COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma.

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

Associations of Dietary Factors with Cutaneous Melanoma: A Case-Control Study in Greece with Literature Review.

INTRODUCTION: It has been postulated that nutrition may influence the risk for cutaneous melanoma (CM); therefore, we aimed to assess the associations of food groups and individual nutrient intakes with CM in a Greek population. METHODS: In this case-control study, 151 patients with histologically confirmed CM, newly diagnosed and treated in the Oncology Department of the "Laikon" University Hospital (Athens, Greece), and 151 age- and sex-matched healthy individuals residing in the Athens metropolitan area, recruited among participants for routine health examinations, were included. All participants completed a questionnaire comprising anthropometric measurements, sociodemographic, lifestyle, and health-related variables. A validated, semiquantitative food frequency questionnaire was used to assess average consumption of 136 food items during the 12 months preceding the onset of disease. Multivariate conditional regression models were used to derive odds ratios (ORs) with 95% confidence intervals (95% CI) regarding the association of nine food groups and seven macronutrients with CM. RESULTS: Statistically significant positive associations with CM were found with higher energy intake (OR: 1.67, 95% CI: 1.22-2.30) and intake of saturated fatty acids (OR: 2.28, 95% CI: 1.00-5.28), after adjusting for sun sensitivity, major depression history, and alcohol intake. Inverse associations with higher intake of milk and dairy products (OR: 0.65, 95% CI: 0.48-0.88), fruits (OR: 0.68, 95% CI: 0.51-0.90), added lipids (OR: 0.65, 95% CI: 0.47-0.91), and sugars and syrups (OR: 0.70, 95% CI: 0.53-0.93) were also observed. CONCLUSIONS: Beyond intrinsic risk factors, our results support associations of CM with multiple food groups and nutrients; if confirmed by prospective studies, these findings can add further knowledge about this fatal cancer.

Reaching the Diagnosis of Checkpoint Inhibitor-Induced Diabetes Mellitus in Different Clinical Scenarios: A Real-World Application of Updated Diagnostic Criteria.

BACKGROUND: Checkpoint inhibitor (CPI)-associated diabetes mellitus (CPI-DM) is a rare immune-related adverse event (irAE) that presents with variable clinical manifestations. Data about its pathogenesis have not yet been adequately studied. METHODS: Applying the recently updated diagnostic criteria from the American Diabetes Association, we retrospectively reviewed the medical records of all CPI-treated patients referred to our endocrinological unit for managing their endocrine irAEs and analyzed the incidence of CPI-DM, its clinical characteristics, and its management. RESULTS: Among the 326 CPI-treated patients with endocrine irAEs, 4 patients met the updated criteria for the diagnosis of CPI-DM, representing 1.22% of all endocrine irAEs in our cohort. These four patients presented with distinct clinical scenarios regarding the irAE onset, the underlying malignancy, the administered CPI regimen, and the type of circulating autoantibodies. CONCLUSION: The variable presentation of CPI-DM and the non-standard sensitivity of the presence of the type 1 DM traditional autoantibodies highlight the need for distinct guidelines and increased awareness of its diagnosis and management.

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial.

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 BRAFV600-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 BRAFV600-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.

The side effect registry immuno-oncology (SERIO) - A tool for systematic analysis of immunotherapy-induced side effects.

BACKGROUND: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes. METHODS: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered. RESULTS: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy. CONCLUSIONS: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

Real-world management practices and characteristics of patients with advanced melanoma initiated on immuno-oncology or targeted therapy in the first-line setting during the period 2015-2018 in Greece. The 'SUMMER' study: a retrospective multicenter chart review project.

This study primarily aimed to generate real-world evidence (RWE) on the profile and first-line treatment (1LT) patterns of patients with advanced (unresectable Stage III/metastatic) cutaneous melanoma initiated on immuno-oncology (IO)- or targeted therapy (TT)-based 1LT between 1 January 2015 and 1 January 2018 (index period), in routine settings of Greece. This was a multicenter, retrospective chart review study. Eligible consented (unless deceased, for whom consent was waived by the hospital) patients were consecutively included by six oncology clinics. The look-back period extended from informed consent or death to initial melanoma diagnosis. Between 9 Junuary 2021 and 9 February 2022, 225 eligible patients (all Caucasians; 60.4% male; 35.6% diagnosed with de novo advanced melanoma) were included. At 1LT initiation, median age was 62.6 years; 2.7/6.7/90.7% of the patients had Stage IIIB/IIIC/IV disease and 9.3% were unresected. Most frequent metastatic sites were the lung (46.7%), non-regional nodes (33.8%), and liver (20.9%). Among patients, 98.2% had single primary melanoma, 45.6% had disease localized on the trunk, and 63.6% were BRAF-mutant. Of the patients, 45.3% initiated 1LT with an IO-based, 53.3% with a TT-based regimen, and three patients (1.3%) received TT-based followed by IO-based or vice versa. Most common 1LT patterns (frequency ≥10%) were BRAFi/MEKi combination (31.6%), anti-PD-1 monotherapy (25.3%), BRAFi monotherapy (21.8%), and anti-CTLA-4 monotherapy (17.8%). Most frequent regimens were Dabrafenib+Trametinib in 25.3%, and monotherapies with Pembrolizumab/Ipilimumab/Vemurafenib/Dabrafenib in 23.6/17.8/11.1/10.7% of patients, respectively. SUMMER provides RWE on 1LT strategies and profile of patients initiated 1L IO- or TT-based therapy in Greece during the 3-year index period.

Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.

PURPOSE: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma. METHODS: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses. RESULTS: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02. CONCLUSION: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial.

PURPOSE: In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. METHODS: In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS: Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION: COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF.

WHAT IS THIS SUMMARY ABOUT?: Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®) are medicines used to treat a type of melanoma that has a change in the BRAF gene, called advanced or metastatic BRAF V600-mutant melanoma. Participants with advanced or metastatic BRAF V600-mutant melanoma took either encorafenib plus binimetinib together (COMBO group), compared with encorafenib alone (ENCO group) or vemurafenib (ZELBORAF®) alone (VEMU group). WHAT WERE THE RESULTS?: In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time. WHAT DO THE RESULTS MEAN?: Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone. Clinical Trial Registration: NCT01909453 (ClinicalTrials.gov).

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody-drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.

Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial.

BACKGROUND: In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. METHODS: Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. RESULTS: Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. CONCLUSION: Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma.

Cytomegalovirus Infections in Patients Treated With Immune Checkpoint Inhibitors for Solid Malignancies.

Cytomegalovirus (CMV) infection/disease has been repeatedly reported in patients treated with immune-checkpoint inhibitors (ICIs) and most commonly involves patients with relapsed/refractory (R/R) immune-related adverse events (irAEs). In the current study, we present a patient with melanoma who developed CMV gastritis during treatment with pembrolizumab in the absence of irAEs and without previous or current immunosuppression. Moreover, we review the literature regarding CMV infection/disease in patients treated with ICIs for solid malignancies. We present the currently available data on the pathogenesis, clinical characteristics, endoscopic findings, and histologic features and highlight the potential differences among cases complicating R/R irAEs versus those occurring in patients who are immunosuppression naive. Finally, we discuss the currently available data regarding potential useful diagnostic tools as well as the management of these patients.

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238.

PURPOSE: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. PATIENTS AND METHODS: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. RESULTS: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. CONCLUSIONS: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.

Challenges in the treatment of melanoma with BRAF and MEK inhibitors in patients with sickle cell disease: case report and review of the literature.

Patients with sickle cell disease (SCD) suffer from complications due to anemia, inflammation, and vaso-occlusion. Factors that trigger sickling and/or inflammation may initiate such complications, while treatment with hydroxyurea (HU) reduces their emergence and prolongs survival. On the contrary, inhibition of the BRAF-MEK-ERK pathway with BRAF and MEK inhibitors (BRAF/MEKi) has revolutionized treatment of melanoma but their use has been correlated with inflammatory adverse events. Thus, treatment of patients with SCD with BRAF/MEKi may be quite challenging and pyrexia in those patients should be managed as a medical emergency. In this article, intrigued by the case of a 36-year-old female patient with S/ß-thal under HU who was treated with dabrafenib and trametinib for melanoma, we analyze the mechanisms underlying inflammation and vaso-occlusion in SCD, the mechanisms of pyrexia and inflammation induced by BRAF/MEKi, their potential interconnections, the shared role of the inflammasome in these two entities, and the protective effect of HU in SCD. Since SCD is the most common inheritable blood disorder, the administration of BRAF/MEKi for melanoma in patients with SCD may be a rather common challenge. Thus, proper treatment with HU may pave the way for an uneventful management of such patients.

Mechanisms of resistance to immune checkpoint inhibitors in melanoma: What we have to overcome?

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less. Reasonably, the primary and acquired resistance to ICIs has entered into the focus of clinical research with positive (e.g., nivolumab and relatlimab combination) and negative feedbacks (e.g., nivolumab with pegylated-IL2, pembrolizumab with T-VEC, nivolumab with epacadostat, and combinatorial triplets of BRAF/MEK inhibitors with immunotherapy). Many intrinsic (intracellular or intra-tumoral) but also extrinsic (systematic) events are considered to be involved in the development of this resistance to ICIs: i) melanoma cell immunogenicity (e.g., tumor mutational burden, antigen-processing machinery and immunogenic cell death, neoantigen affinity and heterogeneity, genomic instability, melanoma dedifferentiation and phenotypic plasticity), ii) immune cell trafficking, T-cell priming, and cell death evasion, iii) melanoma neovascularization, cellular TME components(e.g., Tregs, CAFs) and extracellular matrix modulation, iv) metabolic antagonism in the TME(highly glycolytic status, upregulated CD39/CD73/adenosine pathway, iDO-dependent tryptophan catabolism), v) T-cell exhaustion and negative immune checkpoints, and vi) gut microbiota. In the present overview, we discuss how these parameters compromise the efficacy of ICIs, with an emphasis on the lessons learned by the latest melanoma studies; and in parallel, we describe the main ongoing approaches to overcome the resistance to immunotherapy. Summarizing this information will improve the understanding of how these complicated dynamics contribute to immune escape and will help to develop more effective strategies on how anti-tumor immunity can surpass existing barriers of ICI-refractory melanoma.

Melanuria in a patient with BRAF-mutant metastatic melanoma of unknown primary: Insights on the pathophysiology, differential diagnosis, prognosis, and treatment.

Melanuria is the dark brown discoloration of the urine and an uncommon manifestation in patients with melanoma. It is an ominous sign, usually indicating widespread disease. In this article, through an illustrative case, we discuss the pathophysiological, clinical, and prognostic characteristics of melanuria in melanoma. Moreover, we aim to provide the available data for the prompt diagnosis and treatment of patients presenting with melanuria. We present the case of a 47-year-old man presenting with melanuria and diffure melanosis cutis, who was eventually diagnosed with a BRAF-mutated metastatic melanoma of unknown primary. The patient was started on a BRAF and MEK inhibitor, but he had a rapid disease progression and succumbed to the disease. There is only a limited number of case reports of melanoma patients with melanuria receiving targeted therapies or immune checkpoint inhibitors. In these reports, variable treatment responses have been described. In view of the increasing significance of targeted therapies and immunotherapy for melanoma, more cases are needed to improve our understanding on the prognostic significance of melanuria in the era of novel therapies for melanoma.

Diabetes insipidus: A rare endocrine complication of immune check point inhibitors: A case report and literature review.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are novel therapeutic agents widely used in numerous malignancies. They are known to cause multiple immune-related endocrine adverse events (irAEs); however, anterior pituitary hypophysitis with secondary hypopituitarism is the most frequently reported irAE, especially in patients receiving anti-CTLA-4 treatment. By contrast, posterior pituitary involvement, such as central diabetes insipidus (CDI), is relatively rare and only few case reports have been published. The present report describes the case of a 53-year-old woman with metastatic melanoma treated with nivolumab an anti-PD-L1 monoclonal antibody. At 6 months after the initiation of nivolumab treatment, the patient was diagnosed with deficiency of the corticotrope and thyreotrope axes and in the following 2 months the patient was diagnosed with progressive development of polyuria-polydipsia syndrome. The diagnosis of partial CDI was retained based on plasma and urinary osmolalities, the water deprivation test and baseline copeptin levels as well as on the absence of the bright spot in the posterior pituitary in magnetic resonance imaging. Systematic research of the literature revealed a total of 13 cases reports (including 14 patients) presenting with CDI treated with monotherapy with CTLA-4 (n=5) or PD-1/PD-L1 Abs (n=6) or combined treatments (n=3). The improved understanding of the mechanisms of ICI action along with their extensive use should contribute to the early recognition of irAE symptoms. We hypothesized that clinicians should be aware of this clinical entity and its symptoms and treat it appropriately.