Zusammenfassung Hintergrund und Zielsetzung Während Brentuximab vedotin (BV) oder Strahlentherapie (RTx) gängige Behandlungsoptionen für CD30‐positive kutane T‐Zell‐Lymphome (CTCL) sind, wurde über die Wirksamkeit und Verträglichkeit ihrer gleichzeitigen oder aufeinanderfolgenden Anwendung nur selten berichtet. In dieser retrospektiven Analyse haben wir daher die Kombination von BV und RTx bei CD30‐positiven CTCL‐Patienten untersucht. Patienten und Methodik Wir schlossen 14 CD30‐positive CTCL‐Patienten aus sechs deutschen Tumorzentren ein, die mit BV behandelt wurden; eine RTx wurde innerhalb eines Zeitraums von 3 Monaten vor und bis zu 3 Monaten nach der BV‐Behandlung durchgeführt. Die RTx wurde hauptsächlich als niedrig dosiertes Schema angewendet. Ergebnisse Unerwünschte Ereignisse jeden Schweregrades traten bei 71% der Patienten auf, darunter häufige Nebenwirkungen wie periphere Neuropathie, Neutropenie und Radiodermatitis. Dreizehn Patienten erreichten eine vollständige oder partielle Remission als bestes Gesamtansprechen, jedoch zeigten 50% aller Patienten ein Fortschreiten der Erkrankung. Bei einer medianen Nachbeobachtungszeit von 14,4 Monaten betrug das mediane progressionsfreie Überleben 12,0 Monate, mit einer 1‐Jahres‐Rate von 34,0%. Schlussfolgerungen Die simultane oder sequenzielle Therapie mit BV und RTx war machbar und wurde gut vertragen. Künftige randomisierte Untersuchungen sind erforderlich, um die Vorteile dieses kombinierten Behandlungskonzeptes sowie die angemessene Dosierung von BV und RTx prospektiv zu ermitteln.

Purpose:Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with significant unmet therapeutic needs. However, information on patient preferences for HS therapies is hitherto scarce. Our aim was to investigate the impact of treatment experience on patient preferences for pharmacological and surgical treatment of HS using conjoint analysis. Patients and Methods:Discrete choice experiments were applied for the attributes treatment modality (tablets, subcutaneous injections, surgery with secondary intention healing or primary closure), probability of sustained therapeutic success, probability of mild or severe adverse events, and duration of treatment or wound healing. These attributes were subsequently correlated with treatment experience. Results:Overall, 216 patients with HS considered therapeutic success as most important (Relative Importance Score (RIS):36.2), followed by the treatment modality (RIS:24.0). Patients experienced with biologics favoured subcutaneous injections most (PWU:18.1 vs. -0.5, p=0.020), whereas biologic-naïve patients preferred tablets. Patients who had undergone surgery with secondary intention healing valued this approach (PWU:4.1 vs. -24.8, p=0.004) and therapeutic success (RIS:37.5 vs. 31.6, p=0.017) higher and the duration of wound healing lower (RIS:18.9 vs. 23.3, p=0.037) than others. Conclusion:Individual preferences were depending significantly on treatment experience. Incorporation of this aspect could help to improve personalized care of patients with HS.

Perioperative immune-checkpoint inhibition (ICI) using pembrolizumab (3 doses of pembrolizumab 200 mg every 3 weeks before surgery and 15 doses afterwards) in advanced resectable melanoma has shown substantial pathological response rates and improved event-free survival (EFS) compared to postoperative (adjuvant) ICI. Real-world evidence on efficacy and safety of perioperative ICI in melanoma remains limited. In this retrospective single-centre study, 20 patients with resectable stage IIIB–IV melanoma were treated with perioperative pembrolizumab. Radiological and pathological responses, early survival outcomes and treatment-related adverse events were analysed at a median follow-up of 13.9 months. Eighteen patients (18/20) underwent surgery. A pathological complete response was observed in 44% (8/18), while 56% (10/18) showed a pathological non-response. No patient (0/18) had a pathological partial response. One-year EFS was 66.5% (95% confidence interval (CI) 47.3–93.3), 1-year relapse-free survival 77.6% (95% CI 57.9–100) and 1-year overall survival 89.2% (95% CI 76.0–100, identical with 1-year melanoma-specific survival). Immune-related adverse events occurred in 50% of the patients (≥grade 3 in 15%). Our study confirms the feasibility of perioperative pembrolizumab in a real-world setting and shows promising efficacy and tolerability in melanoma. Pathological response may guide surgical and adjuvant strategies.

Kutane periphere T‐Zell‐Lymphome (PTCL) sind selten und zeigen einen aggressiven Verlauf mit limitiertem Therapieansprechen. Die Wirksamkeit von Brentuximab‐Vedotin bei kutanen PTCL wurde bisher nicht systematisch untersucht. In dieser retrospektiven Datenanalyse evaluierten wir die Therapie mit Brentuximab‐Vedotin als Mono‐ oder Kombinationstherapie bei kutanen CD30‐positiven PTCL (n = 9). Insgesamt zeigten sich gutes Ansprechen und akzeptable Verträglichkeit der Therapie. Ein Patient erzielte eine nahezu komplette Remission, bei fünf Patienten wurde eine partielle Remission und bei zwei Patienten ein gemischtes Ansprechen als bestes Ansprechen ( best overall response , BOR) beobachtet. Im Median vergingen 31,5 Tage (Interquartilabstand 12–53) bis zum Therapieansprechen. Die mediane Ansprechdauer war mit 4,3 Monaten kurz; das mediane Gesamtüberleben seit Einleitung der Brentuximab‐Vedotin‐Therapie betrug 15,2 Monate. Vier von neun Patienten verstarben an ihrer fortgeschrittenen Lymphomerkrankung, ein Patient verstarb aus anderer Ursache. Brentuximab‐Vedotin als Mono‐ oder Kombinationstherapie ist bei Patienten mit kutanem peripheren T‐Zell‐Lymphom eine rasch wirksame und verträgliche Therapieoption bei allerdings nur kurzer Ansprechdauer.

BACKGROUND:Cutaneous peripheral T cell lymphomas (PTCL) are rare and show an aggressive course with limited response to therapy. The efficacy of brentuximab vedotin in cutaneous peripheral T cell lymphomas has not yet been systematically investigated. PATIENTS AND METHODS:In this retrospective analysis, we evaluated brentuximab vedotin as monotherapy or in combination therapy in patients with cutaneous CD30-positive peripheral T cell lymphoma (n  =  9). RESULTS:Overall, the therapy showed good efficacy and acceptable tolerability. One patient achieved an almost complete response, five had a partial response, and two had a mixed response as best overall response. The median time to response was 31.5 days (interquartile range 12-53). The median duration of response was short at 4.3 months. Median overall survival from initiation of brentuximab vedotin was 15.2 months; four of nine patients died from advanced lymphoma and one patient died from an unrelated cause. CONCLUSION:Brentuximab vedotin as monotherapy or combination therapy is a rapidly effective and tolerable treatment option for patients with cutaneous PTCL, although the duration of response is short.

BACKGROUND AND OBJECTIVES:While brentuximab vedotin (BV) and radiotherapy (RTx) are established treatment options for CD30-positive cutaneous T-cell lymphoma (CTCL), data on their simultaneous or sequential use regarding efficacy and tolerability remain scarce. In this retrospective analysis, we evaluated the combination of BV and RTx in patients with CD30-positive CTCL. PATIENTS AND METHODS:We included 14 CD30-positive CTCL patients from six German cancer centers receiving BV; RTx was initiated within a timeframe of 3 months prior/after BV treatment. RTx was mainly applied as a low-dose scheme. RESULTS:Adverse events of any grade occurred in 71% of patients, most commonly peripheral neuropathy, neutropenia, and radiodermatitis. Thirteen patients achieved a complete or partial remission as best overall response, however, 50% of all patients showed disease progression. At a median follow-up of 14.4 months, median progression-free survival was 12.0 months, with a 1-year rate of 34.0%. CONCLUSIONS:The simultaneous or sequential use of RTx during BV treatment was feasible and well tolerated. Future randomized investigations are needed to identify the benefits of this combination treatment regimen as well as adequate dosing of BV and RTx in a prospective manner.

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BackgroundMerkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy. Immune checkpoint inhibition (ICI) with PD-(L)1 blockade has significantly improved treatment outcomes in metastatic disease. In patients with primary resistance to PD-(L)1 inhibition, a high overall response rate (ORR) of 50% to later-line ipilimumab plus nivolumab (IPI/NIVO) has been demonstrated. However, clinical data on patients with progression after an initial response to IPI/NIVO are still lacking.MethodsClinical data of three metastatic MCC patients who were re-exposed to IPI/NIVO after progression were retrospectively evaluated.ResultsTwo of the three patients showed primary resistance to avelumab with progressive disease, while one patient showed complete response (according to RECIST V.1.1). All three patients received combined ICI with IPI/NIVO as subsequent therapy, resulting in an ORR of ∼ 67%. However, all three patients progressed during follow-up and were re-exposed to IPI/NIVO. With a follow-up period ranging from 6.5 to 37.1 months, no PFS event has been detected. ORR for IPI/NIVO re-exposition was equal to that of initial IPI/NIVO treatment.ConclusionIn this retrospective follow-up analysis, we observed a response rate of 67% and long-lasting responses after re-exposition to combined ICI in metastatic MCC patients with progression after initial response or disease control upon their first IPI/NIVO treatment. An important observation from this small analysis is that primary resistance to PD-L1 inhibition may result in a better response to IPI/NIVO.

With the emergence of immune checkpoint inhibitors and targeted therapies, significant progress has been made in the systemic treatment of melanoma. These advancements are now extended to the neoadjuvant setting to manage locally advanced disease. Particularly the use of PD-1 blockade alone or in combination with CTLA-4 blockade has shown promising results in terms of reducing the risk of relapse and mortality. Initial data also show that neoadjuvant immunotherapy allows de-escalation of lymph node surgery. Similarly, neoadjuvant BRAF-MEK inhibition for melanoma with BRAF mutations has produced comparable outcomes, although the response durability is lower compared to immunotherapy. Moreover, the S1801 randomized trial has provided the first evidence of the advantages of the neoadjuvant approach over the conventional approach of surgery followed by adjuvant therapy.

Durch die Entwicklung von Immuncheckpointinhibitoren und zielgerichteten Therapien wurden bei der systemischen Behandlung des Melanoms erhebliche Fortschritte erzielt. Diese Fortschritte werden nun auf die neoadjuvante Behandlung der lokal fortgeschrittenen Erkrankung übertragen. Insbesondere der Einsatz der PD-1-Blockade allein oder in Kombination mit der CTLA-4-Blockade ist vielversprechend bezüglich der Verringerung des Rezidivrisikos und der Sterblichkeit. Erste Daten zeigen, dass eine neoadjuvante Immuntherapie eine Deeskalation der Lymphknotenoperation ermöglichen könnte. In ähnlicher Weise hat die neoadjuvante BRAF-MEK-Hemmung bei Melanomen mit BRAF-Mutationen zu vergleichbaren Ergebnissen geführt, auch wenn die Ansprechdauer im Vergleich zur Immuntherapie geringer ist. Darüber hinaus hat die randomisierte Studie S1801 den ersten Beweis für die Vorteile des neoadjuvanten Ansatzes gegenüber dem konventionellen Ansatz einer Operation mit anschließender adjuvanter Therapie geliefert.

Background: Neoadjuvant immune-checkpoint inhibition (neoICI) with ipilimumab and nivolumab has shown high pathologic response rates as well as a long-lasting relapse-free survival in stage III melanoma patients. However, safety and efficacy data from real-world patients is very limited. Methods: Stage IIIB-IV (M1a) melanoma patients with macroscopic nodal metastases with or without synchronous non-nodal lesions received combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg. Radiological and pathological response as well as relapse-free survival (RFS), event-free survival (EFS), overall survival (OS), melanoma-specific survival (MSS), adverse events (AE) related to neoICI and subsequent therapies were analysed. Results: Between November 2018 and October 2021, 23 patients received a combined neoICI. A pathologic response was achieved in 65% (15/23) of the patients, with 43% (10/23) achieving a pathological complete response. At a median follow-up of 22.8 months, median RFS, EFS, OS and MSS have not been reached. At a 3year landmark, the RFS, EFS, OS and MSS rates were 77.6% (95% CI 60.1-100), 61.8% (95% CI 43.8-87.1), 62.0% (95% CI 42.2-91.0) and 76.7% (95% CI 55.7-100), respectively. Regarding AE, 70% (16/23) had immune-related AE (irAEs) of any grade which were classified as severe (>= grade 3) irAEs in 13% (3/23) of patients. Conclusion: The combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg showed high response rates as well as long lasting relapse-free survival. Besides a promising efficacy, neoICI was well tolerated in our real-world patient cohort with only few high-grade irAEs indicating feasibility of neoICI in a non-trial setting.

Background and Objectives: Treatment options for moderate-to-severe hidradenitis suppurativa (HS) comprise antibiotics, biologics, and different surgical methods. These approaches differ substantially regarding the treatment process, success rates, and adverse events. However, information on patient preferences for HS therapies is hitherto scarce. Our aim was to assess patient preferences for medicamentous and surgical treatment of HS with conjoint analysis. Patients and Methods: In this cross-section study, computerized discrete choice experiments were used to quantify patient preferences for HS therapies decomposed into treatment modality (tablets, subcutaneous injections, surgery with secondary-intention healing or primary closure), probability of sustained therapeutic success, probability of mild or severe adverse events, and duration of treatment or wound healing. Results: Averaged over the cohort (n = 216 patients with HS), sustained therapeutic success was considered as most important (Relative Importance Score [RIS]: 36.2), followed by the treatment modality (RIS: 24.0), and duration of treatment/wound healing (RIS: 19.9), whereas mild or severe adverse events (RIS: 10.7 or 9.3) were regarded as less relevant. Patients preferred tablets, followed by subcutaneous injections, and disliked surgery with primary closure. Preferences differed significantly dependent on age and affected body regions. Conclusions: Awareness of patient preferences is essential for patient-centered care in HS.

Abstract Linked Article: Bai et al. Br J Dermatol 2022; 187:401–410.

Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking. Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed. All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events. In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.

ObjectivesForty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes.MethodsPatients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG.ResultsWe identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response.ConclusionsBRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.

Zusammenfassung Hintergrund und Zielsetzungen Die Behandlungsoptionen für mittelschwere bis schwere Hidradenitis suppurativa (HS) umfassen Antibiotika, Biologika und verschiedene chirurgische Verfahren. Diese Ansätze unterscheiden sich stark bezüglich des Behandlungsprozesses, der Erfolgsraten und der unerwünschten Ereignisse. Informationen zu den Präferenzen der Patienten in Bezug auf HS‐Therapien gibt es aktuell nur wenige. Unser Ziel war es, Patientenpräferenzen für die medikamentöse und chirurgische Behandlung der HS durch Conjoint‐Analyse zu untersuchen. Patienten und Methoden In dieser Querschnittsstudie wurden durch computergestützte „Discrete‐Choice“ Experimente die Präferenzen der Patienten für HS‐Therapien quantifiziert, und zwar aufgeschlüsselt nach Behandlungsmodalität (Tabletten, subkutane Injektionen, chirurgische Eingriffe mit sekundärer Heilungsabsicht oder primärer Verschluss), Wahrscheinlichkeit eines anhaltenden Therapieerfolgs, Wahrscheinlichkeit leichter oder schwerer unerwünschter Ereignisse und Dauer der Behandlung oder Wundheilung. Ergebnisse Gemittelt über die Kohorte (n = 216 Patienten mit HS) wurde der anhaltende Therapieerfolg als am wichtigsten angesehen ( Relative Importance Score [RIS]: 36,2), gefolgt von der Behandlungsmodalität (RIS: 24,0) und der Dauer der Behandlung/Wundheilung (RIS: 19,9), während leichte oder schwere unerwünschte Ereignisse (RIS: 10,7 beziehungsweise 9,3) als weniger wichtig angesehen wurden. Die Patienten bevorzugten Tabletten gegenüber subkutanen Injektionen und lehnten eine Operation mit primärem Verschluss ab. Die Präferenzen unterschieden sich deutlich je nach Alter und den betroffenen Körperregionen. Schlussfolgerung Die Kenntnis der Patientenpräferenzen ist für eine patientenzentrierte Versorgung bei HS von wesentlicher Bedeutung.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

629 of 48 mm, invading the muscles of the buccal floor, the left vallecula and the epiglottis, as well as exuberant cervical, supraclavicular, and axillary lymph node metastasis (figure 1E, F). These findings are consistent with extensive cutaneous and lymph node metastasis of a squamous cell carcinoma (SCC) of the tongue. Due to the advanced age and poor general condition of the patient, associated with the ominous prognosis related to the extent of the disease, we decided on palliative care. Unfortunately, there was a rapid progression of the disease, with an exuberant extension of the cutaneous metastasis within one month (figure 1B), and the patient died after three months. Distant metastasis from squamous cell carcinoma of the head and neck (SCCHN) is uncommon and occurs most often in the lung, liver and bone [1]. Skin metastasis is even more rarely reported, with an incidence of less than 1%, occurring mostly in the neck and chest, and in most instances has been encountered during or after treatment of the primary neoplasm (which was not the case of our patient). Moreover, of the cases with head and neck cancer, laryngeal cancer is most commonly associated with cutaneous metastasis [2], and to the best of our knowledge, the first case of SCC of the base of the tongue with local and distant -including skinmetastasis occurring as initial presentation was reported in 2013 [3]. Furthermore, cutaneous metastasis is associated with poor prognosis and advanced disease [1, 3-6]. The presence of dermal metastasis in a patient with a SCCHN is such a harbinger of poor prognosis that the median survival from onset of cutaneous metastasis is only three months, with a 0% one-year survival rate [4]. Because of this, patients with skin metastases are often placed on palliative care measures; radiation therapy, chemotherapy, as well as surgical excision of the secondary skin lesions when possible, or a combination of these. However, surgical excision (of cutaneous metastasis) is the only therapy that has shown improved survival and quality of life [4, 5].

Approximately 50% of all melanomas harbor an activating BRAF mutation. In patients suffering from an advanced melanoma with such a somatic alteration, combined targeted therapy with a BRAF and MEK inhibitor can be applied to significantly increase the survival probability. Nevertheless, resistance mechanisms, as well as negative predictive biomarkers (elevated lactate dehydrogenase levels, high number of metastatic organ disease sites, brain metastasis), remain a major problem in treating melanoma patients. Recently, a landmark overall survival (OS) rate of 34% after 5 years of combined targeted therapy in treatment-naïve patients was reported. On the other hand, patients harboring a BRAF mutation and receiving first-line immune checkpoint blockade with ipilimumab plus nivolumab showed a 5-year OS rate of 60%. As indicated by these data, long-term survival can be reached in melanoma patients but it remains unclear if this is equivalent to reaching a true cure for metastatic melanoma. In this review, we summarize the recent results for combined targeted therapy and immunotherapy in advanced melanoma harboring an activating BRAF mutation and discuss the impact of baseline characteristics on long-term outcome.