OBJECTIVE Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) with- out brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course. METHODS A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests. RESULTS Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021). CONCLUSIONS ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

Supplemental Figure S1. Levels of serum cytokines in patients over the course of treatment. Serum levels of the cytokines IFN-γ (A), IP-10 (B), TNF-α (C) MIP-1α (D), MIP-1β (E), RANTES (F), GM CSF (G), and IL-8 (H) were measured at baseline and during cycle 8 using a custom V-Plex assay. Assay was performed in triplicate and the average was plotted for each individual patient. *, p=0.0008 for IFN-γ, p=0.0011 for IP-10, p=0.0102 for TNF-α Supplemental Figure S2. Levels of serum cytokines in patients stratified by length of progression-free survival. Serum levels of the cytokines MIP-1α (A), MIP-1β (B), RANTES (C), GM-CSF (D), and IL-8 (E) were measured at baseline and during cycle 8 using a custom V-Plex assay. The assay was performed in triplicate and the average was plotted for each individual patient stratified by progression-free survival greater than or less than 100 days Supplemental Figure S3. Gating strategy for defining monocytic and granulocytic MDSC. Examples of monocytic-dominant (A) and granulocytic-dominant (B) total MDSC. PBMCs procured from pre-therapy blood draws were stained with anti-CD33-APC, anti-HLA-DR-PECy7, anti-CD11b-PE, anti-CD14-V-450, and anti CD15-FITC antibodies; CD33+/HLA-DR- populations were further characterized by CD15, CD14, and CD11b expression. Percentages gleaned from CD15+CD11b+ and CD14+CD11b+ quadrants were back multiplied by total MDSC (CD33+HLA-DR-) to obtain values presented in Table S3.

Supplemental Figure 1. Tumor infiltrating Treg; Supplemental Figure 2. Treg and IFNï§-CD8.

Supplementary Table 1. Toxicities; Supplementary Table 2. Patient characteristics and response evaluation; Supplementary Table 3. Patient Correlative Study Results

Objective(s): Vismodegib, a unique hedgehog pathway inhibitor, has been demonstrated to be effective in the treatment of non-operable and metastatic basal cell carcinoma (BCC). While effective, concerns regarding its role in the development of cutaneous squamous cell carcinoma (CSCC) remain. The primary objective is to describe a unique case of locally advanced BCC of the face and subsequent transformation to CSCC following treatment with vismodegib. Methods: Case report. Results: A 64-year-old Caucasian female presented with a 3-year history of a progressive and erosive lesion involving the entirety of her forehead with involvement of the left medial canthus and upper eyelid. Biopsies performed at the periphery of the lesion demonstrated superficial and nodular BCC. As surgical management would result in significant morbidity, the patient elected for treatment with oral vismodegib, 150 mg daily, with curative intent. Dramatic tumor response was experienced over an 18-month period; however, surveillance MRI demonstrated concern for tumor progression at the periphery of the mass without evidence of intracranial extension or metastases. Subsequent biopsies at the superior and left supraorbital margins demonstrated invasive SCC. Following immunohistochemistry analysis, intravenous nivolumab, 480 mg monthly was initiated; the patient remains progression-free after 18 months of therapy. Conclusion: This case highlights the importance of close surveillance in patients treated with vismodegib for nonoperable BCC. Serial biopsies of new or suspicious appearing tumors should be performed given the potential for CSCC transformation.

BackgroundMerkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.MethodsIn this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.ResultsOverall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.ConclusionsThis study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.Trial registration numberNCT02267603.

Patient survival with renal cell carcinoma (RCC) has improved with the use of molecular targeted agents and immunotherapy. Given the potential activity of these agents in treating brain metastases, the role of aggressive local management with surgery and/or radiation may diminish. The aim of this study was to evaluate the role of aggressive local therapy for RCC brain metastasis in the setting of molecular targeted agents and/or checkpoint inhibitor therapy. A retrospective single-center review between 2011-2018 identified patients that developed brain metastasis from RCC. Data analyzed included demographic information, systemic treatments, intracranial interventions, progression free survival and overall survival (OS). Of 1194 patients, 108(9.0%) were diagnosed with brain metastasis from RCC. OS from diagnosis of brain metastasis (OSBM) was 12.3 months. OSBM was analyzed based on three treatment groups: systemic therapy (ST) only (2.0 months, n = 23), systemic and radiotherapy (RT + ST) (12.3 months, n = 52), and systemic and radiotherapy plus resection (Surg + RT + ST) (21.7 months, n = 33). Survival benefit was seen with Surg + RT + ST compared to ST (P = 0.001), but not RT + ST (P = 0.081). Progression free survival was significantly prolonged with Surg + RT + ST compared to RT + ST (10.9 vs 5.9 months, respectively, P = 0.04). Variables such as performance status and number of brain metastases at the time of brain metastasis diagnosis did not differ significantly. In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate. Prospective clinical trials are necessary to better understand the role of aggressive RCC brain metastasis treatment. Micro Abstract • Renal cell brain metastasis is often excluded from studies and brain metastases effect a large portion of RCC patients. • Retrospective study of 1194 RCC patients, 108 patients had brain metastasis, determination of the role of surgical resection in the setting of recent advances in checkpoint inhibitors. • A benefit was seen in overall survival in patients that had surgical while undergoing radiation therapy and systemic therapies. • In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate(s).

Approximately 7% of deceased donors have unknown cancer at the time of organ procurement. More than half of these have no apparent contraindication to organ donation. The commonest transmitted malignancy is renal cell cancer (19%), followed by melanoma (17%). Donor transmission of melanoma has been fatal in most cases as it is commonly metastatic at the time of diagnosis. Till date, there have been only a few cases with remission of melanoma following transplant nephrectomy and withdrawal of immunosuppression. To our knowledge, the evidence presented here is only the second case of donor-derived melanoma that was successfully treated with Ipilimumab. Our patient has the longest disease-free survival (five years) reported in the literature to date.

Abstract INTRO Programmed cell death protein 1 (PD1)-inhibitor, nivolumab, and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-inhibitor, ipilimumab, have been shown to be efficacious in treatment of metastatic renal cell carcinoma (RCC). Clinical trials utilizing PD1- and CTLA4-inhibitors to treat RCC have demonstrated an increase in survival, however history of brain metastases (BM) has typically excluded patients from these trials. This study evaluated the benefit of these agents in terms of overall survival from RCC diagnosis (OSRCC), from BM diagnosis (OSBM) and frequency of BM occurrence in patients with metastatic RCC. METHODS A retrospective single-center review between 2011–2018 identified 1149 patients treated for RCC. The study group included patients who received immunotherapy and/or non-immunotherapeutic agents during the course of their disease. Data analyzed included demographic information, systemic treatments, OS and status of BM. Two-sided Fisher’s exact test was used to evaluate frequency of BM occurrence. OSRCC and OSBM were assessed using Kaplan-Meier curves and log-rank tests. RESULTS Of 1149 patients, 425 (35.6%) were treated with systemic therapies during their clinical course and divided into two treatment groups: those receiving immunotherapy (n=125) and those receiving non-immunotherapeutic agents (n=300). OSRCC was improved in the immunotherapy group (80.3months 95%CI 58.7–101.9 vs 45.0 95%CI 36.4–53.6, p=0.003), with 1-, 3- and 5-year survival of 93.6%, 74.2% and 62.6%. BM were diagnosed in 113 of 425 patients. Use of immunotherapy was associated with increased OSBM (21.7months vs 8.5, p=0.001). In patients receiving systemic treatment prior to a potential BM diagnosis, BM occurred at a frequency of 8.0% in the immunotherapy group compared to 17.7% for the control (n=100 and n=266 respectively, p=0.021). CONCLUSION Immunotherapy not only improves OSRCC and OSBM, but also decreases the incidence of BM in patients with metastatic RCC. Prospective clinical trials are needed to further evaluate the activity of immunotherapy in treatment of RCC BM.

PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus–positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1–positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION Here, we present the longest observation to date of patients with aMCC receiving first-line anti–programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

Checkpoint inhibitors like programmed cell death-1 (PD1) are changing the way we envisage the prognostication of metastatic carcinomas. Binding of PD1 to PD1-ligand unleashes the power of naturally occurring antitumor T cells by suppressing T-cell migration, proliferation, and cytotoxic activities.1 The flipside of the interruption of the PD1-PDL1 interaction in the kidney transplant is the potential impairment of Forkhead box P3+ regulatory T cell–mediated graft tolerance leading to rejection and making these agents somewhat taboo in this population.1 We report a case of successful treatment of metastatic carcinoma with nivolumab (PD1 inhibitor) and preserved kidney function. A 71-year-old female, status post deceased donor kidney transplant (5 of 6 HLA mismatch, 2A, 2B, and 1DR) in 2004 for autosomal dominant polycystic kidney disease and coincident native nephrectomy underwent induction with antithymoglobulin, glucocorticoid, and maintenance with tacrolimus and mycophenolate. She was diagnosed with Merkel cell cancer (January 2016) and underwent left lateral neck dissection and radiation therapy (May 2016). We discontinued tacrolimus, reduced mycophenolate to half, and initiated prednisone 5 mg/d. In December 2016, she had metastasis to liver and spine. After a lengthy discussion, we commenced nivolumab and prednisone (10 mg), and discontinued mycophenolate. Prior mammalian target of rapamycin inhibitors intolerance precluded their use. Given the literature experience of immediate rejection post-PD1 therapy, we simultaneously prepared her for peritoneal dialysis.2-5 She completed 13 cycles of nivolumab (240 mg, 3 mg/kg per month) without any significant side effects. She had a significant improvement in the quality of life with complete resolution of cancer-related pain and went from a house-confining weakness to driving and shopping on her own. At 1 year of follow-up, renal function remained stable, with negative donor-specific antibodies, a weight gain of 4 kg (52 from 48 kg), serum albumin of 4.3 g/dL, and no further progression of cancer on serial imaging. The 1-year trends of creatinine, eGFR, and urine protein/creatinine is illustrated in Figure 1.FIGURE 1: Line graph representation of creatinine, eGFR, urine protein/creatinine over 1 year period.To date, of the 5 kidney transplant recipients treated with PD1 inhibitors, 4 developed immediate acute rejection and graft loss.2-5 To our knowledge, our case is the second only in the literature of successful treatment without evidence of rejection.5 Given the history of metastatic cancer and no compelling clinical indications, we did not perform a renal biopsy. Though renal function remained stable, in the absence of a biopsy, a potential subacute rejection could not be ruled out. Both our case, and the previous successful case, underwent native nephrectomy.5 It might be mere coincidence or could be a signal to some tolerance pathways triggered by native nephrectomy. To avoid immune-mediated side effects, we used a reduced frequency of nivolumab than general practice (monthly rather than twice monthly). This might be the possible mechanism which helped our patient in maintaining the tolerance to the transplanted kidney and avoiding rejection. The ideal dose and frequency to treat malignancy while avoiding rejection is an area of future research. The skepticism around PD1 inhibitors in renal transplant will continue given lack of supporting case reports. Based on our experience, PD1 inhibitors that are considered contraindication in renal transplantation could still be an option for a selected group of patients.

Melanoma is a highly immunogenic tumor and consequently, efforts have been centered on the development of immune-based treatments for this malignancy [1]. Interferons were initially described in the mid-1950s as proteins that interfere with viral replication [2, 3]. Interferons are cytokines that activate Janus kinases (Jak), which lead to phosphorylation and activation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family [4, 5]. Interferon-alpha (IFN-α) became available for use in clinical trials in the mid-1980s [6]. Results suggested that IFN-α inhibited the proliferation of malignant cells and stimulated immune effectors; therefore, IFN-α was initially used in patients with advanced disease [7, 8]. Since then, several meta-analyses have demonstrated that high-dose adjuvant IFN-α (daily 20 MU/m2 intravenous induction therapy for 1 month followed by maintenance subcutaneous 10 MU/m2 three times per week for at least 1 year) can prolong the disease-free interval in high-risk melanoma patients [9]. The introduction of checkpoint inhibitor therapy has revolutionized the adjuvant therapy of melanoma; however, there remains a role for IFN-α in this setting based on the potential for cancer immune escape or autoimmune events with CTLA-4 and PD-1 blocking antibodies [10–14]. There has also been significant advances in mitogen-activated protein kinase (MAPK) targeted therapies, particularly for BRAF (an intracellular signaling kinase) and MEK (signaling molecule downstream of BRAF). A recent clinical trial demonstrated significant improvement in both relapse-free survival and overall survival with adjuvant dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) in patients with stage III melanoma. These therapies are now approved for adjuvant therapy in BRAF mutated tumors [15]. However, since only approximately 40–50% of melanoma cells harbor an activating BRAF mutation, there still remains a role for IFN-α in this setting as the remaining 50–60% of melanomas would not be susceptible to BRAF-targeted therapies. IFN-α activates the Jak-STAT signaling pathway and induces synthesis of hundreds of different proteins [4, 5]. Our group has shown that STAT1-mediated gene regulation within immune effectors is necessary for mediating the anti-tumor effects of IFN-α and also that the amount IFN-α administered to melanoma patients is likely in excess of the optimal biological dose [4]. Indeed, high doses of IFN-α appear to be no more effective in the induction of phosphorylated STAT1 (p-STAT1) and in the transcription of interferon-stimulated genes (ISGs) than intermediate doses [16, 17]. Our group’s studies in genetically manipulated mice have shown that suppressors of cytokine signaling-1 (SOCS1) and SOCS3 negatively regulate IFN-induced Jak-STAT signal transduction, gene regulation and anti-melanoma activity, and that high doses of IFN-α can induce SOCS proteins [18, 19]. We hypothesized that lower doses of IFN-α would be superior for induction of IFN signal transduction in patient immune cells. A prospective clinical trial was performed wherein patients eligible for adjuvant IFN-α-2b received 1 month of standard intravenous high-dose IFN-α-2b (20 MU/m2) followed by subcutaneous IFN-α-2b at a dose of 10 MU/m2 with dose reductions at set intervals down to a level of 4 MU/m2. Jak-STAT signal transduction and transcription of ISGs in patient peripheral blood mononuclear cells (PBMCs) were monitored during the course of adjuvant IFN-α therapy. The objective of this pilot study was to determine if lower doses of IFN-α were as effective in the induction of IFN signal transduction and gene expression as the standard high dose regimen.

BACKGROUND:Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. METHODS:We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811. FINDINGS:Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). INTERPRETATION:Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. FUNDING:Pfizer.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence. J Natl Compr Canc Netw 2018;16(6):742–774 doi: 10.6004/jnccn.2018.0055 NCCN Categories of Evidence and Consensus Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise noted. Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please Note The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way. The full NCCN Guidelines for Merkel Cell Carcinoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org. © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. Disclosures for the NCCN Merkel Cell Carcinoma Panel At the beginning of each NCCN Guidelines panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself. Individual disclosures for the NCCN Merkel Cell Carcinoma Panel members can be found on page 774. (The most recent version of these guidelines and accompanying disclosures are available on the NCCN Web site at NCCN.org.) These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

Purpose Cabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor-targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR. Patients and Methods Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers. Results For patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus (hazard ratio, 0.33 [95% CI, 0.21 to 0.51]). Median OS was also longer with cabozantinib (20.1 months v 12.1 months; hazard ratio, 0.54 [95% CI, 0.34 to 0.84]), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases. Conclusion Cabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.

AbstractPurpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro. Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891–904. ©2018 AACR.

4517 Background: Standard of care treatment in mRCC after checkpoint inhibitor (CPI) therapy includes VEGFR TKIs, though no prospective data have been published. Axitinib (Axi) is a VEGF-R inhibitor with prior clinical data supporting increased efficacy with dose titration. The existing titration schema of 5mg BID to 7mg BID to 10mg BID every 4 weeks, however, can lead to toxicity due to the magnitude of dose increases. A prospective, multi-center phase II trial of Axi given on an individualized dosing algorithm in mRCC after treatment with CPI was conducted (NCT02579811). Methods: Patients (pts) with clear cell mRCC, adequate organ function and measurable disease whose most recent therapy was anti PD-1 / PD-L1 treatment were eligible. Pts were treated with Axi 5mg BID starting dose with upward dose titration in 1mg BID increments (e.g. 5mg BID to 6mg BID, up to 10mg BID max dose) every 14 days if there was no grade (G) 2 Axi-related mucositis, diarrhea, hand-foot-syndrome, or fatigue. If G2 adverse events (AEs) occurred, pts took a 3-day break then resumed the same dose. Recurrent G2 AEs despite treatment breaks or G3/4 AEs resulted in dose reduction in 1mg BID increments. The primary outcome was progression free survival (PFS) with 38 pts needed to improve PFS from 6.5 months (based on retrospective data of TKI post-CPI) to 9.5 months (a = 0.10; power 80%). Results: The trial has completed accrual (n = 38): 74% male, median age 64, 89% KPS ≥80%, 16%/66%/19% IMDC favorable/intermediate/poor risk, 94% prior nephrectomy, 71% ≥ 2 prior therapies. Most recent therapy was 89% anti PD-1 (63% nivolumab monotherapy; 17% ipilimumab/nivolumab; 9% other) or 11% anti PD-L1 (6% atezolizumab; 3% bevacizumab/atezolizumab; 3% durvalumab). In evaluable pts, the estimated median is PFS 9.2 months, with 54% of pts still on Axi. The ORR is 38.7% (best response PR 38.7%, SD 48.3%, and PD 12.9%). The median highest dose per pt was 6mg BID (range, 5-9) and 44% of pts required dose reduction to < 5mg BID. There were no unexpected toxicities related to Axi. Conclusions: Axitinib on an individualized titration schema resulted in robust clinical efficacy after checkpoint inhibitor therapy. Clinical trial information: NCT02579811.

106 Background: We performed a Phase II study of the combination of the autophagy inhibitor, hydroxychloroquine (HCQ), along with high dose IL-2 in patients with advanced renal cancer. 31 patients were entered on this Cytokine Working Group Study conducted at six member institutions;NCT01550367. This combination in murine models was associated with diminished toxicity and increased efficacy, and, in preliminary studies, diminished high mobility group box 1 (HMGB1) protein, consistent with its established role in serving as a Damage Associated Molecular Pattern (DAMP) molecule and inducer of autophagy. Methods: The Study Design involved initiating oral Hydroxychloroquine 300 mg P.O bid. Aldesleukin (600,000 IU/kg) was administered q8hrs in courses consisting of two cycles separated by 7-14 days and constituting a single course. For patients with stable or responsive disease, additional courses were administered every approximately 85-90 days. Serum, plasma, Paxgene tubes, and peripheral blood mononuclear cells were obtained sequentially prior to therapy initiation and sequentially on D1 and D2 of each cycle following initiation of therapy. Results: 31 patients (9F, 22M) have been registered and 3 confirmed complete responses observed; the current median overall survival has not been reached in the 29pts. The Baseline Karnofsky Score of 100 (17pts), 90 (13pts), and 80(1 pt). The mean age was 57.5 years, range = (45.2, 68.8). 26 patients had a mean of 12.5 doses +/-4.7 (3, 23) with 13 pts receiving a second course and 4, a third. Platelet nadir was diminished from baseline by 26%. Of the 27 patients in the data set, 18 had at least one Grade 4 toxicity at least possibly related to treatment, and 9 patients had at least one Grade 3 adverse event at least possibly related to treatment but no Grade 4 events.Serologic and cellular data and complete clinical data will be submitted with the completed abstract. Conclusions: The combination of high dose aldesleukin and daily oral HCQ was well tolerated. We have concluded this trial and will report mature survival data, toxicity data, and biomarkers/autophagy measures with the final submission. Clinical trial information: NCT01550367.