Brief Communication: Treatment Outcomes for Advanced Melanoma of Unknown Primary Compared With Melanoma With Known Primary.

SUMMARY: Most patients with advanced melanomas have a known primary site [melanoma of known primary (MKP)]. However, 2%-9% of patients are diagnosed with melanoma metastasis of unknown primary (MUP). As MUP and MKP have similar UV-induced mutations and molecular signatures, it is proposed that the primary tumor has regressed completely in patients with MUP. As regression of the primary tumor could be indicative of enhanced recognition of melanoma antigens, we hypothesize that patients with advanced MUP have a better outcome compared with MKP.Patients with advanced MUP from 10 German university hospitals were retrospectively analyzed and matched with MKP based on the type of systemic treatment (BRAF and MEK inhibitors, PD-1 inhibitor monotherapy, combined CTLA-4 and PD-1 inhibitor therapy) therapy line (first or second line) and AJCC stage (IIIC, IV M1a-M1d). Three hundred thirty-seven patients with MUP were identified, and 152 treatments with PD-1 and CTLA-4 inhibitors, 142 treatments with PD-1 inhibitors, and 101 treatments with BRAF and MEK inhibitors were evaluated. Median time to treatment failure was significantly prolonged in patients with MUP treated with PD-1 monotherapy (17 mo, 95% CI: 9-25, P = 0.002) compared with MKP (5 mo, 95% CI: 3.4-6.6), as well as in MUP treated with combined PD-1 and CTLA-4 therapy (11 mo, 95% CI: 4.5-17.5, P < 0.0001) compared with MKP (4 mo, 95% CI: 2.9-5.1) Occurrence of immune-related adverse events and time to treatment failure for patients with BRAF and MEK inhibitors was similar in MKP and MUP. In our multicentre collective, patients with MUP have better outcomes under immunotherapy compared with MKP.

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.

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.

Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

Genetic characterization of advanced conjunctival melanoma and response to systemic treatment.

BACKGROUND: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts. METHODS: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined. RESULTS: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively. CONCLUSIONS: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients.

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24-38), and fear of adverse events (21.1%, 95% CI 16-28) and impaired quality of life (11.9%, 95% CI 7-16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.

Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients.

Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis.

Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients.

BACKGROUND: Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy. METHODS: This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS). RESULTS: 84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin's lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD-1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002). CONCLUSIONS: ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node.

PURPOSE: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up. PATIENTS AND METHODS: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly. RESULTS: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported. CONCLUSION: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.