Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Erythema nodosum-like lesions during BRAF inhibitor therapy: Report on 16 new cases and review of the literature.

IMPORTANCE: BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. OBJECTIVE: To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. DESIGN AND SETTING: Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. RESULTS: Sixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed. CONCLUSION: Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms.

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.

BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.

[Cutaneous side effects of anti-tumor therapy with BRAF and MEK inhibitors]. / Kutane Nebenwirkungen der medikamentösen Tumortherapie mit BRAF- und MEK-Inhibitoren.

BACKGROUND: BRAF and MEK inhibitors are new targeted therapies which are used in the treatment of malignancies, in particular of malignant melanoma. SIDE EFFECTS: Cutaneous side effects are common during the treatment with both types of inhibitors. These side effects include inflammatory reactions such as maculopapular and papulopustular exanthema, hand-foot syndrome, panniculitis, paronychia, photo- and radio-sensitization. As a class effect, BRAF-inhibitors induce proliferative disorders of keratinocytes and melanocytes, such as palmoplantar hyperkeratosis (as part of the hand-foot syndrome), verruciform and acanthoma-like lesions, follicular and Grover disease-like hyperkeratoses, keratoacanthomas, squamous cell carcinomas and atypical melanocytic nevi with transition to secondary melanomas. Furthermore, hair alterations and xerosis are possible. CONCLUSIONS: Treatment with BRAF and MEK inhibitors requires close dermatologic monitoring of the patient. This manuscript summarizes the most frequent cutaneous side effects and their management.

[Alopecia due to chemotherapeutics, hedgehog inhibitors, targeted antibody therapies and immune checkpoint inhibitors : Pathogenesis, clinical picture, diagnostics and prophylaxis]. / Alopezie durch Chemotherapeutika, Hedgehog-Inhibitoren, zielgerichtete Antikörpertherapien und Immuncheckpointinhibitoren : Pathogenese, Klinik, Diagnostik und Prophylaxe.

BACKGROUND: The incidence and severity of alopecia vary mainly depending on the chemotherapeutic agent used or other drug groups. The pathogenetic characteristics of the different forms of alopecia are reflected in the clinical presentation and, in some cases, in the resulting recommendations for prophylaxis. OBJECTIVES: To provide an overview of the pathogenesis, clinical presentation, diagnosis and prophylaxis of alopecia with chemotherapeutic agents, hedgehog inhibitors, targeted therapies and immune checkpoint inhibitors. MATERIALS AND METHODS: Based on the current S3 guideline "Supportive therapy", an extensive literature search was carried out. RESULTS AND CONCLUSION: Chemotherapy-induced hair loss (CIA) occurs in up to 65% of cases. Anagen effluvium is observed as early as 1-3 weeks after the start of treatment and is reversible in most cases. Alopecia associated with inhibitors of the Sonic Hedgehog signaling pathway (HHIA) such as vismodegib or sonidegib are observed in up to 60% of cases. They are characterized by telogen effluvium. BRAF or immune checkpoint inhibitors lead significantly less frequently to alopecia (BRAFA, CPIA). According to taxane-based chemotherapy protocols, scalp cooling can help to prevent higher-grade CIA. If CIA or other forms of alopecia are expected, early contact with self-help organizations and early prescriptions for wigs should be offered.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

[Adjuvant systemic treatment of melanoma]. / Adjuvante systemische Therapie des Melanoms.

Despite intensive clinical and research efforts during the last decades the prognosis for patients with stage IV melanoma still remains fatal. An efficient adjuvant treatment for patients with a high risk of relapse and metastases is one of the most urgent fields in clinical research. Systemic adjuvant chemotherapy was not beneficial in terms of relapse-free or overall survival improvement in several clinical trials. Treatment with IFN-α-2a and -2b treatment was the first and as yet only adjuvant therapy which has been proven to show a benefit in controlled studies and to gain approval in Germany in the indications for adjuvant therapy. Current clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon and on the other hand on testing new compounds, such as the CTLA4 inhibitor ipilimumab or a vaccination against the MAGE-A3 peptide.

[Current aspects of adjuvant therapy of malignant melanoma]. / Aktuelle Aspekte der adjuvanten Therapie des malignen Melanoms.

Despite intensive clinical and research efforts during recent decades, the prognosis of patients with stage IV melanoma still remains poor. Finding effective adjuvant treatment for patients with a high risk of relapse and metastasis is one of the most urgent needs in clinical research. Systemic adjuvant chemotherapy administered in several clinical trials offered no benefit in terms of improved relapse-free or overall survival. Interferon alpha-2a and -2b treatment was the first treatment in the adjuvant setting which has shown a treatment benefit and received approval in Germany. Today clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon as well as on new compounds such as CTLA4 inhibitors like ipilimumab or a vaccination against the MAGE-A3 peptide.

[Skin changes as a result of targeted therapies in oncology patients: cutaneous side effects of targeted therapies in oncology patients]. / Hautveränderungen durch "targeted therapies" bei onkologischen Patienten: Kutane Nebenwirkungen zielgerichteter Therapie bei onkologischen Patienten.

The growing number of patients treated with modern targeted therapies that cause specific cutaneous side effects is drawing attention to the optimal management of these side effects. Experience to date has shown that good management allows the majority of patients to receive the treatment as planned. As a result of the link between dermatological side effects and the success of treatment than can be assumed to exist for many substances, interdisciplinary collaboration between dermatologists and professionals from other disciplines working in the field of oncology is becoming increasingly important.

Hepatic arterial Fotemustine chemotherapy in patients with liver metastases from cutaneous melanoma is as effective as in ocular melanoma.

AIM: Hepatic metastases from melanoma are associated with poor prognosis. Systemic chemotherapy and biological treatments remain unsatisfactory. This study investigated the impact of hepatic arterial chemotherapy in patients with ocular and cutaneous melanoma. METHODS: In a retrospectively analysed observational study, 36 consecutive patients with hepatic metastases from ocular or cutaneous melanoma were assigned for surgical hepatic port-catheter implantation. Fotemustine was delivered weekly for a 4-week period, followed by a 5-week rest and a maintenance period every 3 weeks until progression. Overall survival, response and toxicity were analysed and compared. RESULTS: After port-catheter implantation 30/36 patients were finally treated (18 with ocular and 12 with cutaneous melanoma). A median of 8 infusions per patient were delivered (range 3-24). 30% thrombocytopenia grade >or=3, 7% neutropenia grade >or=3 but no nausea or vomiting grade >or=3 were encountered. Nine out of 30 patients achieved partial remission, 10/30 stable disease; 11/30 patients were progressive. Median survival for all treated patients was 14 months. Partial remission and stable disease were associated with a survival advantage compared to progressive disease (19 vs. 5 months). No significant difference in survival was observed for ocular versus cutaneous melanoma. Serum LDH was a significant predictor of both response and survival. CONCLUSIONS: Hepatic arterial Fotemustine chemotherapy was well tolerated. Meaningful response and survival rates were achieved in ocular as well as cutaneous melanoma. Careful patient selection in consideration of extra-hepatic involvement is crucial for the effectiveness of this treatment. Independent from the primary melanoma site, it is debatable if patients with highly elevated serum-LDH may benefit from this approach.

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab.

INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab. MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings. RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.

Prospective evaluation of follow-up in melanoma patients in Germany - results of a multicentre and longitudinal study.

BACKGROUND: Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially. METHODS: In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis. RESULTS: Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3-4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4year surveillance of 550 patients without tumour recurrence (stage I-IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3-4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these. CONCLUSIONS: We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

[Modern treatment modalities in actinic keratoses of the skin]. / Moderne Behandlungsoptionen bei aktinischen Keratosen der Haut.

It has been estimated that approximately 4 million Germans are suffering from actinic keratoses, which are considered as a carcinoma in situ today. Typically, actinic keratoses appear in sun-exposed skin areas, conventionally they have been treated by curettage and cryotherapy. In the last years, new therapeutic modalities with a high efficacy and patient contentment are available. Among these, the photodynamic therapy (PDT), the anti-tumor treatment with 3 % Diclofenac in 2.5 % hyaluronic acid as well as the introduction of Imiquimod as an immune response modifier are the most important. The rate of complete clearance from actinic keratoses varies between 50 and 90 % in clinical trials. In contrast to the conventional treatment modalities, these new options promise advantages in the treatment of field and offer excellent cosmetic outcomes, too. This overview will report on the actual treatment opportunities and a careful consideration in the year 2006.