Abstract
Background
Checkpoint inhibitors have shown improvement in recurrence-free survival in the post-operative setting for node-positive melanoma and were first approved in late 2015. However, single-agent checkpoint therapies have yet to show benefit to overall survival (OS) for lower-risk stage III cancers. We evaluated the OS benefit of post-operative immunotherapy in the National Cancer Database (NCDB).
Patients and methods
Patient cases were selected from the NCDB 2020 Participant Use File. Patients diagnosed with stage III cutaneous melanoma between 2016 and 2019 who underwent definitive resection for their melanoma were included. OS between those who received post-operative immunotherapy within 84 days of surgery and those who did not was analyzed by the Kaplan–Meier method. Demographic and clinical characteristics between the two groups were compared via Cox proportional hazard models.
Results
14 978 patients with stage III melanoma were included. Of those, 34.9% (n = 5234) received post-operative immunotherapy and 65.1% (n = 9744) did not. Using the American Joint Committee on Cancer version 8 (AJCCv8) staging, 36-month survival was significantly higher in patients who received post-operative immunotherapy compared to no post-operative systemic therapy in those diagnosed with stage IIIB (88.0% versus 84.7%, P = 0.011), IIIC (75.6% versus 68.1%, P < 0.001), or IIID (59.2% versus 48.4%, P = 0.002). No significant improvement in 36-month survival was seen in patients who received post-operative immunotherapy in patients with stage IIIA disease (93.0% versus 92.2%, P = 0.218).
Conclusions
Post-operative immunotherapy had an OS benefit in patients with AJCCv8 stage IIIB, IIIC, and IIID disease, but had no significant survival benefit for patients with stage IIIA melanomas.
Key words: immunotherapy, melanoma, adjuvant immunotherapy
Highlights
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Checkpoint inhibitors are the standard of care for resected stage III melanoma based on improved recurrence-free survival.
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OS was higher when immunotherapy was given after surgery in stage IIIB and worse melanoma in a large database.
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However, in lower-risk stage IIIA melanomas, the survival difference is not statistically significant.
Introduction
Approximately 9% of the 97 610 cases of cutaneous melanomas diagnosed in the United States in 2023 will have regional disease at diagnosis.1 Stage III cutaneous melanoma outcomes are heterogenous and largely dependent upon substage. In the American Joint Committee on Cancer (AJCC) version 8 staging system, stage IIIA melanoma has a high cure rate with a 93% melanoma-specific survival at 5 years; however, higher-risk stage IIIC and IIID disease have a 5-year melanoma-specific survival of only 69% and 32%, respectively.2 Before the checkpoint era, adjuvant options following surgery included highly toxic interferon therapy to reduce risk of local and distant relapse and modestly effective radiation therapy to reduce local recurrence.3,4
Survival of unresectable and metastatic melanoma has improved dramatically with the use of immune checkpoint inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). For example, patients with unresectable or metastatic melanoma who receive both nivolumab and ipilimumab have a 5-year overall survival (OS) of 52%.5,6 Given the findings in metastatic disease, subsequent trials were undertaken evaluating the addition of adjuvant checkpoint inhibition in patients with stage III melanoma following resection. The European Organisation for Research and Treatment of Cancer (EORTC) 18071 demonstrated improved recurrence-free survival (RFS) with ipilimumab versus placebo (RFS of 46.5% versus 34.8%, respectively), CHECKMATE 238 demonstrated improved RFS of nivolumab over ipilimumab, and KEYNOTE 054 demonstrated improved RFS of pembrolizumab compared to placebo at 3.5 years (RFS of 59.8% versus 41.4%, respectively).7, 8, 9 Consequently, immune checkpoint inhibitors were first approved in late 2015 (ipilimumab) and then late 2017 (nivolumab) and 2018 (pembrolizumab) as adjuvant post-operative therapy in stage III resected cutaneous melanomas. However, since that time, a significant survival benefit has only been seen for high-dose ipilimumab in EORTC 18071.10
We aimed to use real-world patient cases from the National Cancer Database (NCDB) to evaluate the survival benefit of immunotherapy following resection of stage III melanoma.
Patients and methods
Data source
The NCDB is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. The NCDB is a prospectively collected pan-cancer database of patients treated in the United States with at least 40 million patient records since its inception in 1989.11 It accounts for 70% of all new cancer diagnoses and 52% of melanoma diagnoses in the United States.12 Patient data were extracted from the 2020 NCDB Participant Use File (PUF; October 2022 release). The study was determined exempt from Institutional Review Board (IRB) approval by The University of California Irvine. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies.
Study population
This retrospective study included stage III cutaneous melanoma cases diagnosed between 1 January 2016 and 31 December 2020 that underwent a definitive surgical procedure and had adequate pathologic TNM (tumor–node–metastasis) staging information. Patients with incomplete pathologic T, N, and M staging were excluded from analysis. Patient cases were staged by both the AJCC seventh and eighth versions. Those who received systemic therapy before surgery, did not have documentation of whether systemic therapy was received, or received chemotherapy alone or in combination (which includes targeted therapies) were excluded.
Cases were sorted by the type of post-operative therapy started within 12 weeks (84 days) of surgery as calculated from the date of definitive surgery to start of systemic therapy. Treatment groups were classified into the non-post-operative systemic therapy or post-operative immunotherapy groups (Figure 1). Patients who received systemic therapy after 84 days were included within the cohort. OS time was calculated from the date of definitive surgery to last contact or death. Other tumor variables included in analysis were site of primary tumor, histologic subtype, ulceration status, lactate dehydrogenase (LDH) level, lymphovascular invasion, and sociodemographic characteristics.
Figure 1.
CONSORT diagram demonstrating patient case selection process. NCDB, National Cancer Database.
Statistical analysis
Covariates examined in the treatment groups included age, sex, year of diagnosis, primary payor, cancer center type, location type, high school education quartile, and income quartile. Primary payor was categorized as the type of insurance reported on the patient’s admission page during the time of initial diagnosis. Cancer center types were further characterized as community cancer programs, comprehensive community cancer centers, academic/research programs, or integrated network cancer programs. Community cancer programs are facilities that accessioned >100 but <500 newly diagnosed cancer cases each year. Comprehensive community cancer programs are facilities that accessioned >500 newly diagnosed cancer cases each year.11 Academic cancer centers are facilities that participate in postgraduate medical education and accessioned >500 newly diagnosed cancer cases each year. Integrated network cancer programs are facilities belonging to an organization that owns a group of facilities that offer integrated and comprehensive cancer care services. Location type was categorized as metropolitan for facilities located in counties with populations of ≥250 000 people, urban for populations between 2500 and 19 999 people, and rural for populations <2500 people. Educational and income levels were classified by the 5-year estimates of the 2016 to 2020 update of the United States Census Bureau’s American Community Survey results. Educational level was defined by the percentage quartile of high school graduates and median income by the quartile range of income.
Continuous variables were presented as means with standard deviation. Categorical variables were presented as number (percentage), with comparisons carried out by chi-square (χ2) analysis. Survival analyses were carried out using the Kaplan–Meier method and log-rank test. Logistic regression was used to examine factors associated with immunotherapy receipt. A two-sided P < 0.05 indicated statistical significance. All statistical analyses were carried out using R version 4.1.2.
Results
Patient characteristics
14 978 patients with stage III melanoma diagnosed after 2016 were included. Of those, 34.9% (n = 5234) received post-operative immunotherapy and 65.1% (n = 9744) did not. 788 patients who received post-operative chemotherapy (including BRAF-targeting therapies) were excluded. The average age was 61 ± 15.58 years for the entire cohort, while the average age was 59 ± 15.23 years for those who received post-operative immunotherapy and 62 ± 15.65 years for those who did not (P < 0.001). The percentage of patients receiving post-operative immunotherapy has increased every year from 13.7% (n = 568/4142) of stage III patients receiving post-operative immunotherapy in 2016 to 55.5% (n = 1916/1539) of patients receiving immunotherapy in 2019.
30.82% (n = 1022/3316) of patients with stage IIIA melanoma (AJCC eighth) received post-operative immunotherapy. Comparatively, 35.20% (n = 1091/3099) of stage IIIB patients, 36.49% (n = 2805/7687) of IIIC patients, and 36.07 % (n = 316/876) of IIID patients received post-operative immunotherapy. Most patients (96.54%) did not receive post-operative radiation therapy. The remainder of patient characteristics are listed in Table 1. Patient characteristics of those diagnosed after 2018 are listed in Supplementary Tables S1-S3, available at https://doi.org/10.1016/j.esmoop.2023.102193.
Table 1.
Key demographic and tumor characteristics
| Characteristic | Total population | Post-operative immunotherapy | P value | |
|---|---|---|---|---|
| No |
Yes |
|||
| n (%) | n (%) | n (%) | ||
| Total | 14 978 | 9744 (65.1) | 5234 (34.9) | |
| Substage seventh edition | ||||
| IIIA | 3715 (24.80) | 2575 (69.31) | 1140 (30.68) | <0.001 |
| IIIB | 4512 (30.12) | 3054 (67.68) | 1458 (32.13) | |
| IIIC | 6751 (45.07) | 4115 (60.95) | 2636 (39.04) | |
| Substage eighth edition | ||||
| IIIA | 3316 (22.14) | 2294 (69.17) | 1022 (30.82) | <0.001 |
| IIIB | 3099 (20.69) | 2008 (64.79) | 1091 (35.2) | |
| IIIC | 7687 (51.32) | 4882 (63.5) | 2805 (36.49) | |
| IIID | 876 (5.85) | 560 (63.92) | 316 (36.07) | |
| Histologic melanoma subtype | ||||
| Malignant melanoma, not otherwise specified | 5705 (38.09) | 3742 (65 059) | 1963 (34.4) | <0.001 |
| Superficial spreading | 4232 (28.25) | 2850 (67.34) | 1382 (32.65) | |
| Nodular | 4050 (27.04) | 2492 (61.53) | 1558 (38.46) | |
| Acral nevus | 576 (3.85) | 379 (65.79) | 197 (34.2) | |
| Lentiginous melanocytic nevus | 273 (1.82) | 184 (67.39) | 89 (32.6) | |
| Desmoplastic | 142 (0.95) | 97 (68.3) | 45 (31.69) | |
| Ulceration status | ||||
| No ulceration | 7691 (51.98) | 5147 (66.92) | 2544 (33.07) | <0.001 |
| Present | 7106 (48.02) | 4487 (63.14) | 2619 (36.85) | |
| Unknown | 181 | 110 | 71 | |
| Radiation therapy | ||||
| No radiation | 14 454 (96.50) | 9401 (62.55) | 5053 (34.95) | 0.8 |
| Post-operative radiation | 524 (3.50) | 343 (65.45) | 181 (34.54) | |
| Lymphovascular invasion | ||||
| Not present | 10 595 (80.47) | 6900 (65.14) | 3695 (34.87) | 0.2 |
| Present | 2571 (19.53) | 1636 (63.63) | 935 (36.37) | |
| Unknown | 1812 | 1208 | 604 | |
| Primary site | ||||
| Trunk | 5214 (34.81) | 3340 (64.06) | 1874 (35.94) | <0.001 |
| Extremities | 6829 (45.59) | 4535 (66.41) | 2294 (33.59) | |
| Head and neck | 1887 (12.60) | 1152 (61.05) | 735 (38.95) | |
| Other/unknown | 1048 (7.00%) | 717 (68.41%) | 331 (31.58%) | |
| Age (years) | 61 ± 15.58 | 62 ± 15.65 | 59 ± 15.23 | <0.001 |
| Race | ||||
| White | 14 491 (96.75) | 9403 (96.50) | 5088 (97.21) | 0.064 |
| Black | 153 (1.02) | 108 (1.11) | 45 (0.86) | |
| Other | 334 (2.23) | 233 (2.39) | 101 (1.93) | |
| Sex | ||||
| Female | 5745 (38.36) | 3742 (38.40) | 2003 (38.27) | 0.9 |
| Male | 9233 (61.64) | 6002 (61.60) | 3231 (61.73) | |
| Year of diagnosis | ||||
| 2016 | 4142 (27.65) | 3574 (86.29) | 568 (13.71) | <0.001 |
| 2017 | 4139 (27.63) | 3053 (73.76) | 1086 (26.23) | |
| 2018 | 3242 (21.65) | 1578 (48.76) | 1664 (51.32) | |
| 2019 | 3455 (23.07) | 1539 (44.53) | 1916 (55.45) | |
| Charlson-Deyo score | ||||
| 0 | 11 919 (79.58) | 7704 (64.63) | 4215 (35.36) | 0.023 |
| 1 | 2014 (13.45) | 1318 (65.44) | 696 (34.55) | |
| 2 | 570 (3.81) | 386 (67.71) | 184 (32.38) | |
| ≥3 | 475 (3.17) | 336 (70.73) | 139 (29.26) | |
Time to event analysis
Survival was compared by the Kaplan–Meier method using the AJCC version 7 staging as shown in Figure 2 and by AJCC version 8 as shown in Figure 3. Median OS was not met in any of the stage III groups by either version of staging. Kaplan–Meier curves for AJCC seventh and eighth edition staging groups are shown in Figures 2 and 3, respectively.
Figure 2.
Kaplan–Meier survival curve for comparing receipt of post-operative immunotherapy versus no post-operative systemic therapy when staged by AJCC version 7. A Stage IIIA, B stage IIIB, and C stage IIIC.
Figure 3.
Kaplan–Meier survival curve comparing post-operative immunotherapy to no post-operative systemic therapy, staged according to AJCC version 8. A Stage IIIA, B stage IIIB, C stage IIIC, and D stage IIID.
Comparing landmark survival rates at 3 years (36 months), patients who received post-operative immunotherapy had a significantly higher survival in stages IIIB and IIIC by AJCC seventh and eighth edition staging. In stage IIIB, 36-month survival was 83.7% [95% confidence interval (CI) 81.6% to 85.9%] for post-operative immunotherapy versus 78.6% (95% CI 77.1% to 80.2%; P < 0.001) for no adjuvant therapy using version 7 staging; for version 8 staging, it was 88.0% (95% CI 85.8% to 90.2%) for post-operative immunotherapy (IO) versus 84.7% (95% CI 83.0% to 86.4%; P = 0.011) for no post-operative therapy. In stage IIIC, 36-month survival was 74.1% (95% CI 72.2% to 76.0%) for post-operative IO versus 64.8% (95% CI 63.3% to 66.4%; P = <0.001) for no post-operative therapy in version 7 staging, whereas in version 8 staging the 3-year landmark survival for post-operative IO was 75.6% (95% CI 73.9% to 77.5%) versus 68.1% (95% CI 66.7% to 69.6%; P < 0.001) for no post-operative therapy.
Patients with stage IIID disease (AJCC version eighth) who received immunotherapy also had improved 36-month survival compared to those who did not [59.2% (95% CI 53.6% to 65.3%) versus 48.4% (95% CI 44.2% to 53.0%); P = 0.001].
Patients with stage IIIA diseases staged by either AJCC version seventh or eighth edition who received immunotherapy did not have a statistically significant OS difference at 36 months compared to those who did not receive immunotherapy. Version 7 stage IIIA 36-month survival was 91.3% (95% CI 89.5% to 93.2%) for post-operative IO versus 90.1% (95% CI 89.5% to 91.9%; P = 0.285) for no post-operative therapy. AJCC version 8 landmark survival for stage IIID was 93.0% (95% CI 91.3% to 94.8%) for post-operative IO versus 92.2% (95% CI 91.0% to 93.4%; P = 0.218) for no post-operative therapy. Table 2 summarizes the landmark survival in version 7 and 8 staging.
Table 2.
36-month survival comparison between those who received post-operative immunotherapy and those who did not
| Stage | 36-month survival estimates % (95% CI) |
P value | |
|---|---|---|---|
| No post-operative immunotherapy | Post-operative immunotherapy | ||
| Seventh edition | |||
| IIIA | 90.1 (89.5-91.9) | 91.3 (89.5-93.2) | 0.285 |
| IIIB | 78.6 (77.1-80.2) | 83.7 (81.6-85.9) | <0.001 |
| IIIC | 64.8 (63.3-66.4) | 74.1 (72.2-76.0) | <0.001 |
| Eighth edition | |||
| IIIA | 92.2 (91.0-93.4) | 93.0 (91.3-94.8) | 0.218 |
| IIIB | 84.7 (83.0-86.4) | 88.0 (85.8-90.2) | 0.011 |
| IIIC | 68.1 (66.7 -69.6) | 75.6 (73.9-77.5) | <0.001 |
| IIID | 48.4 (44.2-53.0) | 59.2 (53.6-65.3) | 0.002 |
CI, confidence interval.
Cox regression model for overall survival
In the multivariable Cox regression model, increasing age [hazard ratio (HR): 1.04; 95% CI 1.03-1.04; P < 0.001]; male sex (HR: 1.13; 95% CI 1.04-1.24; P = 0.005); African American race (HR: 1.59; 95% CI 1.12-2.26; P = 0.01); and Charlson-Deyo comorbidity index scores of 1 (HR: 1.18; 95% CI 1.05-1.31; P < 0.004), 2 (HR 1.54; 95% CI: 1.31-1.81; P < 0.001), or ≥3 (HR 1.81; 95% CI: 1.31-1.81; P < 0.001) were associated with an increased risk of death. Receipt of immunotherapy was associated with a reduced hazard for death (HR: 0.77; 95% CI 0.69-0.85; P < 0.001). Additionally, compared with patients who received care at an academic medical center, those who received care at a community center (HR: 1.50; 95% CI 1.24-1.81; P < 0.001), comprehensive community cancer center (HR: 1.28; 95% CI 1.16-1.42; P < 0.001), or integrated network center (HR: 1.27; 95% CI 1.13-1.41; P < 0.001) were at an increased risk of death. Compared with patients with private insurance, those who were uninsured were at an increased risk for death (HR: 1.47; 95% CI 1.13-1.92; P < 0.005). Patients with Medicaid or Medicare did not have a statistically significant increased risk. The remaining HRs are shown in Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.102193. The HRs for patients diagnosed after 2018 is included in Supplementary Figure S2.
Regression model for immunotherapy receipt
Receipt of immunotherapy varied by demographic and tumor factors. Patients who were older in age were less likely to receive immunotherapy (HR: 0.97; 95% CI 0.97-0.98; P < 0.001). Patients residing in the lowest income quartile ZIP codes were less likely to receive immunotherapy compared to those residing in the highest income quartiles. (odds ratio: 0.81; 95% CI 0.66-0.99; P = 0.037). Similarly, uninsured patients were less likely to receive immunotherapy (HR: 0.53; 95% CI 0.38-0.75; P < 0.001). Biological sex had no relationship to immunotherapy receipt. Various tumor/treatment factors such as lymphovascular invasion, ulceration, and treatment with radiation had no effect on immunotherapy receipt. The logistic regression for immunotherapy receipt by various patient factors is shown in Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2023.102193. The logistic regression for immunotherapy receipt by various patient factors diagnosed after 2018 is shown in Supplementary Figure S4.
Survival analysis in the adjuvant PD-1 era
A separate analysis was completed of the subset of patients who were diagnosed in 2018 or later, which includes the period after adjuvant nivolumab and pembrolizumab were approved. A total of 6697 patients with stage III melanoma diagnosed in 2018 and after were included. Of those patients, 3580 received post-operative immunotherapy and 3117 did not. The average age was 62 ± 15.44 years for the entire cohort, while the average age was 60 ± 15.13 years for those who received post-operative immunotherapy and 64 ± 15.44 years for those who did not (P < 0.001).
Patients with IIIB and IIIC disease staged by either AJCC version seventh or eighth had significant survival benefit at the 36-month mark. Patients with stage IIID disease (AJCC version eighth) were a smaller group (n = 384) and those who received immunotherapy had a numerically higher survival rate (56.0% versus 49.1%; P = 0.122); however, this did not reach statistical significance.
Patients with stage IIIA disease did not have a statistically significant OS difference between post-operative immunotherapy and no post-operative therapy groups. The 36-month landmark survival for post-operative IO versus no post-operative therapy staged by the seventh version was 93.0% (95% CI 90.9% to 95.1%) versus 90.3% (95% CI 87.4% to 93.2%; P = 0.071) and by the eighth version was 94.4% (95% CI 92.5% to 96.4%) versus 92.4% (95% CI 90.2% to 96.0%; P = 0.286). The demographic data, Kaplan–Meier survival curves, Cox regression model, and logistic regression for immunotherapy receipt for patients diagnosed in 2018 or later are provided in Supplementary Table S4, Figure 3 and Supplementary Figures S1, S3, S5 and S6, available at https://doi.org/10.1016/j.esmoop.2023.102193, respectively.
Discussion
We used real-world data from the NCDB to evaluate the survival benefit of post-operative immunotherapy in patients diagnosed with stage III cutaneous melanoma. Among 14 978 patients with stage III disease diagnosed in 2016 or later, we found that patients receiving post-operative immunotherapy have significant survival benefit compared to those who did not receive post-operative immunotherapy (HR 0.77; 95% CI 0.69-0.85; P < 0.001).
Previous randomized clinical trials demonstrated an improved RFS in stage III melanoma by using adjuvant immunotherapy. These studies led to the rapid adoption of post-operative immunotherapy following the approval of ipilimumab in 2015, nivolumab in 2017, and pembrolizumab in 2019.13, 14, 15 The data in these studies were not yet mature enough to demonstrate improvement in OS in stage III melanoma at the time of publication. For example, median survival was not met in EORTC 18071 at the time of publication, but longer-term follow-up at a median of 5.3 years demonstrated improvement in OS using ipilimumab compared to placebo (HR 0.73; 95% CI 0.60-0.89; P = 0.002).10 The three-armed intergroup E1609 also evaluated two doses of ipilimumab 10 mg/kg (Ipi10) and ipilimumab 3 mg/kg (ipi3) versus high-dose interferon alpha. In comparison to interferon, ipi3 yielded an improved survival (HR 0.78; 95.6% repeated CI 0.61-0.99; P = 0.044); however, while Ipi10 trended to increased survival, the results were not statistically significant. Stage IIIA patients were excluded from this trial.16 Similarly, in KEYNOTE-054 and CHECKMATE 238, a statistically significant OS benefit has not yet been seen for the treatment population.7, 8, 9 Given the observed benefit of immunotherapy in the clinical trial settings, retrospective studies have evaluated real-world efficacy of immunotherapy in melanoma. One real-world study of 1371 patients diagnosed with stage III melanoma in Sweden between 2016 and 2020 contradicted the results of the randomized clinical trial and demonstrated that the introduction of adjuvant treatment did not show a statistically significant improvement in overall or melanoma-specific survival, across various subgroups. However, this study did not assess how many patients received immunotherapy in the post-operative setting and had a follow-up of only 24 months, limiting the generalizability and conclusions of the study.17
Utilizing a large database, we found that those with higher-risk stage IIIB, IIIC, and IIID diagnoses staged by either AJCC seventh or eighth edition had a significantly improved survival at 36 months after definitive surgery compared to those who did not receive post-operative immunotherapy. The 36-month analysis interval was chosen as it aligns with the time point highlighted in the initial reports of adjuvant therapy trials and was the longest 12-month interval with sufficient survival follow-up at this analysis. Similar to trial data, we observed a survival benefit at the 36-month mark with stage III melanoma overall and in high-risk melanoma subgroups; however, there was no benefit in patients with stage IIIA melanoma. Our results are concordant with the randomized control trials (RCTs) which have also not demonstrated significant improvements in RFS or OS in stage IIIA melanoma.7, 8, 9, 10 Furthermore, the prior trials evaluating post-operative treatment in stage III melanoma utilized have so far used AJCC seventh edition staging and include patients who are described as high risk with sentinel node-positive and nodal metastasis that are at least 1 mm in diameter. It is important to note that due to changes in AJCC version 8 staging, patients with stage IIIA disease by AJCC eighth edition have an even further improved melanoma-specific survival compared to IIIA by AJCC seventh edition convention.18
Given the lack of OS benefit for stage IIIA disease, our results further support the need for extensive discussion with patients before initiation of adjuvant therapy in those with stage IIIA disease.19 This requires a personalized decision for patients. For many patients, prevention of a recurrence is worthwhile while others would only want a treatment that helps them liver longer or get cured. While immunotherapeutic agents have improved side-effect profiles compared to chemotherapy and many targeted therapies, it is still associated with immune-related adverse events that can be lifelong or even potentially debilitating. For example, in KEYNOTE-054, grades 3 to 5 adverse events were observed in 14.7% compared to 3.4% of patients in the placebo group.7 In CHECKMATE 238, 14.4% of the patients in the nivolumab group and 45.9% of those in the ipilimumab group suffered from grade 3 or 4 adverse events.9
We observed a rapid increase in post-operative immunotherapy use in the real-world setting. In 2019, 55.5% of stage III patients received post-operative immunotherapy compared to only 13.7% of patients in 2016. Fears of side-effects from adjuvant treatment by patients and physicians are one of the main reluctances to undergo adjuvant systemic treatment.20 The inflection point in this rise which was most dramatic in 2018 and 2019 following the approval of single-agent anti-PD-1 checkpoint therapy in the post-operative setting, suggesting the balanced improved toxicity and outcome of anti-PD-1 over anti-CTLA-4, likely led to higher adoption.21
While we found a survival benefit with adjuvant therapy, many patients with stage IIIB-D melanoma still die because of recurrent metastatic disease. Strategies to locally advanced melanomas have now transitioned to neoadjuvant therapies with pembrolizumab in SWOG1805 and with dual-agent nivolumab and ipilimumab in OPACINeo and with combination nivolumab and relatlimab.22, 23, 24 Further neoadjuvant and adjuvant trials are ongoing to evaluate potential combination strategies (NCT05665595, NCT05002569).
Real-world data have increasingly been used to both evaluate treatment outcomes following trials and to supplement trial data.25 When strict criteria for data selection are utilized, outcomes can mimic RCT findings.26 Our real-world study population was >15 times the size of even the largest trial carried out. This allowed for statistically significant differences in survival, or a lack thereof, to be observed earlier than would be possible in clinical trials.
Limitations
The NCDB is not a population database and is subject to selection bias and lacks granular details about specific systemic treatments, recurrence outcomes, specific comorbidities, and sociodemographic information about the individual. Specific agents received as immunotherapy (e.g. anti-CTLA-4, anti-PD-1), targeted therapy, or chemotherapy are not accessible from the NCDB PUF. BRAF mutation data are not reported either. Furthermore, while neoadjuvant immunotherapy is rapidly becoming the mainstay of node-positive treatment in melanoma, small numbers of patients receiving IO before surgery did not allow for a substantiative analysis of these patients.24 Additionally, it is possible that survival benefits could widen and become more statistically significant in longer-term follow-up in the lower-risk stages.
Conclusions
Real-world data from the NCDB demonstrated improved survival for stage IIIB and higher melanomas receiving post-operative immunotherapy. However, no significant survival benefit was observed in stage IIIA melanoma.
Acknowledgements
We thank the Commission on Cancer and The American College of Surgeons for access to the National Cancer Database. The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.
Funding
This work was supported by institutional funding from the Department of Medicine Chair’s Trainee Innovation Grant Funding within the Department of Medicine at The University of California Irvine Medical Center (no grant number).
Disclosure
The authors have declared no conflicts of interest.
Supplementary data
References
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