Assessment of Retinal Pigment Epithelium Alterations and Chorioretinal Vascular Network Analyses in Patients under Treatment with BRAF/MEK Inhibitor for Different Malignancies: A Pilot Study.

In the last two decades, an increasing number of so-called molecular-targeted therapies have become available for the treatment of patients with advanced malignancies. These drugs have included inhibitors of proteins in the MAPK pathway, such as BRAF and MEK inhibitors, which are characterized by a distinct toxicity profile. The eye is particularly susceptible to adverse effects due to MEK inhibitors, and the term MEKAR (MEK-inhibitor-associated retinopathy) indicates the presence of subretinal fluid, mimicking central serous chorioretinopathy (CSC). The pathogenesis of the retinal alterations related to MAPK pathway inhibitors is still unclear, and questions are still open. The present study aims to assess the presence of retinal pigment epithelium alterations as predictive parameters for retinal toxicity, analyzing, at the same time, the chorioretinal vascular network in patients undergoing BRAF/MEK inhibitor treatment for different malignancies.

Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial.

BACKGROUND: Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces immunogenic cell death, thereby providing maturation signals and enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDCs, in order to reinvigorate the cancer-immunity cycle. METHODS: In this phase I trial, patients with advanced melanoma who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastases with T-VEC on day 1 followed by IT injection of CD1c (BDCA-1)+ myDCs +/- CD141 (BDCA-3)+ myDCs on day 2. T-VEC injections were repeated on day 21 and every 14 days thereafter. The number of IT administered CD1c (BDCA-1)+ myDCs was escalated from 0.5×106, to 1×106, to a maximum of 10×106 cells in three sequential cohorts. In cohort 4, all isolated CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDCs were used for IT injection. Primary objectives were safety and feasibility. Repetitive biopsies of treated lesions were performed. RESULTS: In total, 13 patients were enrolled (cohort 1 n=2; cohort 2 n=2; cohort 3 n=3; cohort 4 n=6). Patients received a median of 6 (range 3-8) T-VEC injections. The treatment was safe with most frequent adverse events being fatigue (n=11 (85%)), fever (n=8 (62%)), and chills/influenza-like symptoms (n=6 (46%)). Nine (69%) and four patients (31%), respectively, experienced pain or redness at the injection-site. Clinical responses were documented in injected and non-injected lesions. Two patients (cohort 3) who previously progressed on anti-PD-1 therapy (and one patient also on anti-CTLA-4 therapy) developed a durable, pathologically confirmed complete response that is ongoing at 33 and 35 months following initiation of study treatment. One additional patient treated (cohort 4) had an unconfirmed partial response as best response; two additional patients had a mixed response (with durable complete responses of some injected and non-injected lesions). On-treatment biopsies revealed a strong infiltration by inflammatory cells in regressing lesions. CONCLUSIONS: IT coinjection of autologous CD1c (BDCA-1)+ +/- CD141 (BDCA-3)+ myDCs with T-VEC is feasible, tolerable and resulted in encouraging early signs of antitumor activity in immune checkpoint inhibitor-refractory melanoma patients. TRIAL REGISTRATION NUMBER: NCT03747744.

A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors.

Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

COVID-19 and Cushing's disease in a patient with ACTH-secreting pituitary carcinoma.

SUMMARY: The pandemic caused by severe acute respiratory syndrome coronavirus 2 is of an unprecedented magnitude and has made it challenging to properly treat patients with urgent or rare endocrine disorders. Little is known about the risk of coronavirus disease 2019 (COVID-19) in patients with rare endocrine malignancies, such as pituitary carcinoma. We describe the case of a 43-year-old patient with adrenocorticotrophic hormone-secreting pituitary carcinoma who developed a severe COVID-19 infection. He had stabilized Cushing's disease after multiple lines of treatment and was currently receiving maintenance immunotherapy with nivolumab (240 mg every 2 weeks) and steroidogenesis inhibition with ketoconazole (800 mg daily). On admission, he was urgently intubated for respiratory exhaustion. Supplementation of corticosteroid requirements consisted of high-dose dexamethasone, in analogy with the RECOVERY trial, followed by the reintroduction of ketoconazole under the coverage of a hydrocortisone stress regimen, which was continued at a dose depending on the current level of stress. He had a prolonged and complicated stay at the intensive care unit but was eventually discharged and able to continue his rehabilitation. The case points out that multiple risk factors for severe COVID-19 are present in patients with Cushing's syndrome. 'Block-replacement' therapy with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred in this patient population. LEARNING POINTS: Comorbidities for severe coronavirus disease 2019 (COVID-19) are frequently present in patients with Cushing's syndrome. 'Block-replacement' with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred to reduce the need for biochemical monitoring and avoid adrenal insufficiency. The optimal corticosteroid dose/choice for COVID-19 is unclear, especially in patients with endogenous glucocorticoid excess. First-line surgery vs initial disease control with steroidogenesis inhibitors for Cushing's disease should be discussed depending on the current healthcare situation.

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.

BACKGROUND: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. METHODS: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. RESULTS: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39-72), and 85.7% (95% CI, 70-100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. CONCLUSIONS: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

Melanoma with genetic alterations beyond the BRAFV600 mutation: management and new insights.

PURPOSE OF REVIEW: Molecular-targeted therapy with BRAF-/MEK-inhibitors has shown impressive activity in patients with advanced BRAFV600 mutant melanoma. In this review, we aim to summarize recent data and possible future therapeutic strategies involving small-molecule molecular-targeted therapies for advanced BRAFV600 wild-type melanoma. RECENT FINDINGS: In patients with NRASQ61 mutant melanoma, downstream MEK-inhibition has shown some albeit low activity. MEK-inhibitors combined with novel RAF dimer inhibitors, such as belvarafenib, or with CDK4/6-inhibitors have promising activity in NRAS mutant melanoma in early-phase trials. In patients with non-V600 BRAF mutant melanoma, MEK-inhibition with or without BRAF-inhibition appears to be effective, although large-scale prospective trials are lacking. As non-V600 BRAF mutants signal as dimers, novel RAF dimer inhibitors are also under investigation in this setting. MEK-inhibition is under investigation in NF1 mutant melanoma. Finally, in patients with BRAF/NRAS/NF1 wild-type melanoma, imatinib or nilotinib can be effective in cKIT mutant melanoma. Despite preclinical data suggesting synergistic activity, the combination of the MEK-inhibitor cobimetinib with the immune checkpoint inhibitor atezolizumab was not superior to the immune checkpoint inhibitor pembrolizumab. SUMMARY: As of today, no molecular-targeted therapies have shown to improve survival in patients with advanced BRAFV600 wild-type melanoma. Combinatorial strategies, involving MEK-inhibitors, RAF dimer inhibitors and CDK4/6-inhibitors, are currently under investigation and have promising activity in advanced BRAFV600 wild-type melanoma.

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial.

BACKGROUND: Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30-39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. METHODS: Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. RESULTS: Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1-4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2-152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). CONCLUSION: IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. TRIAL REGISTRATION: NCT03233152.

Acute exudative polymorphous vitelliform maculopathy during pembrolizumab treatment for metastatic melanoma: a case report.

BACKGROUND: The use of immunomodulating therapy to treat various cancers has been on the rise and these immune checkpoint inhibitors are known to cause ocular side effects. In this article a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) is reported which developed during a first line treatment with pembrolizumab. CASE PRESENTATION: A 54-year-old woman was referred because of blurry vision in both eyes with a yellow spot in the central visual field of the left eye. These symptoms started after four treatments with pembrolizumab (a monoclonal antibody against the programmed cell death receptor-1) for a metastatic recurrent vaginal mucosal melanoma. Her best corrected visual acuity was 10/10 in both eyes with a correction of + 2.00 bilaterally. There were no inflammatory findings in the anterior segment or the vitreous. Fundoscopy revealed an attenuation of the foveal reflex with subtle yellow-white subretinal macular deposits (vitelliform lesions) in both eyes. Fluorescein angiography did not show staining or leakage in the mid-phase, neither a late staining. Spectral-domain optical coherence tomography of the macula illustrated bilateral neurosensory retinal detachment with a thick, highly reflective band at the outer photoreceptor segment. En face structural OCT at the level of the photoreceptors showed focal areas of increased signal corresponding to hyperreflective vitelliform material. The treatment with pembrolizumab was ceased immediately. During the following visits we slowly saw an improvement of the neurosensory retinal detachment. After almost four months a total resolution of the subretinal fluid was visualized in both eyes without the use of additional treatment, though the vitelliform deposits persisted. CONCLUSIONS: The development of AEPVM in melanoma patients could be triggered by treatment with Pembrolizumab. Pembrolizumab has the potential to disturb indirectly the retinal pigment epithelium homeostasis with accumulation of lipofuscin deposits and subretinal fluid, both signs of AEPVM.

C-reactive protein as a biomarker for immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors in the adjuvant setting.

The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP

Sarcoid-like reaction in a BRAF V600E-mutated metastatic melanoma patient during treatment with BRAF/MEK-targeted therapy.

Treatment with combined BRAF and MEK inhibition is widely accepted as a first-line treatment option for patients with advanced BRAF V600E mutant melanoma. It is generally well-tolerated and has limited side-effects. However, we report a case of a sarcoid-like syndrome induced by treatment with dabrafenib/trametinib (D/T) in a patient with stage IV-M1d melanoma. Sarcoid-like syndrome is a known side-effect of immune checkpoint-inhibition therapy but has only rarely been described in BRAF/MEK inhibition. However, recognizing this side-effect is important because of potential misinterpretation as progressive disease and influence on treatment. We describe a 48-year-old female patient who initially presented with solitary brain metastasis and diffuse lung lesions. She was treated with D/T to which she had an initial response in all lesions. One year later, new hilar and mediastinal lymphadenopathies were detected. Imaging was suggestive of the sarcoid-like syndrome. An endoscopic biopsy of the enlarged lymph node showed no melanoma cells. Treatment was continued. Three months later, the patient experienced a drop in hemoglobin, which prompted further investigations into possible occult intestinal metastasis. Video capsule examination revealed a metastatic lesion in the small intestine. A treatment switch to the combination of checkpoint inhibitors nivolumab and ipilimumab successfully treated both lung and small intestine lesions. After the third dose of this combination therapy, she developed an immune-related pneumonitis. Treatment with corticosteroids resolved the pneumonitis and decreased metabolism in the sarcoid-like syndrome. The treatment was not restarted afterward. She remains free of the disease up to today, 2.5 years after diagnosis.

Early Reassessment of Total Metabolic Tumor Volume on FDG-PET/CT in Advanced Melanoma Patients Treated with Pembrolizumab Predicts Long-Term Outcome.

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival. We identified all patients with advanced melanoma who were treated with Pembrolizumab in our medical center and underwent a baseline and at least one follow-up FDG-PET/CT. The total metabolic tumor volume (TMTV) was calculated, and the evolution was compared to survival parameters. A total of 77 patients underwent a baseline and at least one follow-up FDG-PET/CT, 36 patients had follow-up imaging within 2-4 months, and 21 patients an FDG-PET/CT 5-6 months after baseline. When the TMTV evolution was categorized into two subgroups (stable/decrease versus increase), an association was found between stability or decrease in TMTV and better PFS and OS. A similar trend, however non-significant, was observed at 5-6 months. The evolution in TMTV as assessed by FDG-PET/CT 2-4 months after treatment initiation is associated with long-term outcomes in patients with advanced melanoma treated with Pembrolizumab.

A Phase 2 Clinical Trial of Trametinib and Low-Dose Dabrafenib in Patients with Advanced Pretreated NRASQ61R/K/L Mutant Melanoma (TraMel-WT).

BACKGROUND: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. METHODS: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. RESULTS: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. CONCLUSIONS: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.

Choriocapillaris Assessment In Patients Under Mek-Inhibitor Therapy For Cutaneous Melanoma: An Optical Coherence Tomography Angiography Study.

PURPOSE: The present study investigates by optical coherence tomography angiography (OCTA) the retinal capillary plexus and choriocapillaris flow voids and their possible correlation with MEKAR. METHODS: 34 eyes of 17 patients (61.5 years [30.4-77.4]) with stage IV cutaneous melanoma were included prospectively. All patients showed disease progression under treatment with Nivolumab/Ipilimumab and were subsequently treated with the MEK-inhibitor Trametinib 2 mg once daily. At the start and every 6 weeks during follow-up of 4 months, patients underwent a complete ophthalmologic exam, OCTA and when needed fluorescein angiography. RESULTS: Statistical analysis was performed on 17 eyes of 9 patients. Eight patients were excluded due to missing OCTA images or due to drop-out because of decease or change of treatment. Comparing vessel area density (P = .625 and 0.681, respectively), vessel skeleton density (P = .996 and 0.766, respectively) of the superficial and deep capillary plexus, flow void number and total flow void area (mm2 and %) (P = .495; 0.197 and 0.298, respectively) of choriocapillaris slab, before and after treatment, revealed no significant difference. The evolution of choriocapillaris flow void parameter did not significantly differ in patients, who developed MEKAR compared to patients who did not. CONCLUSION: In patients receiving MEK-inhibitor with and without MEKAR, no significant different characteristics of the retinal capillary plexus and choriocapillaris were found. These data suggest that the development of MEKAR, has no correlation with vascular alteration.

Whole-Body MRI for the Detection of Recurrence in Melanoma Patients at High Risk of Relapse.

Introduction: No standard protocol for surveillance for melanoma patients is established. Whole-body magnetic resonance imaging (whole-body MRI) is a safe and sensitive technique that avoids exposure to X-rays and contrast agents. This prospective study explores the use of whole-body MRI for the early detection of recurrences. Material and Methods: Patients with American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7) stages IIIb/c or -IV melanoma who were disease-free following resection of macrometastases (cohort A), or obtained a durable complete response (CR) or partial response (PR) following systemic therapy (cohort B), were included. All patients underwent whole-body MRI, including T1, Short Tau Inversion Recovery, and diffusion-weighted imaging, every 4 months the first 3 years of follow-up and every 6 months in the following 2 years. A total body skin examination was performed every 6 months. Results: From November 2014 to November 2019, 111 patients were included (four screen failures, cohort A: 68 patients; cohort B: 39 patients). The median follow-up was 32 months. Twenty-six patients were diagnosed with suspected lesions. Of these, 15 patients were diagnosed with a recurrence on MRI. Eleven suspected lesions were considered to be of non-neoplastic origin. In addition, nine patients detected a solitary subcutaneous metastasis during self-examination, and two patients presented in between MRIs with recurrences. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were, respectively, 58%, 98%, 58%, 98%, and 98%. Sensitivity and specificity for the detection of distant metastases was respectively 88% and 98%. No patient experienced a clinically meaningful (>grade 1) adverse event. Conclusions: Whole-body MRI for the surveillance of melanoma patients is a safe and sensitive technique sparing patients' cumulative exposure to X-rays and contrast media.

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab.

BACKGROUND: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. METHODS: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. RESULTS: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm3. No significant associations were observed between baseline GEP scores and survival. CONCLUSION: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?

BACKGROUND: Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. CASE: We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. DISCUSSION: Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. CONCLUSION: ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

Intratumoral Combinatorial Administration of CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial.

Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG1 monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)+ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 106 CD1c (BDCA-1)+ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumonitis (n = 2), colitis (n = 1), and bullous pemphigoid (n = 1). The best response was a durable partial response in a patient with stage IV melanoma who previously progressed on checkpoint inhibitors. Our combinatorial therapeutic approach, including IT injection of CD1c (BDCA-1)+ myDCs, is feasible and safe, and it resulted in encouraging signs of antitumor activity in patients with advanced solid tumors.

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx).

BACKGROUND: No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB. METHODS: Adult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint. RESULTS: Between June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0-1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events. CONCLUSION: The combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1.

Patients with neurofibromatosis type 1 (NF1) have an increased lifetime risk for the development of nervous system tumors, including high-grade gliomas (glioblastoma). NF1 is associated with the loss of expression of neurofibromin 1 (NF1 gene product). This hyperactivates the mitogen-activated protein kinase pathway, leading to cellular proliferation and survival. MEK-inhibitor monotherapy is a promising treatment strategy in this setting, but is associated with distinct adverse events, most prominently cutaneous toxicity. We report the case of a young NF1 patient with a recurrent, heavily pretreated mesencephalic glioblastoma who was treated with the MEK-inhibitor trametinib (2 mg once daily). A partial response was documented, but unfortunately, he developed dose-limiting cutaneous toxicity (rash, paronychia). Based on interim results of a phase 2 trial in advanced BRAF V600 wild-type melanoma indicating that a low dose of the BRAF-inhibitor dabrafenib is able to counter trametinib-related cutaneous toxicity, dabrafenib 50 mg twice daily was added. The cutaneous adverse events gradually recovered after addition of dabrafenib to trametinib. The patient eventually achieved a durable complete response, has excellent tolerance of his treatment and remains fully active.

An atypical sarcoid-like reaction during anti-protein death 1 treatment in a patient with metastatic melanoma.

We report a case of anti-protein death 1-induced sarcoid-like reaction in a 63-year-old Caucasian male who was diagnosed with stage IV-M1a melanoma. He was initially treated with pembrolizumab monotherapy (Q3W) and had a complete response after 14 cycles. However, relapse was suspected 3 months later with appearance of hilar, mediastinal and hepatic hilar lymph nodes as well as a skin lesion. Biopsy of both the hilar lymph nodes and the skin lesion demonstrated sarcomatoid granulomatosis. Pembrolizumab was discontinued temporarily. While on F-FDG-PET/CT, all sarcoid-like lesions regressed in size and activity, a new hypermetabolic solitary skeletal lesion was detected in a lumbar vertebra, suspicious for metastasis. However, since the patient was asymptomatic, a watchful-waiting attitude was taken. During this period, a spontaneous and complete resolution of the metabolic activity was observed of the skeletal lesion. Until today, the patient remains in complete remission. Current case presents an atypical presentation and evolution of anti-PD-1-induced sarcoid-like reaction, illustrating the difficulty of differentiating it from disease progression. Before considering (re-)initiation of anti-melanoma therapy, a tissue biopsy of one of the suspected lesions may be performed to confirm diagnosis. Physicians treating patients with ICI should be aware of this difficulty and critically assess the nature of lesions suspect of progression in patients responding to ICI and presenting with a sarcoid-like reaction.