Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple") wild type melanomas.

BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

Early versus late response to PD-1-based immunotherapy in metastatic melanoma.

BACKGROUND: Immune checkpoint inhibition (ICI) currently is the most effective treatment to induce durable responses in metastatic melanoma. The aims of this study are the characterization of patients with early, late and non-response to ICI and analysis of survival outcomes in a real-world patient cohort. METHODS: Patients who received PD-1-based immunotherapy for non-resectable stage-IV melanoma in any therapy line were selected from the prospective multicenter real-world DeCOG study ADOREG-TRIM (NCT05750511). Patients showing complete (CR) or partial (PR) response already during the first 3 months of treatment (Early Responders, EarlyR) were compared to patients showing CR/PR at a later time (Late Responders, LateR), a stable disease (SD) and to patients showing progressive disease (Non-Responders, NonR). RESULTS: Of 522 patients, 8.2 % were EarlyR (n = 43), 19.0 % were LateR (n = 99), 37.0 % had a SD (n = 193) and 35.8 % were NonR (n = 187). EarlyR, LateR and SD patients had comparable baseline characteristics. Multivariate logbinomial regression analyses adjusted for age and sex revealed positive tumor PD-L1 (RR=1.99, 95 %-CI=1.14-3.46, p = 0.015), and normal serum CRP (RR=1.59, 95 %-CI=0.93-2.70, p = 0.036) as independently associated with the achievement of an early response compared to NonR. The median progression-free and overall survival was 46.0 months (95 % CI 19.1; NR) and 47.8 months (95 %-CI 36.9; NR) for EarlyR, NR (95 %-CI NR; NR) for LateR, 8.1 months (7.0; 10.4) and 35.4 months (29.2; NR) for SD, and 2.0 months (95 %-CI 1.9; 2.1) and 6.1 months (95 %-CI 4.6; 8.8) for NonR patients. CONCLUSION: Less than 10 % of metastatic melanoma patients achieved an early response during the first 3 months of PD-1-based immunotherapy. Early responders were not superior to late responders in terms of response durability and survival.

Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy.

BACKGROUND: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma who recur during or after adjuvant immunotherapy, including those that may or may not have undergone prior CLND. In this study, we aimed to answer this question. METHODS: Patients with resected stage III melanoma who received adjuvant anti-programmed cell death protein-1 (PD-1) (±ipilimumab) immunotherapy with a subsequent locoregional (lymph node and/or in-transit metastases) recurrence were retrospectively identified. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was rate of subsequent locoregional recurrence; secondary outcomes were locoregional recurrence-free survival (lr-RFS2) and overall RFS (RFS2) to second recurrence. RESULTS: In total, 71 patients were identified: 42 (59%) men, 30 (42%) BRAF V600E mutant, 43 (61%) stage IIIC at diagnosis. Median time to first recurrence was 7 months (1-44), 24 (34%) received adjuvant RT and 47 (66%) did not. Thirty-three patients (46%) developed a second recurrence at a median of 5 months (1-22). The rate of locoregional relapse at second recurrence was lower in those who received adjuvant RT (8%, 2/24) compared with those who did not (36%, 17/47, p=0.01). Adjuvant RT at first recurrence was associated with an improved lr-RFS2 (HR 0.16, p=0.015), with a trend towards an improved RFS2 (HR 0.54, p=0.072) and no effect on risk of distant recurrence or overall survival. CONCLUSION: This is the first study to investigate the role of adjuvant RT in patients with melanoma with locoregional disease recurrence during or after adjuvant anti-PD-1-based immunotherapy. Adjuvant RT was associated with improved lr-RFS2, but not risk of distant recurrence, demonstrating a likely benefit in locoregional disease control in the modern era. Further prospective studies are required to validate these results.

Characterisation and outcome of RAC1 mutated melanoma.

BACKGROUND: Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear. METHODS: We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes. RESULTS: From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months. CONCLUSIONS: RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study.

PURPOSE: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. PATIENTS AND METHODS: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). RESULTS: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. CONCLUSIONS: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

COVID-19 vaccination in advanced skin cancer patients receiving systemic anticancer treatment: A prospective singlecenter study investigating seroconversion rates.

Background: COVID-19 vaccination reduces risk of SARS-CoV-2 infection, COVID-19 severity and death. However, the rate of seroconversion after COVID-19 vaccination in cancer patients requiring systemic anticancer treatment is poorly investigated. The aim of the present study was to determine the rate of seroconversion after COVID-19 vaccination in advanced skin cancer patients under active systemic anticancer treatment. Methods: This prospective single-center study of a consecutive sample of advanced skin cancer patients was performed from May 2020 until October 2021. Inclusion criteria were systemic treatment for advanced skin cancer, known COVID-19 vaccination status, repetitive anti-SARS-CoV-2-S IgG serum quantification and first and second COVID-19 vaccination. Primary outcome was the rate of anti-SARS-CoV-2-S IgG seroconversion after complete COVID-19 vaccination. Results: Of 60 patients with advanced skin cancers, 52 patients (86.7%) received immune checkpoint inhibition (ICI), seven (11.7%) targeted agents (TT), one (1.7%) chemotherapy. Median follow-up time was 12.7 months. During study progress ten patients had died from skin cancer prior to vaccination completion, six patients were lost to follow-up and three patients had refused vaccination. 41 patients completed COVID-19 vaccination with two doses and known serological status. Of those, serum testing revealed n=3 patients (7.3%) as anti-SARS-CoV-2-S IgG positive prior to vaccination, n=32 patients (78.0%) showed a seroconversion, n=6 patients (14.6%) did not achieve a seroconversion. Patients failing serological response were immunocompromised due to concomitant hematological malignancy, previous chemotherapy or autoimmune disease requiring immunosuppressive comedications. Immunosuppressive comedication due to severe adverse events of ICI therapy did not impair seroconversion following COVID-19 vaccination. Of 41 completely vaccinated patients, 35 (85.4%) were under treatment with ICI, five (12.2%) with TT, and one (2.4%) with chemotherapy. 27 patients (65.9%) were treated non adjuvantly. Of these patients, 13 patients had achieved objective response (complete/partial response) as best tumor response (48.2%). Conclusion and relevance: Rate of anti-SARS-CoV-2-S IgG seroconversion in advanced skin cancer patients under systemic anticancer treatment after complete COVID-19 vaccination is comparable to other cancer entities. An impaired serological response was observed in patients who were immunocompromised due to concomitant diseases or previous chemotherapies. Immunosuppressive comedication due to severe adverse events of ICI did not impair the serological response to COVID-19 vaccination.

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.

GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi's sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.