Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/ kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/ kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immunerelated colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure. Melanoma Res 31: 464

With more than 82 million cases worldwide and almost two million deaths, the Covid-19 global pandemic shows little sign of abating. However, its effect on quality of life (QoL) in skin cancer patients has not been systematically evaluated to date. Given that QoL impairments may be associated with increased psychological morbidity, and may interfere with engagement with cancer therapy and follow-up, we prospectively evaluated quality of life in skin cancer patients using the Covid-19 Emotional Impact Survey (C-19EIS) and the EORTC QLQ-C30 questionnaires. 101 patients (48 females and 53 males) completed both questionnaires. The mean C-19EIS score was 3.8 on a scale from 0 (no impact) to 12 (severe impact). Patients undergoing systemic therapy showed significantly impaired physical (p = 0.006) and social functioning (p = 0.003). However, when compared to the published normative EORTC QLQ-C30 data, there was no evidence that the Covid-19 pandemic had significantly impacted upon overall quality of life. Subscales of the EORTC QLQ-C30 were significantly inversely correlated with the C-19EIS, validating its use in skin cancer patients. Despite the Covid-19 pandemic, skin cancer patients in our tertiary referral center were surprisingly resilient. However, given the geographical variations in the rates of Sars-CoV-2 infection it is possible that the low incidence in Northern Germany may have resulted in a lack of general QoL impairments. Multi-center studies are required to further determine the impact of Covid-19 on psychological wellbeing in skin cancer patients in order to develop supportive interventions and to ensure that engagement with cancer care services is maintained in order to enable early detection of cancer progression and/or recurrence.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several human malignancies, particularly metastatic skin cancer. However, immune-related myocarditis (irM), an immune-mediated adverse event (irAE), is often fatal. In the absence of a reliable biomarker, measurement of pre-ICI therapy serum troponin concentration has been proposed to identify patients at risk of developing irM, although real-world studies examining this strategy are lacking. Thus, we retrospectively analyzed the case records of all patients who commenced ICI therapy between January 2018 and December 2019 in a single university skin cancer center (n = 121) to (i) determine the incidence of irM, (ii) establish the frequency of pretreatment serum hsTnT elevations, and (iii) to establish whether this identified patients who subsequently developed irM. Only one patient developed irM, resulting in an overall incidence of 0.8%. Pretreatment hsTnT was measured in 47 patients and was elevated in 13 (28%). Elevated serum hsTnT concentrations were associated with chronic renal failure (p = 0.02) and diabetes (p < 0.0002). Pretreatment hsTnT was not elevated in the patient who developed fulminant irM. Pre-immunotherapy serum hsTnT concentrations were often asymptomatically elevated in patients with advanced skin cancer, none of whom subsequently developed irM during ICI therapy. However, large studies are required to assess the positive and negative predictive values of hsTnT for the development of irM. In the meantime, elevated hsTnT concentrations should be investigated before initiation of immunotherapy and closely monitored during early treatment cycles, where the risk of irM is greatest.

Despite the dramatic improvement in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic melanoma treated with immune checkpoint inhibitors, up to 60% will develop treatment resistance and 50% will die from their disease. Therefore, although dacarbazine is no longer a mainstay of modern melanoma management, we examined the extent to, and in which context, it may still play a role. A retrospective analysis of electronic medical records of patients who had received dacarbazine treatment between October 2014 and October 2021, following innate or acquired resistance to immune checkpoint inhibitors, was performed to determine PFS and OS and examine tolerability. Nine patients with locally advanced (n = 1) or metastatic melanoma (n = 8) were identified (average age: 74 years, 4 males and 5 females). The number of cycles of dacarbazine ranged from 2 to 45 (mean = 12). One-third of patients developed a complete (n = 2) or partial (n = 1) response, two-thirds did not respond to treatment. The median PFS time was 90 days. Common adverse events included blood dyscrasias; one patient developed a grade 3 hepatitis, although it was unclear if this was due to the chemotherapy or the preceding combined immunotherapy. Dacarbazine may still be a valid option in the setting of treatment for refractory, relapsed, or progressive disease. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially restore sensitivity to immune checkpoint-based therapy.

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.