 dermatologic irAEs, 5 of colitis, 2 of hepatitis, 3 endocrine-related irAEs, and 7 of other irAEs. The number of irAEs based on BMI between the nivolumab-relatlimab group versus ipilimumab-nivolumab group were as follows: BMI ≤ 30 (11 vs. 33) and BMI > 30 (5 vs. 24).

There were varying times amongst each category of irAE when evaluating the median time to onset of adverse events between treatment groups. (Figure 3). The median time (in days) to onset of the most common irAEs were as follows: dermatologic (67 days), endocrine (105 days), colitis (43 days), hepatitis (91 days), and pneumonitis (262 days). Figure 4 describes the median time to adverse event onset between the nivolumab-relatlimab and ipilimumab-nivolumab groups. The median time (in days) to onset of the most common irAEs between nivolumab-relatlimab versus ipilimumab-nivolumab were as follows: dermatologic (101 vs. 42), endocrine (111 vs 105), colitis (265 vs. 42), hepatitis (220 vs. 91), and pneumonitis (0 vs. 262).

Figure 4 represents the Kaplan-Meier curve of retention by treatment group. The median time to therapy discontinuation was 131 days (95% confidence interval, CI 97–600+) for nivolumab-relatlimab group, 53 days (95% CI 41–600+, p = 0.001) for ipilimumab 3 mg/kg plus nivolumab 1 mg/kg group, and 203 days (95% CI 113–387, p = 0.39) for ipilimumab 1 mg/kg plus nivolumab 3 mg/kg group. A total of 33 (70.2%) of patients discontinued treatment, 11 (73.3%) in the nivolumab-relatlimab group, 14 in the (60.9%) ipilimumab 1 mg/kg plus nivolumab 3 mg/kg group, and 8 (88.9%) in the ipilimumab 3 mg/kg plus nivolumab 1 mg/kg group. Reasons for discontinuation included: death in 5 (10.6%) of patients, progression of disease in 9 (19.1%) of patients, surgery 1 (2.1%), 8 (17%) patients due to irAE, and 11 (23.4%) of patients had other reasons for stopping treatment (i.e., patient preference, supportive care). Treatment discontinuation due to an irAE occurred in 1 (6.7%) of patients in the nivolumab-relatlimab group, 6 (26.1%) in the ipilimumab 1 mg/kg plus nivolumab 3 mg/kg group, and 1 (11.1%) of patients in the ipilimumab 3 mg/kg plus nivolumab 1 mg/kg group.

Discussion

This single health system analysis evaluated the longitudinal development of severe irAEs in patients with advanced melanoma who were treated with combination immune checkpoint inhibitor therapy, specifically nivolumab-relatlimab and ipilimumab-nivolumab. Results demonstrated those treated with ipilimumab-nivolumab had a higher incidence of severe, grade 3 irAEs in comparison to those treated with nivolumab-relatlimab (37.5% vs. 20%). This trend was also seen when comparing all grades of irAEs developed in each treatment group and hospitalizations due to irAEs (53.1% vs. 20%) though not statistically significant.

Of the irAEs evaluated, the incidence rates are consistent with the current literature. Tawbi et al. reported a similar incidence of severe (grade 3 or 4) irAEs in 18.9% of patients treated with nivolumab-relatlimab. In this study rash, colitis, and hypothyroidism were the most common irAEs seen amongst the nivolumab-relatlimab group, which is also consistent with the findings of Tawbi et al.¹¹ In CheckMate067, the combination of ipilimumab-nivolumab had a higher risk of mild irAEs such as rash, colitis, and hypothyroidism, as well as a higher incidence of severe irAEs when compared to nivolumab alone (55% vs 16%). The incidence of severe irAEs in this study was lower than what is reported in the findings of Zhou S et al. for the ipilimumab-nivolumab group.¹² One possible explanation for this could be that the patients who received ipilimumab-nivolumab commonly received ipilimumab 1 mg/kg plus nivolumab 3 m/kg dosing regimen (n = 23) in comparison to the ipilimumab 3mkg/kg plus nivolumab 1 mg/kg) dosing regimen (n = 9) used in CheckMate067. Lebbé C et al. evaluated these two dosing strategies of ipilimumab-nivolumab and found a lower incidence of grade 3 or 4 of irAEs in patients treated with ipilimumab 1 mg/kg plus nivolumab 3 m/kg versus ipilimumab 3mkg/kg plus nivolumab 1 mg/kg (33.9% vs. 47.8%).¹³ The most common irAEs experienced in this study with the ipilimumab-nivolumab group was rash, colitis, and hypothyroidism, which is similar to the results found in by Wolchok JD et al. and Lebbé C et al.

Data from Wang J et al. and Cardeña-Gutiérrez A et al., suggests that a lower baseline body mass index (BMI) may be a predictive factor for higher grade irAEs with immune checkpoint inhibitor therapy^14,15 Meanwhile other studies from Eun Y et al. and Cortellini A et al., found that a higher BMI was associated with higher risk of irAEs.^16,17 In this study, there were 73 immune related adverse events. Forty-four (60%) of those occurred in patients with a BMI ≤30, meanwhile 29 (40%) of those occurred in those with a BMI >30. One potential reason our study did not find a statistically significant difference in the incidence of irAEs based on BMI could be due to the number of patients and unclear use of adjusted body weight in patients with a BMI > 30 kg/m². Additionally, there were approximately two times as many patients in the group of patients with a BMI ≤ 30 (n = 31) than those with a BMI >30 (n = 16).

It is known that treatment with combination agents increases the incidence, severity, and onset of irAEs.¹⁸ The onset of irAEs in this study generally aligned with patients in other studies. The patients in this study did have a longer time to onset for dermatologic (9 weeks vs. 4 weeks) and hepatic (13 weeks vs. 6 weeks) irAEs than what was previously reported in literature.^8,19–21 There are a variety of factors that could be contributing to the difference in our results, as the class of ICI, dose, patient-specific factors, and duration of therapy can all impact the onset and frequency of irAEs. Additionally given the retrospective nature of this study inconsistent documentation of chart notes, such as the underreporting of patient symptoms, could have impacted these findings. In comparison to ipilimumab-nivolumab, the nivolumab-relatlimab group appeared to take a longer duration of time for irAEs to develop. The median time (in days) to onset of the most common irAEs between the two groups were as follows: dermatologic (101 vs 42), endocrine (111 vs 91), colitis (265 vs. 42), and hepatitis (220 vs. 91).

These results showed that duration of therapy during treatment was longer for those treated with nivolumab-relatlimab and ipilimumab 1 mg/kg plus nivolumab 3 mg/kg in comparison to those treated with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg, which is consistent with the current literature. The discontinuation rate of ICI therapy due to irAEs in our study in comparison to current literature were as follows: nivolumab-relatlimab (6.7% vs. 14.6%), ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (11.1% vs. 27.5%), and ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (26.1% vs 16.7%).^11–13 An explanation for the differences in these rates could be from the shorter follow up time between certain groups, as well as the quantity of patients within each group nivolumab-relatlimab (n = 15), ipilimumab 3mkg/kg plus nivolumab 1 mg/kg regimen (n = 9), and ipilimumab 1 mg/kg plus nivolumab 3 m/kg (n = 23).

Immune-related adverse events are common amongst patients utilizing combination immune checkpoint inhibitor therapy; however, use of combination agents has been shown to increase response rates in patients.⁴ Currently both combinations, nivolumab-relatlimab and ipilimumab-nivolumab are approved for advanced cutaneous melanoma, but no randomized controlled trials exist between the two combinations.¹⁰ Analyzing the safety of these different treatment regimens and characterizing what differences, if any, these treatments have in different patient populations (i.e., brain metastasis, rapidly progressing disease, highly symptomatic) is valuable for providers to make informed decisions in the absence of randomized controlled trials. These findings suggest that the combination of nivolumab-relatlimab may have an improved safety profile than ipilimumab-nivolumab in the real-world setting.

The results of this study do have limitations due to the small size, retrospective nature, and reliance on correct documentation. An accurate comparison of the incidence of immune-related adverse events is limited, given the sample size of patients who received combination checkpoint inhibitor therapy in this study. Immune related adverse events were identified through retrospective chart review, which is subject to inconsistent documentation and potentially underreporting of patient symptoms. Data was collected from across the health system which has site and provider specific follow up practices for patients; is not standardized across the health system. Nivolumab-relatlimab is a combination therapy recently approved and added to the market. This resulted in a low sample size across the health system, additionally these patients had a shorter follow-up time than the ipilimumab-nivolumab group. Providers had the discretion to decide which dosing strategy of ipilimumab-nivolumab (ipilimumab 1 mg/kg plus nivolumab 3 mg/kg or ipilimumab 3 mg/kg plus nivolumab 1 mg/kg), which may alter results. Furthermore, providers may have bias when selecting one combination of agents over another along with dosing strategy and reporting bias. There may have also been variability in selection between adjusted versus actual body weight amongst providers when dosing which could lead to bias in our results. Patients who were not clinically managed per guidelines or who had delays in treatment of immune related adverse events could potentially have higher grades of immune related adverse events. Additionally, some patients previously received immune checkpoint inhibitor therapy that differed in cumulative dose and number of cycles given that could have affected these results.

In conclusion, this retrospective study suggests that for patients with advanced melanoma, treatment with nivolumab-relatlimab could be preferred as a combination ICI given the lower incidence of severe irAEs, longer onset of irAEs, and lower rate of treatment discontinuation though information regarding relapse free survival or overall survival comparisons is needed. Future studies comparing these two combinations head-to-head in patients with advanced melanoma are necessary to help guide clinical decisions of healthcare providers and improve the quality of care for patients treated with these agents.

Footnotes

Author contributions

- BK, BE, CB, and DM researched literature and conceived the study. BK, BE, CB, and DM were involved in protocol development. BK was involved in gaining ethical approval and collection of data. BK, SW, and HL were involved in the statistical and data analysis portion of the study. BK drafted the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Brooke Kielkowski

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