Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

BRAF/MEK Inhibition as a Bridge to Immunotherapy for Symptomatic BRAF V600 Melanoma Brain Metastases: A Case Series.

Targeted and immune therapies have changed the paradigm of treatment for patients with metastatic melanoma. Treatment of patients with symptomatic melanoma brain metastases, however, is complicated by the frequent use of immune suppression for the management of vasogenic edema and the urgency in addressing disease burden. Use of BRAF/MEK inhibitors in patients with a corresponding BRAF V600 mutation often results in rapid response but is hindered by high rates of disease relapse and progression. Immunotherapy has higher durability of response, but the rate of response is slower and responses can be significantly diminished for patients on concurrent steroid therapy. Considering this gap in evidence-based guidance for optimal adjuvant therapy sequence in immunosuppressed patients with BRAF V600-mutant melanoma brain metastases, we report on 4 cases utilizing BRAF/MEK inhibitors as a bridging therapy for brain metastases management before initiation of immune checkpoint inhibitor therapy. Future prospective studies will be required to determine the optimal treatment sequencing for patients in this population with high unmet medical need.

Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Homologous Recombination Deficiency (HRD) in Cutaneous Oncology.

Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment.

CD33 mRNA Has Elevated Expression Levels in the Leukocytes of Peripheral Blood in Patients with Late-Onset Alzheimer's Disease.

BACKGROUND/AIMS: In despite of conflicting results among different ethnic groups, the rs3865444 of CD33 gene has previously been identified as a risk factor for late-onset Alzheimer's disease (LOAD).This study was aimed to evaluate the association between rs3865444 SNP with LOAD occurrence, and to investigate whether CD33 mRNA expression will change in the leukocytes of peripheral blood in LOAD patients. METHODS: The rs3865444 polymorphism was genotyped in 233 LOAD and 238 control subjects using the Tetra-ARMS-PCR method. CD33 mRNAs expression in leukocytes were assessed and analyzed using the real-time qPCR method. We used in silico approach to analyze potential effects imparted by rs3865444 polymorphism in LOAD pathogenesis. RESULTS: Our results show a significant increase in CD33 mRNA expression levels in white blood cells of LOAD patients, however, the association between CD33 rs3865444 polymorphism and LOAD was found to be not significant. We also noticed that LOAD patients with the C/A genotype had higher CD33 mRNA levels in their peripheral blood than those of the control group. CONCLUSIONS: rs3865444, located upstream of the 5'CD33 coding region, might positively influence CD33 mRNAs expression in leukocytes of LOAD versus healthy people. This is likely to happen through interfering rs3865444 (C) with the functional activity of several other transcription factors given that rs3865444 is in linkage disequilibrium with other functional polymorphisms in this coding region according to an in silico study. We propose that CD33 mRNAs elevation in peripheral immune cells - as a potential biomarker in LOAD - is related to peripheral immune system impairment.

Normalization of electroretinogram and symptom resolution of melanoma-associated retinopathy with negative autoantibodies after treatment with programmed death-1 (PD-1) inhibitors for metastatic melanoma.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody-protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect.

Successful Use of BRAF/MEK Inhibitors as a Neoadjuvant Approach in the Definitive Treatment of Papillary Craniopharyngioma.

Craniopharyngiomas are rare tumors that arise in the suprasellar region of the brain and are known for their aggressive nature despite their WHO grade I. This is due to the complex neuroanatomy of the sellar/suprasellar region and their proximity to the optic nerve apparatus, hypothalamic-pituitary tract, and other critical neuroanatomical structures. Definitive treatment is based on a multidisciplinary approach and often involves a combination of surgical, radiation, and medical therapy. However, there is high morbidity associated with surgery and RT due to the complex neuroanatomy of this region. Recently, BRAFV600E somatic mutation has been identified in most papillary craniopharyngiomas. This discovery has led to the novel use of RAF pathway inhibitors to treat these tumors. We report the successful use of dabrafenib (BRAF inhibitor) and trametinib (mitogen-activated protein kinase kinase inhibitor) in the neoadjuvant setting followed by definitive stereotactic radiosurgery. We propose an algorithm based on available literature on the integration of targeted therapy in the management of papillary craniopharyngiomas. Our observations, together with prior case reports, advocate the incorporation of targeted therapy for unresectable craniopharyngiomas and reinforce that treatment with dual-targeted therapy is safe and effective.

Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation.

BACKGROUND: Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity. CASE PRESENTATION: A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening. CONCLUSIONS: Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy.

Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.

Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With BRAF-Mutated High-Grade Glioma.

BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non-small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective.

Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma.

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.

Analysis of point mutations and copy number variation in Grade II and III meningioma.

Meningiomas are among the most common tumors of the adult central nervous system (CNS). They are classified by the World Health Organization into three pathologic grades with increasing severity: grade I are benign with favorable treatment outcomes and low recurrence rates while grade III display malignant behavior and poor progression-free survival. Previous studies have shown that inactivation of NF-2 is the most common genetic event in high-grade meningioma; however, there is dearth of molecular data to distinguish grade II (AM-II) from the even more aggressive grade III (AM-III). As part of a routine diagnostic workup, 19 AM-II and 5 AM-III were submitted for targeted sequencing on a panel of twenty-four genes relevant to CNS tumors. The data generated during the course of clinical care was collected and re-analyzed with the aim of identifying molecular features to distinguish AM-II and AM-III. Our cases contained several well-characterized, potentially actionable mutations, but we did not find any novel, recurrent sequence variants. Copy number variations were common in both AM-II and AM-III; chr22q loss was the most prevalent followed in decreasing frequency by losses of chr1p, chr14q, and chr10. In particular, chr10 loss was noted in 4 of 5 AM-III cases but none of the AM-II cases. This suggests that chr10 loss may serve as a diagnostic and perhaps a prognostic marker to differentiate AM-II from AM-III. If confirmed in larger studies, our finding could further aid the classification of meningioma.

Impact of concurrent chemotherapy with radiation therapy for elderly patients with newly diagnosed glioblastoma: a review of the National Cancer Data Base.

To investigate the utilization and overall survival (OS) impact of concurrent chemotherapy in combination with radiation therapy (RT) for elderly glioblastoma (GBM) patients. Elderly patients (age >70) with supratentorial and nonmetastatic GBM who received RT of 20-75 Gy with concurrent single-agent chemotherapy (ChemoRT) or without (RT alone) during 2004-2012 were identified from the National Cancer Data Base (NCDB). The Cochran-Armitage test was used for trend analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were determined using Cox proportional hazards. Propensity score analysis was performed to reduce selection bias in treatment allocation. A total of 5252 patients were identified (RT alone: n = 1389; ChemoRT: n = 3863). There was increasing utilization of chemotherapy during this period (45-80%, P < .001). A similar trend was also observed for the subset of age >80 (25-68%, P < .001). ChemoRT was associated with significantly better OS than RT alone (HR 0.79, 95% CI 0.70-0.89, P < .001) on multivariate analysis, and similar OS benefit was demonstrated with 1202 pairs of propensity-matched patients (HR 0.79, 95% CI 0.73-0.86, P < .001). For the matched pair, the median OS was 5.8 months with ChemoRT and 5.0 months with RT alone; the 2-year OS rate was 9% with ChemoRT and 4% with RT alone (P < .001). Concurrent chemotherapy has been administered with RT for the majority of elderly GBM patients. Addition of chemotherapy to RT for elderly GBM patients is associated with significantly improve OS in routine clinical practice.

Case report: Increased efficacy of cetuximab after pembrolizumab failure in cutaneous squamous cell carcinoma.

Immunotherapy is the first-line option for treating advanced cutaneous squamous cell carcinoma (cSCC). However, up to half of patients experience no benefit and treatment resistance, warranting newer therapeutic approaches. Combinatory approaches, including cetuximab, may help overcome immunotherapy resistance and improve response rates in advanced cSCC. We report three cases of metastatic cSCC that achieved significant clinical responses after cetuximab therapy following initial progression on pembrolizumab. We have retrospectively reviewed these cases at a single academic center between 2018 and 2023. All patients initially progressed on pembrolizumab, after which cetuximab (mono- or combination therapy) was added with two complete responses and one partial response. Initial responses were noted within 2 to 7 months of starting cetuximab. While the benefit of cetuximab and immunotherapy in head-and-neck squamous cell carcinoma has growing evidence, information regarding cSCC remains limited. This study adds three cases to the underreported literature on treating advanced cSCC with cetuximab after initially failing immunotherapy.

ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes.

ARID genes encode subunits of SWI/SNF chromatin remodeling complexes and are frequently mutated in human cancers. We investigated the correlation between ARID mutations, molecular features, and clinical outcomes in melanoma patients. Cutaneous melanoma samples (n = 1577) were analyzed by next-generation sequencing. Samples were stratified by pathogenic/likely pathogenic mutation in ARID genes (ARID1A/2/1B/5B). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Tumor mutation burden (TMB)-high was defined as ≥ 10 mutations/Mb. Transcriptomic signatures predictive of response to immune checkpoint inhibitors-interferon gamma and T-cell inflamed score were calculated. Real-world overall survival (OS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from time of tissue collection until last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p values adjusted for multiple comparisons. ARID2 mutations were more prevalent in cutaneous melanoma compared to ARID1A (11.0%: n = 451 vs 2.8%: n = 113), with concurrent ARID1A/ARID2 mutation in 1.1% (n = 46) of samples. ARID mutations were associated with a high prevalence of RAS pathway mutations-NF1 (ARID1A, 52.6%; ARID2, 48.5%; ARID1A/2, 63.6%; and ARID-WT, 13.3%; p < 0.0001) and KRAS (ARID1A, 3.5%; ARID2, 3.1%; ARID1A/2, 6.5%; and ARID-WT, 1.0%; p = 0.018)), although BRAF mutations were less common in ARID-mutated cohorts (ARID1A, 31.9%; ARID2, 35.6%; ARID1A/2, 26.1%; and ARID-WT, 50.4%; p < 0.0001). TMB-high was more common in ARID-mutated samples (ARID1A, 80.9%; ARID2, 89.9%; ARID1A/2, 100%; and ARID-WT, 49.4%; p < 0.0001), while PD-L1 positivity was similar across subgroups (ARID1A, 43.8%; ARID2, 51.1%; ARID1A/2, 52.5%; and ARID-WT, 44.9%; p = 0.109). Patients with ARID1A mutations had a higher prevalence of dMMR/MSI-H compared to those with ARID-WT (2.7% vs 0.2%, p = 0.030). Median IFN-γ and T-cell signatures were higher in ARID2-mutated samples compared to ARID-WT (IFN-γ: - 0.15 vs - 0.21, p = 0.0066; T-cell: 23.5 vs - 18.5, p = 0.041). ARID2-mutated patients had improved survival compared to ARID-WT; (HR: 1.22 (95% CI 1.0-1.5), p = 0.022). No additional OS benefit was observed with anti-PD-1 therapy for ARID2 mutation compared to ARID-WT. Melanoma patients with ARID mutations exhibited higher prevalence of markers associated with ICI response, including TMB-H, and immune-related signatures. Our data also suggests improved survival outcome in patients with ARID2 mutations, irrespective of anti-PD1 therapy.

A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Case Report: Stereotactic body radiation treatment for immunotherapy escaped oligometastatic progression in cutaneous melanoma and merkel cell carcinoma.

Oligometastatic progression represents a unique manifestation of tumor immune-escape that can lead to disease progression during treatment with immune checkpoint inhibitor (ICI). The diagnosis and further optimal management of oligometastatic progression through ICI remains unclear. Diagnostic challenges include practical limitations due to the anatomical sites of oligometastatic progression, such as the para-aortic region, where traditional tissue biopsy carries high risk, and circulating-tumor DNA (ctDNA) could aid in diagnosis and disease monitoring as a supplement to surveillance imaging. In this report, we describe two cases of one patient with metastatic melanoma and the other with metastatic Merkel cell carcinoma (MCC) who were treated with ICI and later developed localized resistance due to oligometastatic progression. We further highlight our experience using stereotactic body radiation therapy (SBRT) as a salvage approach to treat the oligometastatic progression. In addition, we describe the temporal and dynamic relationship of circulating-tumor DNA (ctDNA) prior to, during and after SBRT, which highly suggested the diagnosis without obtaining a histological specimen. Our cases highlight a potential role for SBRT in the management of oligometastatic progression. However, large prospective trials are essential to confirm the utility of this approach.