A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma.

PURPOSE: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small-molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases. MATERIALS AND METHODS: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients and an initial evaluation of efficacy after 13 patients. RESULTS: From April 2018 to April 2019, 13 patients were enrolled. Patients were predominantly female (69%) with a median age of 64 years (34-76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months. CONCLUSIONS: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition. SIGNIFICANCE: Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy.

Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases. OBJECTIVES: This retrospective study aimed to assess potential relationships between primary tumour site and site of initial distant metastasis, time to distant metastasis, overall survival (OS) and MCC-specific death (MSD). METHODS: Patients with local or regional (Stage I-III) disease who were treated with curative intent and progressed to Stage IV were included in this study (n = 151). Fisher's exact test was used to assess differences in patterns of initial distant metastases based on primary tumour site. Time to initial distant metastasis was calculated from date of MCC diagnosis. OS and MSD were calculated from date of initial distant metastasis to date of death from any or MCC-related causes, respectively. RESULTS: Of 151 patients included in analysis, 89 (58.9%) had a single initial distant metastatic site, and 62 (41.1%) had multiple sites. Patients with upper limb primary tumours were significantly less likely to develop distant lymph node or liver metastases (p = 0.02 and 0.04, respectively). Median time to distant metastasis was 11 months (IQR 6.7-17.9 months). Median OS was 15.3 months, and was shorter for patients with liver (7.0 months, p = 0.0004) or bone metastases (8.9 months, p < 0.0001). Using skin/soft tissue metastasis as a reference group, patients with multiple metastatic sites had significantly higher hazards of MSD (HR = 3.46 univariate, 3.77 multivariate analysis). Time to distant metastasis, OS and MSD did not differ by viral status. CONCLUSION: Sites of initial distant metastasis are related to primary tumour sites and survival outcomes. Because patients often have multiple initial metastases, full-body cross-sectional rather than region-specific imaging may facilitate earlier detection of metastatic disease.

Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors. METHODS: We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival. RESULTS: Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper. CONCLUSION: mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals [ClinicalTrials.gov identifier: NCT04339062]).

Multicenter Evaluation of Radiation and Immune Checkpoint Inhibitor Therapy in Mucosal Melanoma and Review of Recent Literature.

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM. Methods and Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020. Recurrence rates were estimated using cumulative incidence in the presence of the competing risk of death. Results: Mucosal sites were head/neck (n = 29, 78%), vaginal (n = 7, 19%), and anorectal (n = 1, 3%). Patients received ICI prior to or concurrent with RT (n = 14, 38%), following RT (n = 5, 14%), or at recurrence (n = 18, 49%). The objective response rate for evaluable patients was 31% for ICI as initial treatment (95% CI, 11%-59%) and 19% for ICI at recurrence (95% CI, 4%-46%). Median follow-up was 26 months for living patients; median overall survival (OS) was 54 months (95% CI, 31 months-not reached). Two-year OS was 85%; distant metastasis-free survival 44%. The 2-year cumulative incidence of local recurrence (LR) was 26% (95% CI, 13%-41%). For 9 patients with unresectable disease, 2-year OS was 88% (95% CI, 35%-98%); LR was 25% (95% CI, 3%-58%). For 5 patients with positive nodes at diagnosis, 2-year OS was 100%; LR was 0%. Conclusions: High rates of local control were achieved with RT with or without oncologic resection and ICI for localized and locally advanced MM. In particular, favorable local control was possible even for patients with unresectable or node-positive disease. Although risk of distant failure remains high, patients with MM may benefit from aggressive local therapy including RT in the setting of immunotherapy treatment.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.

Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance.

BACKGROUND: We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. METHODS: Using Vessel Architectural Imaging (VAI), a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial- and venous-dominance, and vascular permeability were measured before and after treatment with pembrolizumab. RESULTS: BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend towards a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI. CONCLUSIONS: This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

Exploring anxiety as an influencing factor of the impact of exercise and mind-body prehabilitation on cognitive functioning among women undergoing breast cancer surgery.

OBJECTIVE: The purpose of this secondary analysis was to describe the prevalence of anxiety, depression, and perceived stress among women newly diagnosed with breast cancer and the impact of baseline and changes in anxiety on cognitive functioning following exercise and mind-body prehabilitation interventions. METHODS: The sample consisted of 49 women with newly diagnosed breast cancer (stages I-III) who planned to undergo breast cancer surgery at two academic cancer centers. Participants were randomized to receive an exercise or mind-body prehabilitation intervention between the time of diagnosis and breast cancer surgery. Participants completed self-report measures of anxiety, depression (HADS), perceived stress, and cognitive functioning (EORTC-QLQ-C30) at study enrollment and prior to surgery (post-intervention). The relationships between change in cognitive functioning and change in anxiety among all participants were estimated using linear regression modeling. RESULTS: A significant proportion of women with newly diagnosed breast cancer had clinically significant anxiety (34.0%). Greater anxiety was moderately associated with worse cognitive functioning (r = -0.33) at baseline. Linear modeling found that changes in cognitive functioning and anxiety were inversely related: Each one-unit decrease in anxiety was associated with a two-unit improvement in cognitive function (p = .06). CONCLUSIONS: Anxiety was common in women with newly diagnosed breast cancer and was related to worse cognitive functioning. Assessment of anxiety at the time of diagnosis may allow for earlier anxiety management and subsequent improvement in cognitive functioning.

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy.

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

EDIL3 as an Angiogenic Target of Immune Exclusion Following Checkpoint Blockade.

Immune checkpoint blockade (ICB) has become the standard of care for several solid tumors. Multiple combinatorial approaches have been studied to improve therapeutic efficacy. The combination of antiangiogenic agents and ICB has demonstrated efficacy in several cancers. To improve the mechanistic understanding of synergies with these treatment modalities, we performed screens of sera from long-term responding patients treated with ipilimumab and bevacizumab. We discovered a high-titer antibody response against EGF-like repeats and discoidin I-like domains protein 3 (EDIL3) that correlated with favorable clinical outcomes. EDIL3 is an extracellular protein, previously identified as a marker of poor prognosis in various malignancies. Our Tumor Immune Dysfunction and Exclusion analysis predicted that EDIL3 was associated with immune exclusion signatures for cytotoxic immune cell infiltration and nonresponse to ICB. Cancer-associated fibroblasts (CAF) were predicted as the source of EDIL3 in immune exclusion-related cells. Furthermore, The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) and CheckMate 064 data analyses correlated high levels of EDIL3 with increased pan-fibroblast TGFß response, enrichment of angiogenic signatures, and induction of epithelial-to-mesenchymal transition. Our in vitro studies validated EDIL3 overexpression and TGFß regulation in patient-derived CAFs. In pretreatment serum samples from patients, circulating levels of EDIL3 were associated with circulating levels of VEGF, and like VEGF, EDIL3 increased the angiogenic abilities of patient-derived tumor endothelial cells (TEC). Mechanistically, three-dimensional microfluidic cultures and two-dimensional transmigration assays with TEC endorsed EDIL3-mediated disruption of the lymphocyte function-associated antigen-1 (LFA-1)-ICAM-1 interaction as a possible means of T-cell exclusion. We propose EDIL3 as a potential target for improving the transendothelial migration of immune cells and efficacy of ICB therapy.

Pancreatitis and Hyperlipasemia in the Setting of Immune Checkpoint Inhibitor Therapy.

BACKGROUND: Immune checkpoint inhibitor-induced pancreatic injury (ICI-PI) ranges from asymptomatic hyperlipasemia to symptomatic acute pancreatitis (AP). The proportion of pancreatic injury while receiving ICIs that is attributable to therapy remains unclear. We evaluated the etiology of hyperlipasemia in patients receiving ICIs, and the clinical characteristics, management, and outcomes of ICI-PI. PATIENTS AND METHODS: We assessed 6,450 consecutive adult patients with cancer who received ICI doses between 2011 and 2019, 364 of whom had at least 1 instance of elevated serum lipase after ICI initiation and were included in our trial. Primary outcomes were the development of ICI-PI and ICI-induced acute pancreatitis (ICI-AP). RESULTS: Pancreatic injury was attributable to ICI use in 105 individuals (29% of those with hyperlipasemia; 1.6% overall). Of 27 patients with ICI-AP, 4 (15%) presented asymptomatically with hyperlipasemia and pancreatic inflammation on imaging. In multivariable regression, the presence of other immune-related adverse events was positively associated with ICI-AP (≥2 events: odds ratio, 5.43; 95% CI, 1.47-26.03). Compared with patients with other ICI-PI, those with ICI-AP more frequently required steroids (74% vs 4%), intravenous fluids (85% vs 10%), hospitalization (89% vs 9%), and permanent cessation of ICIs due to pancreatic injury (70% vs 3%), and less frequently continued therapy uninterrupted (0% vs 40%) (P<.01 for all). Of the 105 patients, 3 (3%) developed exocrine insufficiency and 9 (9%) developed endocrine insufficiency, which were concentrated among those with ICI-AP. CONCLUSIONS: A minority of occurrences of pancreatitis and hyperlipasemia in patients receiving ICIs are due to these therapies, supporting NCCN recommendations to exclude alternative etiologies. Because a notable proportion of patients with ICI-AP were asymptomatic but warranted treatment per current guidelines, abdominal imaging is diagnostically valuable in those with significant hyperlipasemia. Patients with ICI-AP should be monitored for exocrine pancreatic insufficiency. Many with hyperlipasemia who do not meet the criteria for AP can continue therapy uninterrupted.

Prognostic Value of Inflammatory Bowel Disease-associated Biomarkers in Patients With Immune Checkpoint Inhibitor Enterocolitis: A Retrospective Cohort Study.

In the emerging field of immune checkpoint inhibitor enterocolitis, biomarkers to predict disease course are lacking. Select genetic polymorphisms (ATG16L1T300A) and serum amyloid A warrant further study as potential biomarkers associated with severe ICI enterocolitis.

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.

Granulocyte-Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade.

With the successful development of immune checkpoint blockade, there remains the continued need to improve efficacy and decrease toxicities. The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to ipilimumab has previously demonstrated both an improvement in efficacy and decrease in the incidence of high-grade adverse events. ICOS+CD4+ or ICOS+CD8+ peripheral blood T cells are significantly greater in the patients treated with ipilimumab plus GM-CSF than in the patients treated with ipilimumab alone. To better understand the effects of GM-CSF on inducible T-cell costimulator (ICOS) and clinical outcomes, the relative roles of identified soluble ICOS and membrane-bound ICOS were evaluated. The ICOS splice variant was secreted and found to have immunologic suppressive effects. Changes in soluble ICOS splice variant levels in treated patients correlated with clinical outcomes. GM-CSF enhanced membrane-bound ICOS in an IL12-dependent manner but did not increase soluble ICOS levels. Whereas soluble ICOS plays a role in immune suppression, GM-CSF efficacy involves increasing membrane-bound ICOS and induction of dendritic cell development. Thus, soluble ICOS splice variants may be used as a biomarker for GM-CSF and immune checkpoint blockade-based therapies.

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients.

PURPOSE: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS: The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.

Diffuse large B-cell lymphomas have spatially defined, tumor immune microenvironments revealed by high-parameter imaging.

Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common aggressive non-Hodgkin lymphoma and a biologically heterogeneous disease. Despite the development of effective immunotherapies, the organization of the DLBCL tumor-immune microenvironment (TIME) remains poorly understood.We interrogated the intact TIME of 51 de novo DLBCLs with triplicate sampling to characterize 337 995 tumor and immune cells using a 27-plex antibody panel that captured cell lineage, architectural, and functional markers. We spatially assigned individual cells, identified local cell neighborhoods, and established their topographical organization in situ. We found that the organization of local tumor and immune cells can be modeled by 6 composite cell neighborhood types (CNTs). Differential CNT representation divided cases into 3 aggregate TIME categories: immune-deficient, dendritic cell-enriched (DC-enriched), and macrophage-enriched (Mac-enriched). Cases with immune-deficient TIMEs have tumor cell-rich CNTs, in which the few infiltrating immune cells are enriched near CD31+ vessels, in keeping with limited immune activity. Cases with DC-enriched TIMEs selectively include tumor cell-poor/immune cell-rich CNTs with high numbers of CD11c+ DCs and antigen-experienced T cells also enriched near CD31+ vessels, in keeping with increased immune activity. Cases with Mac-enriched TIMEs selectively include tumor cell-poor/immune cell-rich CNTs with high numbers of CD163+ macrophages and CD8 T cells throughout the microenvironment, accompanied by increased IDO-1 and LAG-3 and decreased HLA-DR expression and genetic signatures in keeping with immune evasion. Our findings reveal that the heterogenous cellular components of DLBCL are not randomly distributed but organized into CNTs that define aggregate TIMEs with distinct cellular, spatial, and functional features.

A phase I/II study of LY3022855 with BRAF/MEK inhibition in patients with Melanoma.

BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition.

BACKGROUND: Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy. METHODS: We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110. RESULTS: Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached). CONCLUSION: MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

Brief Communication on Pathologic Assessment of Persistent Stable Metastatic Lesions in Patients Treated With Anti-CTLA-4 or Anti-CTLA-4 + Anti-PD-1 Therapy.

Despite the wide use of immune checkpoint inhibition for the treatment of melanoma, the mechanisms leading to long-term stable disease are incompletely understood. Patients with metastatic melanoma who had received ipilimumab alone or ipilimumab plus nivolumab 2+years prior and attained at least 6 months of stable disease were identified. Positron emission tomography/computed tomography (PET/CT) was performed. Pretreatment and posttreatment biopsies of areas of stable disease were assessed for tumor, fibrosis, and inflammation. Seven patients underwent PET/CT and tissue biopsy. Fluorodeoxyglucose avid lesions on PET/CT ranged from no activity to an SUV of 22. In 6 patients, the residual stable lesions were composed of necrosis and fibrosis with a prominent pigment containing macrophages and no residual melanoma. In 1 patient, a nodal lesion demonstrated melanoma with active inflammation. In most patients with durable stable disease after treatment with ipilimumab or ipilimumab/nivolumab, residual lesions demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest ongoing immune surveillance. One patient did demonstrate residual melanoma, indicating the need for ongoing monitoring of this patient population.