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Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial ( n  = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM. Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016–002114-50. The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.

Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected. The most frequent ones are BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. In many cases, mutations in these genes appear in a mutually exclusive manner, have different risk of metastasis, and are consequently of prognostic importance. The majority of UM cases are sporadic but a few percentage of the cases occurs in families with an inherited predisposition for this malignancy. In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families. This cancer syndrome has been denoted as the tumor predisposition syndrome.

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV 600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAF V600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy. SECOMBIT was a clinical trial testing different sequences of immunotherapy (ipilimumab plus nivolumab) and targeted therapy (encorafenib plus binimetinib) for untreated BRAF-mutated metastatic melanoma. Here the authors report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy, and preliminary biomarkers evaluation.

The mammary gland undergoes significant proliferative stages after birth, but little is known about how the developmental changes impact DNA double-strand break (DSB) repair. Mutations in multiple genes involved in homology-directed repair (HDR), considered a particularly accurate pathway for repairing DSBs, are linked to breast cancer susceptibility, including BRCA2 . Using reporter mice that express an inducible endonuclease, we find that HDR is particularly robust in mammary tissue during puberty and pregnancy, accounting for 34–40% of detected repair events, more than in other tissues examined. Brca2 hypomorphic mutation leads to HDR defects in mammary epithelium during puberty and pregnancy, including in different epithelial lineages. Notably, a similar dependence on Brca2 is observed in other proliferative tissues, including small intestine epithelium. Our results suggest that the greater reliance on HDR in the proliferating mammary gland, rather than a specific dependence on BRCA2, may increase its susceptibility to tumorigenesis incurred by BRCA2 mutation. Mutations in homology-directed repair genes like BRCA2 are linked to breast cancer susceptibility. Here the authors generate mice with an inducible DNA break-reporter system and see high levels of homology-directed repair in proliferative mammary tissue and a general reliance on BRCA2 in various tissues.

Homology-directed repair (HDR) is a critical pathway for the repair of DNA double-strand breaks (DSBs) in mammalian cells. Efficient HDR is thought to be crucial for maintenance of genomic integrity during organismal development and tumor suppression. However, most mammalian HDR studies have focused on transformed and immortalized cell lines. We report here the generation of a Direct Repeat (DR)-GFP reporter-based mouse model to study HDR in primary cell types derived from diverse lineages. Embryonic and adult fibroblasts from these mice as well as cells derived from mammary epithelium, ovary, and neonatal brain were observed to undergo HDR at I-SceI endonuclease-induced DSBs at similar frequencies. When the DR-GFP reporter was crossed into mice carrying a hypomorphic mutation in the breast cancer susceptibility gene Brca1 , a significant reduction in HDR was detected, showing that BRCA1 is critical for HDR in somatic cell types. Consistent with an HDR defect, Brca1 mutant mice are highly sensitive to the cross-linking agent mitomycin C. By contrast, loss of the DSB signaling ataxia telangiectasia-mutated (ATM) kinase did not significantly alter HDR levels, indicating that ATM is dispensable for HDR. Notably, chemical inhibition of ATM interfered with HDR. The DR-GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, nontransformed cellular milieu.

Background The study aims to investigate the efficacy of stereotactic body radiation therapy (SBRT) in melanoma patients with oligometastatic disease (OMD), and to assess the prognostic value of the European Society for Radiotherapy and Oncology (ESTRO) and European Organization for Research and Treatment of Cancer (EORTC) nomenclature for these patients. Method This is a single-center, retrospective study including all melanoma patients with OMD ( n  = 66) receiving SBRT between 2010 and 2023. Patients were categorized based on the timing of SBRT of OMD according to the ESTRO/EORTC classification. We analyzed local control, progression-free survival (PFS), overall survival (OS), safety, and prognostic factors. Results The median follow-up was 72.5 months. Patients were categorized at the timepoint of SBRT as having de novo ( n  = 20), repeat ( n  = 25), or induced ( n  = 21) OMD. The most common OMD subcategories were repeat oligorecurrence (33.3%) and metachronous oligorecurrence (16.7%). Concurrent systemic treatment was administered in 30.3% of the patients. Local control rates at 1, 2, and 3 years was 96.3%, 93.2%, and 93,2%, respectively. The median PFS and OS were 7.7 (95% CI 4.9–12.4) and 26.5 (95% CI 17.6–38.8) months, respectively. No significant differences in PFS or OS were observed between patients with de novo, repeat, or induced OMDs. Similarly, survival outcomes did not differ between patients classified into the oligorecurrence, oligoprogression, or oligopersistence cohorts. However, patients who underwent SBRT targeting all metastatic sites demonstrated significantly improved PFS and OS compared to those with additional non-irradiated lesions ( p  = 0.022 and p  = 0.002, respectively). Moreover, patients with a single metastasis had significantly better PFS and OS than those with 2–5 metastases ( p  = 0.045 and p  = 0.021). However, only ECOG performance status remained significant in the multivariable analysis. Additionally, 19 patients (29%) experienced grade 1–2 SBRT-related side effects. Conclusion SBRT was well tolerated and demonstrated excellent local control rates in melanoma with OMD. Our findings indicate that there was no significant difference in PFS or OS between the OMDs, suggesting that the prognostic implication of the ESTRO/EORTC classification in melanoma may warrant further evaluation in prospective studies.

Background While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells. Methods The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0–1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months. Discussion The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM. Trial registration ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016–002114-50.

In several countries, whole-body imaging has been introduced in the routine follow-up of individuals with high-risk cutaneous malignant melanoma after surgery. However, there is scarce evidence that earlier detection of recurrent disease by regular scanning improves survival. In this interim analysis, we investigated whether imaging in the follow-up programme for high-risk cutaneous malignant melanoma improves survival and assessed whether the study should continue to include participants. TRIM is a multicentre, randomised, phase 3 trial in Sweden. Eligible participants are aged 18 years and older with sufficient renal function for intravenously contrast-enhanced CT and are expected to be fit for treatment in case of recurrence. After radical surgery of stage IIB–C and III cutaneous malignant melanoma, participants were randomly assigned (1:1, stratified by tumour stage and method of radiological assessment) to 3 years of follow-up by physical examinations alone (standard group) or to physical examinations plus whole-body imaging with CT or [18F]fluorodeoxyglucose-PET-CT at baseline, 6, 12, 24, and 36 months (experimental group). The goal is to include 1300 participants. The primary endpoint is overall survival at 5 years and will be reported in the final analysis when data are mature. In this interim report, no endpoints were predefined; we present overall survival, relapse-free survival, locoregional relapse-free survival, and distant metastasis-free survival, analysed by intention to intervene. This study is registered with ClinicalTrials.gov, NCT03116412, and recruitment is ongoing. Between June 8, 2017, and July 28, 2023, 983 participants were randomly allocated to the standard (n=498; 296 [59%] male, 202 [41%] female) or experimental (n=485; 309 [64%] male, 176 [36%] female) group. There were no statistically significant differences in overall survival (not reached [NR; 95% CI NR–NR] vs NR [NR–NR]; hazard ratio [HR] 1·04 [95% CI 0·71–1·51], p=0·85) or distant metastasis-free survival (NR [NR–NR] vs NR [NR–NR]; HR 1·20 [0·89–1·64], p=0·24) between the groups at a median follow-up time of 33·6 months (IQR 16·3–49·8). 3-year overall survival rates were 88·2% (95% CI 85·0–91·6) in the standard group versus 87·7% (84·3–91·3) in the experimental group and distant metastasis-free survival was 81·6% (77·9–85·6) in the standard group versus 79·3% (75·3–83·5) in the control group. This interim analysis indicated that there is no benefit from imaging in the follow-up programme for individuals with high-risk cutaneous malignant melanoma. However, only a few participants have completed the follow-up time of 5 years, and the numerical difference between the study groups in distant metastasis-free survival motivates us to continue the study according to protocol. Stiftelsen Onkologiska Klinikens i Uppsala Forskningsfond and Uppsala University Hospital.

Background Adjuvant treatment with PD-1 inhibitors for 12 months has been the established standard of care for patients with resected stage IIB-IV cutaneous melanoma. In other solid tumours (e.g. breast and colorectal), a shorter duration of adjuvant chemotherapy has been shown to be non-inferior with improved toxicity profile. More recently, neoadjuvant immunotherapy with immune checkpoint inhibitors for clinically detectable stage III and stage IV disease has been introduced. There is no clear biological rationale for the chosen duration, and no studies have investigated duration of adjuvant treatment with immune checkpoint inhibitors. A reduced duration of adjuvant therapy could lead to less toxicity from reduced drug exposure, patients returning to normal life sooner, significantly lower drug costs and better healthcare resource utilization. There remains significant interest from patients and clinicians to address this important question. Methods Grand SLAM is a prospective phase III randomised, controlled international multi-centre non-inferiority study. The primary objective is to investigate if short (6 months) has equal efficacy as long (12 months) duration of (neo-)adjuvant immune checkpoint inhibition in relation to distant metastasis-free survival and relapse-free survival at landmark analysis at 2 years. After radical surgery of stage IIB-C, III or IV cutaneous melanoma, patients are randomly assigned 1:1 to short or long adjuvant treatment with either nivolumab or pembrolizumab. Patients who have received neoadjuvant treatment with major pathological response are excluded. The sample size of 1,880 patients was determined based on a non-inferiority margin of 4%, a significance level of 0.045 and 80% statistical power. An interim analysis will be conducted when 2/3 of patients are accrued. Biomarkers and the role of food supplements for relapse (MelKo) will be investigated in prespecified substudies. Discussion This is the first randomised study to assess a shorter duration of adjuvant anti PD-1 antibody in cutaneous melanoma patients. As of March 2026, the study is recruiting patients in the Nordic countries. Centres in other countries will open shortly. Trial registration NCT06488482. Date of registration: 2024-06-10.

Background The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. Methods The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/− whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. Discussion This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. Results The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. Trial registration ClinicalTrials.gov , NCT 03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412