Real-world effectiveness of immune checkpoint inhibitors and BRAF/MEK inhibitors among Veteran patients with cutaneous melanoma

Abstract: The Veterans Health Administration is the largest integrated health care system in the United States, caring for more than 9 million individuals. Despite higher cutaneous melanoma (CM) risk and poorer melanoma-specific survival (MSS), Veterans Affairs patients have been historically underrepresented in national datasets and clinical trials. We examined the real-world effectiveness of immune checkpoint inhibitors and BRAF/MEK inhibitors (BRAF/MEKi) among veteran patients with CM in the adjuvant and systemic settings to better understand treatment response in this high-risk population. We included 677 patients with histologically confirmed CM diagnosed from 2009 through 2019 within the Veterans Affairs Cancer Registry System treated with first-line immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte associated protein 4 [anti-CTLA-4], anti-programmed death protein 1 [anti-PD-1], anti-PD-1/anti-CTLA-4) or BRAF/MEKi who met eligibility criteria. X2 and Kruskal-Wallis tests evaluated unadjusted demographic differences. Unadjusted Kaplan-Meier survival analyses and log-rank tests assessed overall survival (OS) and MSS by treatment type. Univariable and multivariable Cox proportional hazards models estimated mortality hazard ratios and 95% CIs by treatment type. Generally, veteran patients receiving immune checkpoint inhibitors or BRAF/MEKi were older (median age, 68 years), male (98%), White (96%), and had substantial comorbidities (eg, hypertension, congestive heart failure, diabetes mellitus). Anti-PD-1 monotherapy was the most prevalent first-line treatment in both adjuvant (66.7%) and systemic settings (50.3%). Most anti-PD-1/anti-CTLA-4 combination therapy was standard dosing. In the adjuvant setting, anti-PD-1 monotherapy exhibited the highest unadjusted 5-year OS (58.9%) and MSS (91.2%). In the systemic setting, anti-PD-1 monotherapy exhibited the highest unadjusted 3-year OS (48.4%), while anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combination therapy exhibited the highest unadjusted MSS (70.4% and 64.7%, respectively). In multivariable analyses in the adjuvant setting, anti-PD-1 monotherapy demonstrated the lowest melanoma-specific mortality. In the systemic setting, BRAF/MEKi (adjusted hazard ratio = 2.61, 95% CI = 1.74-3.90) and anti-CTLA-4 monotherapy (adjusted hazard ratio = 1.87, 95% CI = 1.15-3.02) showed significantly greater melanoma-specific mortality than anti-PD-1 monotherapy, but no significant difference was observed between anti-PD-1 monotherapy and combination immunotherapy (adjusted hazard ratio = 1.34, 95% CI = 0.70-2.56). Our study provides valuable insights into the real-world effectiveness of targeted and immunotherapy among veterans with CM. Anti-PD-1 monotherapy demonstrated improved MSS in the adjuvant setting, while anti-PD-1 monotherapy and anti-PD-1/antiCTLA-4 combination therapy were the most effective treatments in the systemic setting. Although current CM guidelines recommend either anti-PD-1/anti-CTLA-4 combination therapy or anti-PD-1 monotherapy as first-line for advanced CM, our findings emphasize the effectiveness of anti-PD-1 monotherapy in veterans. Despite lower OS rates observed compared to trial data, our results support trends seen in prior trial data and emphasize the importance of examining treatment outcomes in specific population