The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria. We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019–2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6–9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings.

We report long-term clinical and immunologic outcomes from the MM1636 trial (NCT03047928), which evaluated a peptide vaccine targeting IDO and PD-L1 in combination with nivolumab in patients with advanced melanoma. At a five-year follow-up, the combination demonstrated durable clinical efficacy, with a 25.5-month median progression-free survival. Serum proteomic profiling identified vaccine-specific immune signatures, with increase in CCL3, CCL4, and TNFα emerging as biomarkers of long progression-free survival. Increase in these markers were not observed in a matched anti-PD-1 monotherapy cohort, suggesting distinct immune modulation by the vaccine. Functional studies confirmed vaccine-induced targeting of myeloid cells and associated increase in these cytokines. These findings provide evidence for durable benefit from immune modulatory vaccination and nominate CCL3, CCL4, and TNFα as candidate biomarkers for response.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment and are increasingly used in the adjuvant and neoadjuvant setting for malignancies such as melanoma, which often affect younger adults. With improving survival, concerns about long-term safety, including potential effects on fertility, are growing. We conducted a national, multicenter, prospective observational study of female patients < 45 years treated with adjuvant anti-PD-1 therapy for resectable stage III-IV melanoma from 2018 to 2024. Ovarian function was assessed at baseline and at 3, 6, 12, and 18 months after treatment initiation. Each visit included transvaginal ultrasound for antral follicle count (AFC) and serum analysis of anti-Müllerian hormone (AMH), estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and inhibin-B. Seventeen female patients were enrolled (mean age 28.9 years, range 17-38). Median follow-up was 5.1 years. Ovarian morphology and AFC remained normal and stable at all time points. No decline in AMH was observed during or after treatment. FSH, LH, estradiol, progesterone, and inhibin-B levels fluctuated within physiological ranges consistent with normal menstrual cycling. After completing adjuvant therapy, five patients had at least one child, and one was pregnant at data cut-off. Two patients developed endocrine immune-related toxicity (type 1 diabetes and hypophysitis); both conceived post-treatment. This prospective evaluation of ovarian function during and after adjuvant anti-PD-1 therapy in melanoma found no evidence of treatment-related ovarian insufficiency, including in patients with endocrine toxicities. These findings are important for counseling young patients receiving adjuvant therapy who may wish to conceive in the future.