Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

PURPOSE: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. METHODS: In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. RESULTS: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). CONCLUSION: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

BACKGROUND: Immune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients. METHODS: We analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded. RESULTS: Overall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR. CONCLUSION: Our results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.

Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Extended surgical safety margins and ulceration are associated with an improved prognosis in pleomorphic dermal sarcomas.

BACKGROUND: Pleomorphic dermal sarcomas (PDS) are frequent UV-induced sarcomas of the skin of intermediate grade malignant potential. Despite the fact that PDS have a noteworthy potential to recur (up to 28%) as well as to metastasize (up to 20%), there are no specific clinical guidelines with respect to follow-up these patients. Moreover, little is known about clinical, histological or molecular prognostic factors in PDS. OBJECTIVE: The aim of the present study was to identify risk factors to predict relapse in a large multicentre sample cohort of PDS which could aid to optimize personalized treatment recommendations regarding surgical safety margins and adjuvant radiotherapy. METHODS: Patients with a diagnosis of PDS were selected from nine European institutions based on the histopathologic criteria described by Fletcher. Clinicopathologic and follow-up data were collected and statistically analysed calculating univariate hazard ratios with 95% confidence intervals by use of the Cox proportional-hazards model and a significance level of P < 0.05. Patients with an incomplete excision of the tumour were excluded. RESULTS: Univariate Cox regression analysis of possible prognostic factors for progression-free survival (PFS) performed in 92 patients revealed that an excision margin of <2 cm is significantly associated with relapse of PDS [hazard ratio 4.478 (95% CI 1.536-13.055), P = 0.006]. Ulceration of the tumour was associated with a significantly better prognosis [0.396 (0.174-0.904), P = 0.028] whereas adjuvant radiotherapy did not reach statistical significance to improve prognosis in patients with PDS [0.775 (0.231-2.593), P = 0.679]. Gender, age, immunosuppression, intratumoural necrosis, tumour location, vertical thickness or horizontal diameter did not significantly influence PFS in PDS. CONCLUSION: We identified surgical safety margins of <2 cm and absence of ulceration as risk factors for relapse in patients with PDS. These findings may be implemented into both the primary treatment as well as the further monitoring of patients with PDS.

[Liver injury induced by immune checkpoint inhibitor-therapy : Example of an immune-mediated drug side effect]. / Leberschaden durch Therapie mit Immun-Checkpoint-Inhibitoren : Beispiel einer immunvermittelten Medikamentennebenwirkung.

BACKGROUND: Drug-induced liver injury is increasing, especially in elderly patients with polymedication and multimorbidity. OBJECTIVES: Clinicopathologic correlation of immune-mediated liver injury, specifically liver injury following therapy with immune checkpoint inhibitors against PD-1, PDL-1, and CTLA4. METHODS: Histologic assessment of liver biopsies of nine patients after therapy with immune checkpoint inhibitors and correlation with clinical parameters. RESULTS: In all nine patients, liver injury was apparent after variable administration of immune checkpoint inhibitors. Transaminase levels were increased up to a maximum of 3818 U/l. Liver histology showed liver injury resembling autoimmune hepatitis respective cholangitis. In two patients, veno-occlusive disease was seen. Corticosteroid therapy was initiated in eight patients, subsequently four patients showed decreasing transaminases and five patients died of tumor progress. In three patients, it remains unclear whether liver injury by immune checkpoint inhibitors may have ultimately contributed to the fatal course, especially in one patient with liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Therapy with immune checkpoint inhibitors may lead to potentially fatal immune phenomena in susceptible patients, which may affect liver and/or other organs independently. Other causes of hepatopathy need to be ruled out clinically and/or histologically.

Long-term survival with modern therapeutic agents against metastatic melanoma-vemurafenib and ipilimumab in a daily life setting.

Despite new therapeutic options, metastatic melanoma remains to be one of the most fatal tumors. With the development of BRAF inhibitors and immune checkpoint inhibitors, overall survival could be prolonged significantly for the first time. Clinical studies implied that even long-term survival is possible with both types of drugs, but predictive markers are so far missing. In this study, we analyzed survival data from patients that received the first-in-class substances vemurafenib and ipilimumab, respectively, during the time period from registration of the drugs until availability of combination treatments. We aimed to evaluate the possibility of long-term survival in a daily life setting and to characterize patients that benefit from these drugs in order to gain insight into predictive attributes. Eighty patients were evaluated who were treated with either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was analyzed. Subgroup analysis was performed for patients who were still alive 24 months after induction of therapy (long-term survival). Median overall survival (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative predictors of long-term survival in the vemurafenib group were brain and liver metastases, as well as elevated LDH, S100ß and liver enzymes. For ipilimumab, an increase in lymphocytes and eosinophils during course of treatment correlated with long-term survival. Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach. Combination of drugs and observational studies in larger patient cohorts are necessary to further validate our findings.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PURPOSE: The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. PATIENTS AND METHODS: Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. RESULTS: 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. CONCLUSIONS: The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. TRIAL REGISTRATION NUMBER: NCT01149343, Results.

A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma.

BACKGROUND: The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial. PATIENTS AND METHODS: Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS). RESULTS: A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm. CONCLUSIONS: nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.

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.

Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients.

BACKGROUND: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. METHODS: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. RESULTS: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. CONCLUSION: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

[Treatment side effects and follow-up of malignant melanoma]. / Therapienebenwirkungen und Nachsorge bei malignem Melanom.

Side effects in the therapy of malignant melanoma are primarily of importance for radiologists in advanced tumor stages. The available treatment options and their respective side effect profiles have undergone a profound change in recent years after the introduction of modern oncological therapies (e.g. immunotherapy and targeted therapy) with an increasing focus on individual tumor biology and differ significantly from those of classical chemotherapy. The immunotherapeutic agents, in particular ipilimumab, take on a special position because of their specific immune-mediated mechanisms of action and the associated side effects, so-called immune-related adverse events (irAE). The majority of the treatment effects are manifested on the skin (> 50 %) and are generally not detectable by diagnostic radiology. Only a comparatively small proportion of treatment side effects is detectable with diagnostic imaging (15-20 %) but as in the example of therapy-induced colitis with ipilimumab, may be rapidly fatal. In addition to colitis (10-20 %) further therapy side effects apparent in diagnostic imaging are hypophysitis (1.8-17 %), thyroiditis (0.8 %), myositis (1.7 %), fasciitis and sarcoid-like lymph node alterations (6.8 %). To detect radiologically detectable side effects early on and to delineate them especially from tumor progression and (opportunistic) infections, detailed knowledge of the therapeutic methods for melanoma, the mechanisms of action and in particular the sometimes very specific side effects is imperative for radiologists.

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.

BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

[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.

Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety.

BACKGROUND: Even though progress has been made, the detection of melanoma still poses a challenge. In light of this situation, the Nevisense electrical impedance spectroscopy (EIS) system (SciBase AB, Stockholm, Sweden) was designed and shown to have the potential to be used as an adjunct diagnostic tool for melanoma detection. OBJECTIVES: To assess the effectiveness and safety of the Nevisense system in the distinction of benign lesions of the skin from melanoma with electrical impedance spectroscopy. METHODS: This multicentre, prospective, and blinded clinical study was conducted at five American and 17 European investigational sites. All eligible skin lesions in the study were examined with the EIS-based Nevisense system, photographed, removed by excisional biopsy and subjected to histopathological evaluation. A postprocedure clinical follow-up was conducted at 7 ± 3 days from the initial measurement. A total of 1951 patients with 2416 lesions were enrolled into the study; 1943 lesions were eligible and evaluable for the primary efficacy end point, including 265 melanomas - 112 in situ and 153 invasive melanomas with a median Breslow thickness of 0·57 mm [48 basal cell carcinomas (BCCs) and seven squamous cell carcinomas (SCCs)]. RESULTS: The observed sensitivity of Nevisense was 96·6% (256 of 265 melanomas) with an exact one-sided 95% lower confidence bound estimated at 94·2% and an observed specificity of 34·4%, and an exact two-sided 95% confidence bound estimated at 32·0-36·9%. The positive and negative predictive values of Nevisense were 21·1% and 98·2%, respectively. The observed sensitivity for nonmelanoma skin cancer was 100% (55 of 48 BCCs and seven SCCs) with an exact two-sided 95% confidence bound estimated at 93·5-100·0%. CONCLUSIONS: Nevisense is an accurate and safe device to support clinicians in the detection of cutaneous melanoma.

Characterizing psychosocial distress in melanoma patients using the expert rating instrument PO-Bado SF.

BACKGROUND: Although psychosocial distress has been evaluated well in cancer entities like breast or prostate cancer, its impact on melanoma patients still needs to be characterized. The objectives of this study were to (i) evaluate psychosocial distress in melanoma patients using an expert rating instrument [basic documentation for psycho-oncology short version (PO-Bado SF)]; (ii) determine associated demographic and clinical variables; and (iii) assess the acceptance of using PO-Bado SF as a routine procedure in a skin cancer unit. METHODS: A cross-sectional group of 696 melanoma patients was recruited. During the routine contact, doctors assessed the patients subjective distress using PO-Bado SF. Sociodemographic data, tumour data, treatment and the course of the disease were extracted from the patients' charts. RESULTS: PO-Bado SF was completed in 688 of 696 (99%) participating patients, revealing a high acceptance. In 51 (7%) patients, the PO-Bado SF cut-off score indicated the potential need of psychosocial support. Patients with previous or ongoing radiotherapy, a history of major surgery due to organ metastases, younger age and shorter time since diagnosis were considered significantly more distressed than patients without these criteria. Patients were most distressed by suffering from anxiety/worries and/or tensions. In younger patients emotional variables and other problems like social or family problems were deemed more relevant while functional limitations in daily living were reasons for higher distress in older patients. CONCLUSION: PO-Bado SF is a useful, well-accepted, practical and economic screening tool to identify distressed melanoma patients. Although most melanoma patients seem to cope well with their disease, special attention should be given to young patients in the first years after initial diagnosis and to patients with advanced disease, radiotherapy and major surgery due to their disease. Combination of expert rating tools with self-report screening instruments could further characterize the specific sources of distress to optimize psychosocial support.

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.

[Systemic therapy for malignant melanoma]. / Medikamentöse Therapie des malignen Melanoms.

For decades dacarbazine was the standard in the therapy for metastatic melanoma even though response rates were low. In recent years multiple pharmacological approaches have led to new therapy options including immune modulators like anti-CTLA4 antibodies and kinase inhibitors of the MAPK signaling pathway that showed better response rates and increased overall survival. However, since immune modulators lead only in a small subgroup of patients to long-term responses and kinase inhibitors lose their function due to development of resistance after several months, continuation of clinical studies is strongly required. Classical chemotherapeutic drugs will remain a basic part of the therapy especially as combinations of different treatment options have to be focused on in order to achieve better long-term survival rates.