The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab.

BACKGROUND: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. METHOD: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. RESULTS: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. CONCLUSIONS: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.

Boost of innate immunity cytokines as biomarkers of response to extracorporeal photopheresis in patients with leukaemic cutaneous T-cell lymphoma.

BACKGROUND: Extracorporeal photopheresis (ECP) has emerged as a systemic first-line immunomodulatory therapy in leukaemic cutaneous T-cell lymphoma (L-CTCL) and is now beginning to be utilized in other T-cell-mediated diseases. Although ECP has been used for nearly 30 years, its mechanisms of action are not sufficiently understood, and biomarkers for response are scarce. OBJECTIVES: We aimed to investigate the immunomodulatory effects of ECP on cytokine secretion patterns in patients with L-CTCL, to help elucidate its mechanism of action. METHODS: A total of 25 patients with L-CTCL and 15 healthy donors (HDs) were enrolled in this retrospective cohort study. Concentrations of 22 cytokines were simultaneously quantified by using multiplex bead-based immunoassays. Neoplastic cells in patients' blood were evaluated by flow cytometry. RESULTS: Firstly, we observed a distinct cytokine profile pattern difference between L-CTCLs and HDs. There was a significant loss of tumour necrosis factor (TNF)-α, and significant increase of interleukins (IL)-9, IL-12 and IL-13 in the sera of patients with L-CTCL compared with HDs. Secondly, patients with L-CTCL who received ECP were classified as treatment responders and nonresponders according to the quantitative reduction of malignant burden in their blood. We evaluated cytokine levels in culture supernatants from patients' peripheral blood mononuclear cells (PBMCs) at baseline and 27 weeks after ECP initiation. Strikingly, PBMCs purified from ECP responders released statistically higher concentrations of innate immune cytokines IL-1α, IL-1ß, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α in comparison with ECP nonresponders. In parallel, responders showed clearance of erythema, reduction of malignant clonal T cells in the blood, and a potent boost of relevant innate immune cytokines in individual patients with L-CTCL. CONCLUSIONS: Taken together, our results demonstrate that ECP stimulates the innate immune network, and facilitates redirection of the tumour-biased immunosuppressive microenvironment towards proactive antitumour immune responses. The alterations of IL-1α, IL-1ß, GM-CSF and TNF-α can be used as biomarkers of response to ECP in patients with L-CTCL.

The impact of the COVID-19 pandemic on the diagnosis of cutaneous melanomas: A retrospective cohort study from five European skin cancer reference centres.

BACKGROUND: The COVID-19 lockdown had a dramatic impact on primary care access and resulted in postponed skin cancer screenings. This raises concerns for a diagnostic delay on primary cutaneous melanomas, which can subsequently increase morbidity and mortality. OBJECTIVES: The aim of the study was to investigate the impact of the COVID-19-related restrictions on the melanoma diagnosis in five European skin cancer reference centres in Switzerland, Germany, Austria and Italy. METHODS: A total of 7865 cutaneous melanoma cases were collected between 01 September 2018 and 31 August 2021. The time period was stratified into pre-COVID (pre-lockdown) and post-COVID (lockdown and post-lockdown) according to the established restrictions in each country. The data collection included demographic, clinical and histopathological data from histologically confirmed cutaneous melanomas. Personal and family history of melanoma, and presence of immunosuppression were used to assess the diagnosis delay in high-risk individuals. RESULTS: There was an overall increase of the Breslow tumour thickness (mean 1.25 mm vs. 1.02 mm) during the post-COVID period, as well as an increase in the proportion of T3-T4 melanomas, rates of ulceration and the number of mitotic rates ≥2 (all, p < 0.001). Patients with immunosuppression and personal history of melanoma showed a decrease in the mean log10-transformed Breslow during lockdown and post-COVID. In the multivariate analysis, age at melanoma diagnosis (p < 0.01) and personal history of melanoma (p < 0.01) showed significant differences in the mean Breslow thickness. CONCLUSIONS: The study confirms the diagnostic delay in cutaneous melanomas due to the COVID-19 lockdown. High-risk individuals, such as patients with personal history of melanoma and elderly individuals, were more hesitant to restart their regular skin cancer screenings post-COVID. Further studies with longer follow-up are required to evaluate the consequences of this diagnostic delay in long-term outcomes.

Radiotherapy as a Treatment Option for Local Disease Control in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline-based chemotherapy with rituximab is recommended as first-line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control in patients with solitary or localized lesions. METHODS: We report the results of a retrospective analysis of PCDLBC, LT patients treated either with RT alone or with physician's decision as first-line treatment, aiming to assess disease progression and/or first recurrence in these treatment groups. RESULTS: We retrospectively analyzed 20 patients treated either with RT alone (n = 8) or with investigator's choice treatment (n = 12), which included chemotherapy alone or combined with local therapy (RT and wide local excision). Complete response (CR) was achieved in 8 patients from the first group and 9 patients from the second group, with 1 treatment failure. Six patients treated with RT alone progressed with a median time to progression (TTP) of 12.5 months. In the second group, 5 patients progressed with a median TTP of 5.2 months. RT showed good local disease control in both groups without any skin relapses during the follow-up period. CONCLUSION: RT as first-line monotherapy followed by watchful waiting did not significantly improve the overall risk of disease progression but resulted in good local disease control. After progression, RT could still easily be combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous disease group of unknown etiology with a complex immunological background. As CTCL arises from T cells that have a vital role in the antitumor response, their therapy is largely aimed at reversing the immunological mechanisms leading to or manifesting during this malignancy. Early disease stages can be controlled with skin-directed therapy in most CTCL cases. Still, advanced CTCL has a dismal prognosis and warrants systemic therapy. Despite considerable progress in understanding the pathophysiology of the disease and the numerous systemic treatment options available, long-term remission rates with conventional treatments alone are still low. Allogeneic hematopoietic stem cell transplantation is currently the only curative option for advanced CTCL, including mycosis fungoides and Sézary syndrome. The aims of this review is to summarize the recent findings on the immunology of this heterogeneous disease and to present the advances in its clinical management.

Update on adjuvant melanoma therapy.

PURPOSE OF REVIEW: We review the results from relevant clinical trials and discuss current strategies in the melanoma adjuvant setting. RECENT FINDINGS: The favorable therapeutic efficacy and the significant less toxicity of nivolumab compared with ipilimumab, fully substitutes today's approval of ipilimumab, regardless mutation status, whereas in BRAF-mutated patients, dabrafenib and trametinib seem to confirm their high efficacy also in adjuvant setting. The use of interferon is restricted to patients with ulcerated melanoma and countries with no access to the new drugs. SUMMARY: Systemic adjuvant treatment after complete disease resection in high-risk melanoma patients aims to increase relapse-free survival (RFS) and overall survival (OS). According to the eighth edition of melanoma classification of American Joint Committee on Cancer (AJCC), the prognosis in stage III patients is heterogeneous and depends not only on N (nodal) but also on T (tumor thickness) category criteria. Recent data from randomized, phase-3 clinical trials analyzing the use of adjuvant anti-programmed death-1 and targeted therapies ultimately affect the standard of care and change the landscape of the adjuvant treatment.

The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe.

PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments.

Skin Cancer Precursors: From Cancer Genomics to Early Diagnosis.

Skin cancers, including melanoma and keratinocyte carcinomas, are responsible for increasing health care burden internationally. Risk stratification and early detection are paramount for prevention and less risky treatment to overall improve patient outcomes and disease morbidity. Here, the authors discuss the key concepts leading to skin cancer initiation and progression. The authors also outline precursor and progression models for melanoma and keratinocyte carcinomas, including discussion of genetic alterations associated with the various stages of progression. Finally, the authors discuss the significance of immunoediting and the drivers behind increased risk of cutaneous malignancy in the state of immune dysregulation.

Seasonal patterns of toxicity in melanoma patients treated with combination anti-PD-1 and anti-CTLA-4 immunotherapy.

BACKGROUND: Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. METHODS: We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. RESULTS: 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). CONCLUSIONS: Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.

Monitoring melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance.

Resistance to targeted therapy remains a major clinical challenge in melanoma. To uncover resistance mechanisms, we perform single-cell RNA sequencing on fine-needle aspirates from resistant and responding tumors of patients undergoing BRAFi/MEKi treatment. Among the genes most prominently expressed in resistant tumors is POSTN, predicted to signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after therapy exhibit high POSTN expression levels and high numbers of TTR macrophages. POSTN polarizes human macrophages toward a TTR phenotype and promotes resistance to targeted therapy in a melanoma mouse model, which is associated with a phenotype change in intratumoral macrophages. Finally, polarized TTR macrophages directly protect human melanoma cells from MEKi-induced killing via CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages may offer a strategy to overcome resistance to targeted therapy in melanoma.

Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Efficacy and safety of 'Second Adjuvant' therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy.

BACKGROUND: Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi. PATIENTS AND METHODS: Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group). RESULTS: 73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). CONCLUSION: This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

Outcomes of patients with resected stage III/IV acral or mucosal melanoma, treated with adjuvant anti-PD-1 based therapy.

IMPORTANCE: Acral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. OBJECTIVE: To determine the efficacy of adjuvant PD1 in resected AM or MM. DESIGN: An international, retrospective cohort study SETTING: Data up to November 2021 collected from 20 centres across 10 countries. PARTICIPANTS: One hundred and ninety four patients with resected stage III or IV1 AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. MAIN OUTCOMES AND MEASURES: Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. RESULTS: Forty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52-0.92, p = 0.0127)], DMFS [HR0.58 (0.38-0.89, p = 0.0134)] and OS [HR of 0.59 (0.38-0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69-2.68,p-value 0.3799], DMFS or OS. CONCLUSION AND RELEVANCE: After adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.

Internal Thoracic Vein Tumor Thrombus From Sternal Melanoma Metastasis on 18 F-FDG PET/CT.

ABSTRACT: We present 18 F-FDG PET/CT findings of an internal thoracic vein tumor thrombus from melanoma in a 76-year-old woman. Restaging 18 F-FDG PET/CT shows a progressive disease with an internal thoracic vein tumor thrombus from a sternal bone metastasis. Although cutaneous malignant melanoma may metastasize to any body part, a direct tumor invasion of veins and the formation of a tumor thrombus represent an extremely rare complication.

Value of troponin T versus I in the diagnosis of immune checkpoint inhibitor-related myocarditis and myositis: rechallenge?

A 54-year old patient with metastatic melanoma presented with asymptomatic myositis and myocarditis after combined immune checkpoint inhibitors (ICI) therapy (anti-programmed cell death receptor-1, anti-lymphocyte activating gene-3, and anti-indoleamine 2,3-dioxygenase-1). The diagnosis was based on the typical time window after ICI, recurrence upon re-challenge, elevations of CK, high-sensitive troponin T (hs-TnT) and I (hs-TnI), mild NT-proBNP increase, and positive magnetic resonance imaging criteria. Notably, hsTnI was found to more rapidly increase and fall and to be more heart-specific than TnT in the context of ICI-related myocarditis. This led to ICI therapy withdrawal and switch to a less effective systemic therapy. This case report highlights the differential value of hs-TnT and hs-TnI for diagnosis and monitoring of ICI-related myositis and myocarditis.

Efficacy of ipilimumab 3 mg/kg following progression on low-dose ipilimumab in metastatic melanoma.

BACKGROUND: Differing doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy. METHODS: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3± anti-PD1 antibody were eligible. Best investigator-determined Response Evaluation Criteria in Solid Tumours response, progression-free survival (PFS) and overall survival (OS) were analysed. RESULTS: Total 36 patients received low-dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting. Of which, 20 (56%) had primary resistance and 16 (44%) had acquired resistance. All patients received IPI3 for unresectable stage III or IV melanoma; median age 60 (29-78), 18 (50%) M1d disease, 32 (89%) Eastern Cooperative Oncology Group performance status 0-1. Around 35 (97%) received IPI3 with nivolumab and 1 received IPI3 alone. The response rate to IPI3 was 9/36 (25%). In patients with primary resistance, the response rate was 6/20 (30%). After a median follow-up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded; 1-year PFS and OS were 73% and 100%, respectively. CONCLUSIONS: IPI3 following recurrence/progression on low dose IPI has clinical activity, including in primary resistance. IPI dosing is therefore critical in a subset of patients.

Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.

Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives.

Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma.