Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by ...inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients ...with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.
We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.
Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed.
Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.
ClinicalTrials.gov NCT01355120.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17–22 weeks. We assessed dabrafenib in patients with ...Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. Methods We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov , number NCT01266967. Findings Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0–51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9–43·4) of 65 in cohort B. One (6·7%, 0·2–31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4–47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five 6% patients in cohort A, of whom one also had keratoacanthoma; six 7% in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten 6% patients), intracranial haemorrhage (ten 6%; one treatment-related), and squamous-cell carcinoma (11 6%). Interpretation Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. Funding GlaxoSmithKline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options ...for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
Anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, ...combined anti-PD-1 plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis.
Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32–70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12–17.6 months), two patients experienced melanoma relapse.
In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment.
•Potentially higher rate of sarcoidosis-like reactions (SLR) in patients who receive adjuvant immunotherapy than in patients with metastatic disease.•Differentiation between SLR and progression of disease in most cases only possible with biopsy.•No clinical symptoms of the SLR in our patients, no steroid treatment required.•No progression of the SLR after continuation of treatment.•Patients that developed SLR and patients that did not had an equal relapse rate (20%).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or ...secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8
+
T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo.
Case presentations
We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.
Results and conclusion
Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8
+
T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with ...BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%–15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF ...inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules.
In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment.
Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent.
Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.
Melanoma causes the majority of skin cancer-related deaths. Despite novel therapy options, metastatic melanoma still has a poor prognosis. Immune checkpoint inhibition (ICI) therapy has been shown to ...prolong overall survival in patients with advanced melanoma, but mucosal melanomas respond less favorably compared to melanomas of cutaneous origin. We report on a patient with a mucosal melanoma of the rectum diagnosed in June 2020. Since a surgical intervention in order to achieve a tumor-free situation would have required an amputation of the rectum, a neo-adjuvant systemic immunotherapy with ipilimumab and nivolumab was initiated. As restaging and colonoscopy after four doses of this combination immunotherapy showed a partial response, the patient decided against the pre-planned surgery and a maintenance therapy with nivolumab was started. Repeated colonoscopy showed a complete response after four doses of nivolumab. After ongoing ICI therapy with nivolumab and no evidence of tumor relapse, immunotherapy was stopped in July 2022 after nearly 2 years of continuous treatment. The patient remained tumor-free during further follow-up. Neo-adjuvant immunotherapy is getting more explored in advanced melanoma. By administering ICI therapy before surgical resection of an essentially operable tumor, a stronger and more diverse immunological response is supposed to be achieved. Our reported case demonstrates that this approach could also be effective in mucosal melanoma despite of its generally lower response to immunotherapy.
Activating mutations in the TERT promoter leading to increased telomerase expression were recently identified in cutaneous melanoma and subsequently in many other types of cancer. These mutations ...lead to increased telomerase expression, allowing cells to proliferate continuously without entering apoptosis or senescence. Atypical fibroxanthomas and pleomorphic dermal sarcomas are genetically poorly understood tumors developing in the skin of older patients. Known genetic events in these tumors are mutations in TP53 (atypical fibroxanthoma and pleomorphic dermal sarcoma) and RAS (pleomorphic dermal sarcoma) genes, often having a UV signature. We analyzed a cohort of 27 atypical fibroxanthomas and 34 pleomorphic dermal sarcomas for the presence of TERT promoter mutations by conventional Sanger sequencing. TERT promoter mutations were identified in 25 (93%) atypical fibroxanthomas and in 26 (76%) pleomorphic dermal sarcomas. Mutations were found to have a UV signature (C>T or CC>TT) and were largely identical to those detected in cutaneous melanoma. Our data show that TERT promoter mutations are the most frequent mutations in atypical fibroxanthomas and pleomorphic dermal sarcomas reported to date. The identified mutations confirm the pathogenetic role of UV exposure in both atypical fibroxanthomas and pleomorphic dermal sarcomas and suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis of these tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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