Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events.

Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.

Digital decision support for structural improvement of melanoma tumor boards: using standard cases to optimize workflow.

PURPOSE: Choosing optimal cancer treatment is challenging, and certified cancer centers must present all patients in multidisciplinary tumor boards (MDT). Our aim was to develop a decision support system (DSS) to provide treatment recommendations for apparently simple cases already at conference registration and to classify these as "standard cases". According to certification requirements, discussion of standard cases is optional and would thus allow more time for complex cases. METHODS: We created a smartphone query that simulated a tumor conference registration and requested all information needed to provide a recommendation. In total, 111 out of 705 malignant melanoma cases discussed at a skin cancer center from 2017 to 2020 were identified as potential standard cases, for which a digital twin recommendation was then generated by DSS. RESULTS: The system provided reliable advice in all 111 cases and showed 97% concordance of MDT and DSS for therapeutic recommendations, regardless of tumor stage. Discrepancies included two cases (2%) where DSS advised discussions at MDT and one case (1%) with deviating recommendation due to advanced patient age. CONCLUSIONS: Our work aimed not to replace clinical expertise but to alleviate MDT workload and enhance focus on complex cases. Overall, our DSS proved to be a suitable tool for identifying standard cases as such, providing correct treatment recommendations, and thus reducing the time burden of tumor conferences in favor for the comprehensive discussion of complex cases. The aim is to implement the DSS in routine tumor board software for further qualitative assessment of its impact on oncological care.

Case Report: Sudden very late-onset near fatal PD1 inhibitor-associated myocarditis with out-of-hospital cardiac arrest after >2.5 years of pembrolizumab treatment.

Introduction: Immune checkpoint inhibitors have advanced the outcomes of many different types of cancer. A rare but extraordinarily severe complication of these agents resembles immune checkpoint inhibitor-related myocarditis, which typically occurs within the first few weeks after treatment initiation with a mortality of 25%-50%. Case report: A 57-year-old woman had uneventfully received pembrolizumab for metastatic non-small cell lung cancer for over 2.5 years and was admitted after an out-of-hospital cardiac arrest due to ventricular fibrillation. After successful cardiopulmonary resuscitation, the initial diagnostic work-up showed elevated cardiac enzymes and a limited left-ventricular ejection fraction, while coronary angiography did not show relevant stenosis. Despite cardiac MRI being unsuggestive of myocarditis, myocardial biopsies were obtained and histologically confirmed anti-PD-1 antibody-associated myocarditis. After the initiation of prednisone at 1 mg/kg body weight, the patient gradually recovered and was discharged three weeks later with markedly improved cardiac function. Conclusion: This case resembles the first description of a very late onset irMyocarditis, occurring over 2.5 years after the start of treatment. It demonstrates the importance of contemplating that severe immune-related toxicities with a sudden onset clinical presentation may occur even after long uneventful periods of anti-PD-1 immune checkpoint inhibitor treatment. Furthermore, it underlines the critical importance of myocardial biopsies in this setting, especially when cardiac MRI remains inconclusive. Moreover, it demonstrates the necessity and benefits of early immunosuppressive treatment if immune-related myocarditis is considered a differential diagnosis.

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial.

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Oligometastatic disease and visceral resections in advanced malignant melanoma: a propensity-matched analysis.

PURPOSE: Malignant melanoma is among the tumours with the highest increase in incidence of solid tumours in Germany. While most patients are diagnosed at an early stage and show a good prognosis, advanced stages of malignant melanoma are accompanied with a poor prognosis and limited treatment options. Comparable to other tumour entities, the resection of visceral metastases could lead to a better prognosis. Supplementary, the subgroup of oligometastatic patients might benefit from surgical therapy to a greater extent. METHODS: This retrospective study analysed 351 patients treated between 2006 and 2017 at the University Hospital of Cologne. A total of 121 patients showed visceral metastases, with which we compared patients with a diffuse tumour spread to patients in an oligometastatic state. Furthermore, we evaluated the effect of visceral resection of oligometastatic, malignant melanoma. RESULTS: Our analysis showed that patients with an oligometastatic malignant melanoma had a significantly better prognosis than patients with a diffuse pattern of metastases, if they showed visceral metastases. Furthermore, the resection of visceral metastases leads to a significant gain in median overall survival time (13.6 vs. 34.2 months) and in progression-free survival (9.6 vs. 3.8 months). CONCLUSION: The resection of visceral metastases is a rational treatment option in advanced malignant melanoma. Although our study is limited by a small cohort of patients (n = 18), we believe that the resection of visceral metastases will be fundamental in the treatment of malignant melanoma. In particular, patients in an oligometastatic stage could be an eligible group for surgical treatment.

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity.

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis.

BACKGROUND: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. METHODS: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. RESULTS: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. CONCLUSION: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Treatment Monitoring of Immunotherapy and Targeted Therapy Using 18F-FET PET in Patients with Melanoma and Lung Cancer Brain Metastases: Initial Experiences.

We investigated the value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastasis (BM) since contrast-enhanced MRI often remains inconclusive. Methods: We retrospectively identified 40 patients with 107 BMs secondary to melanoma (n = 29 with 75 BMs) or non-small cell lung cancer (n = 11 with 32 BMs) treated with ICI or TT who had 18F-FET PET (n = 60 scans) for treatment monitoring from 2015 to 2019. Most patients (n = 37; 92.5%) had radiotherapy during the course of the disease. In 27 patients, 18F-FET PET was used to differentiate treatment-related changes from BM relapse after ICI or TT. In 13 patients, 18F-FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 mo). In all lesions, static and dynamic 18F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios [TBR], time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathologic findings as a reference. Results: A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P = 0.003). Metabolic responders to ICI or TT on 18F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P = 0.004). Furthermore, at follow-up, time to peak in metabolic responders increased significantly (P = 0.019). Conclusion:18F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.

BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study.

BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy. In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.

Health-related quality of life, fatigue, and depression under low-dose IFN-α therapy in melanoma patients.

Adjuvant melanoma treatment with interferon-α (IFN-α) has proven to be accompanied by several side effects and to decrease patients' health-related quality of life (HRQOL), fatigue and depression being essential factors at that. Although a large body of evidence exists for HRQOL under IFN-α therapy, we now specifically address this topic combining the HRQOL survey in the first months of IFN-α low-dose treatment with a structured assessment of relevant neuropsychiatric side effects, fatigue and depression, with specific validated assessment tools. The present study is a longitudinal observational study assessing fatigue, depression, and HRQOL with specific assessment tools at 3 assessment points over 6 months. The IFN-α treatment group consisted of 48 patients with current IFN-α therapy (3 MU 3 times weekly) from a consecutively recruited melanoma collective and compared with a parallelized nontreatment group (n=48) in routine clinical practice. A descriptive analysis and generalized linear models were applied to compare the groups. Physical fatigue increased significantly within the first months of IFN-α treatment, whereas cognitive and emotional fatigue and depression symptoms did not show this increase. The hypothesis of a significant deterioration of HRQOL after IFN-α initiation was not confirmed. The treatment group did, however, show a different course of global HRQOL than the comparison group, with a significant improvement in the nontreatment group. Patients under low-dose IFN-α therapy primarily suffer from physical side effects, mainly physical fatigue, in the early phases of treatment. The HRQOL improvement evident in the nontreatment group was not observed in the IFN-α group.

Ocular diseases in metastatic cutaneous melanoma: review of 108 consecutive patients in two German tertiary centers.

PURPOSE: To analyze the incidence and spectrum of ocular disease in patients with metastatic cutaneous melanoma. METHODS: One hundred and eight consecutive patients with metastatic cutaneous melanoma were screened for ocular diseases using standardized eye examination, including measurement of visual acuity and intraocular pressure, slit-lamp examination, funduscopy in mydriasis, and spectral-domain optical coherence tomography (SDOCT) of the retina. Selected cases with atypical findings underwent electrophysiological studies. One patient was examined for hypercortisolism by a dexamethasone suppression test. RESULTS: Ocular diseases were found in 65 out of 108 patients (60 %) with metastatic cutaneous melanoma, significantly more often in older patients (p = 0.004). Cataract was present in 27 patients (25 %), pseudophakia in 22 patients (20 %), macular disease in 29 patients (28 %), diabetic retinopathy in ten patients (9 %), hypertensive retinal disease in 14 patients (13 %), retinal venous and arterial occlusive disease in three patients (3 %), optic neuropathy in four patients (4 %), and uveitis in one patient (1 %). Eight patients (8 %) had choroidal or iridal nevi, one patient (1 %) choroidal hemangioma, and one patient (1 %) choroidal metastasis. No patient had periocular neoplastic lesions. Paraneoplastic retinopathy manifesting as acute exudative polymorphous vitelliform maculopathy (AEPVM)-like disease was diagnosed in two patients (2 %) with multifocal central serous chorioretinopathy and development of vitelliform or fibrin-like subretinal deposits in one patient. CONCLUSIONS: Patients with metastatic cutaneous melanoma reveal ocular diseases with a spectrum similar to the normal population of this age range. Very rarely, uveal metastasis as well as paraneoplastic retinopathy can occur.

Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAF mutations.

BACKGROUND: The approval of vemurafenib in the US 2011 and in Europe 2012 improved the therapy of not resectable or metastatic melanoma. Patients carrying a substitution of valine to glutamic acid at codon 600 (p.V600E) or a substitution of valine to leucine (p.V600K) in BRAF show complete or partial response. Therefore, the precise identification of the underlying somatic mutations is essential. Herein, we evaluate the sensitivity, specificity and feasibility of six different methods for the detection of BRAF mutations. METHODS: Samples harboring p.V600E mutations as well as rare mutations in BRAF exon 15 were compared to wildtype samples. DNA was extracted from formalin-fixed paraffin-embedded tissues by manual micro-dissection and automated extraction. BRAF mutational analysis was carried out by high resolution melting (HRM) analysis, pyrosequencing, allele specific PCR, next generation sequencing (NGS) and immunohistochemistry (IHC). All mutations were independently reassessed by Sanger sequencing. Due to the limited tumor tissue available different numbers of samples were analyzed with each method (82, 72, 60, 72, 49 and 82 respectively). RESULTS: There was no difference in sensitivity between the HRM analysis and Sanger sequencing (98%). All mutations down to 6.6% allele frequency could be detected with 100% specificity. In contrast, pyrosequencing detected 100% of the mutations down to 5% allele frequency but exhibited only 90% specificity. The allele specific PCR failed to detect 16.3% of the mutations eligible for therapy with vemurafenib. NGS could analyze 100% of the cases with 100% specificity but exhibited 97.5% sensitivity. IHC showed once cross-reactivity with p.V600R but was a good amendment to HRM. CONCLUSION: Therefore, at present, a combination of HRM and IHC is recommended to increase sensitivity and specificity for routine diagnostic to fulfill the European requirements concerning vemurafenib therapy of melanoma patients.

Induction of durable responses by oral etoposide monochemotherapy in patients with metastatic Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, rare tumour of the skin. For advanced cases with distant organ metastases several different regimens of chemotherapeutics have been described. Disease specific 5-year survival rates for these patients are approximately 11%. In this case series we report our experience with orally administered etoposide (100 mg at days 1 to 10 in a 31 day cycle) in 4 patients. We treated two male and two female patients with a median age of 68.5 years. In our four treated patients the disease control rate (complete remission, partial remission, stable disease) was 100%. Three out of four patients reached complete remission. Promisingly, two of our patients had long lasting, durable responses which, until now, have lasted for 16 and 36 months, respectively. The mean follow up time after start of therapy was 14.25 months (range 1-36 months). Etoposide treatment was generally well tolerated, the most common side effect was neutropenia, in one case CTC grade 3. In conclusion, orally administered etoposide in metastatic Merkel cell carcinoma was highly effective and well tolerated.