Real‐world outcomes using PD‐1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland

Abstract

Background: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. Methods: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. Results: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. Conclusions: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

Melanoma is not just one disease, but many

“…1 Real-world evidence also confirmed outcomes using modern adjuvant treatments. 2 Thus, results from clinical trials are not limited to research settings with (in some cases rigorous) inclusion and exclusion criteria, but can be provided to patients in clinical routine. This is the result of a joint effort of everyone involved: academic research, pharmaceutical drug development, and parties involved in their clinical implementation.…”

“…Basic research has provided us with insights in the various different trajectories leading up to the clinical finding of malignant melanocytes in the skin or other organs. The latter has also laid the foundation for the development of important treatment options that we can thankfully call standard of care in most countries today: As highlighted by outcome research in this special issue, survival of patients with advanced disease has made a leap compared to historic results: more than 50% improvement in survival over the course of 10 years — that's just incredible! 1 Real‐world evidence also confirmed outcomes using modern adjuvant treatments 2 . Thus, results from clinical trials are not limited to research settings with (in some cases rigorous) inclusion and exclusion criteria, but can be provided to patients in clinical routine.…”

Adjuvant treatment in advanced melanoma: How far have we come?

“…The patient population enrolled in randomized controlled trials is stringently selected and may not represent the heterogeneous population of patients that physicians will evaluate and treat on a daily basis in their clinical practice. The study presented by Schumann K 6 and colleagues in this issue of JEADV offers an important contribution in this regard providing new insights into the characteristics and treatment outcomes of high risk melanoma patients receiving adjuvant systemic treatment. Their study included real world data of 1198 patients from 39 skin cancer centres in Germany, Austria and Switzerland receiving adjuvant treatment with either ICBs or combination of Dabrafenib and Trametinib (D + T).…”

Advanced melanoma—A curable disease? Implications of systemic treatment on patients' daily life

“…For example, in a recent publication in the Journal of the European Academy of Dermatology and Venereology, a group from 13 skin cancer centres in Germany, Austria and Switzerland examined the real-world situation in current adjuvant melanoma therapy using PD-1 antibodies or BRAF/MEK inhibitors. 12 However, the goal of all our efforts is the well-being of our patients. Thus, how does study-based evidence translate into clinical practice and, in particular, into our patients' treatment decisions and experience?…”

“…Beyond the data from controlled trials, however, real‐world data are also are sustainably relevant for the assessment of treatment options in clinical practice. For example, in a recent publication in the Journal of the European Academy of Dermatology and Venereology, a group from 13 skin cancer centres in Germany, Austria and Switzerland examined the real‐world situation in current adjuvant melanoma therapy using PD‐1 antibodies or BRAF/MEK inhibitors 12 …”