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Nonmelanoma skin cancers (NMSCs), which encompass a variety of cutaneous malignancies, are frequently managed with surgery, radiation therapy, cytotoxic chemotherapy, systemic immunotherapy, and active surveillance. In this tumor board–style forum, a panel of experts used several case studies as a basis to review these approaches and to describe existing clinical challenges. The current NCCN Guidelines for NMSC, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of NMSCs, also provide key considerations and recommendations for the treatment of this patient population.

Purpose:Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%–50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.Experimental Design:We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.Results:Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.Conclusions:Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.

BackgroundNeoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM.MethodUnder an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities.ResultsWe identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients.ConclusionNeoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients.

Background The last revision of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual included a specific system for cutaneous squamous cell carcinoma (CSCC) of the head and neck. Here, we assessed the prognostic performance of six candidate modified T-classification models in head and neck CSCC patients. Methods Analysis of 916 patients with head and neck CSCC given treatment with curative intent at The University of Texas MD Anderson Cancer Center between 1995 and 2019 was performed. The main outcome was disease-specific survival (DSS), and the impact of depth of invasion (DOI) was analyzed using multivariable regression models. Candidate models were developed using the optimal DOI cut points for each AJCC T classification based on goodness of fit of the model and the simplicity of the model. Staging systems were compared using Harrell's concordance index. Results Median age was 70 years (range, 19–97years) and median follow-up time of 22 months (range, 1–250months). The median DOI was 6.0 mm (range, 0.1–70.0 mm). The five-year DSS rate was 80.7% (95%CI, 77.4–83.7%). We found significant association between DOI (hazard ratio, 1.21 [95%CI: 1.01–1.43]) and DSS on multivariable analysis. Based on a low Akaike information criterion score, improvement in the concordance index, and Kaplan–Meier curves, model 6 surpassed the AJCC staging system. Conclusions Incorporation of DOI in the current AJCC staging system improves discrimination of T classifications in head and neck CSCC patients. Lay summary The current staging system for head and neck cutaneous squamous cell carcinoma demonstrates wide prognostic variability and provides suboptimal risk stratification. Incorporation of depth of invasion in the T-classification system improves risk prediction and patient counseling. Precis We propose improved head and neck cutaneous squamous cell carcinoma T staging that will include depth of invasion and should be considered in future versions of the American Joint Committee on Cancer after external validation.

Background The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. Methods This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. Results No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). Conclusions The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.

Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms.To develop recommendations for the care of adults with EMPD.A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD.The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

BackgroundThe adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen–loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses.DesignWe tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival.ResultsTen patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8+ TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated.ConclusionsThe combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups.Trial registration numberNCT00338377.

Background The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. Methods The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. Results A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. Conclusions Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.

The use of immune-checkpoint inhibitors (CPI) has become an important modality in the treatment of metastatic melanoma (MM). However, most patients (pts) do not experience durable responses and new treatment options are needed to improve clinical outcomes. Our pre-clinical studies have demonstrated that intratumoral CD40 activation synergizes with anti-PD-1 based therapy and induces systemic and distant anti-tumor effects. In this ongoing phase I/II study, we assessed intratumoral sotigalimab (APX005M), a CD40 agonist antibody, in combination with systemic pembrolizumab in CPI treatment naïve, unresectable stage III or IV MM. A total of 40 participants will be enrolled. As of December 15, 2021, 30 pts were enrolled. Pts received sotigalimab every 3 weeks for a total of 4 doses. The dose escalation portion of the trial has been completed, with 14 pts enrolled in 5 dosing cohorts of sotigalimab at 0.1, 0.5, 1, 3 and 10 mg. The primary objectives include safety and tolerability, determination of the recommended phase 2 dose (RP2D), and assessment of the overall response rate (ORR) by RECIST v1.1. Biomarker analyses of blood and tumor samples were performed to measure immune activation using immunophenotyping including imaging mass cytometry, TCR sequencing, and a cross-cohort comparison of gene expression data (sotigalimab plus pembrolizumab versus anti-PD1 monotherapy). The combination therapy has been well-tolerated, and there were no study discontinuations or death due to treatment-related adverse events (TRAEs). Most common TRAEs were injection-site reactions; six pts experienced grade-3 immune-related adverse events. Efficacy analysis of 30 pts with post-baseline disease evaluations demonstrated an ORR of 50% (5 CR and 10 PR) in distant lesions and a disease control rate of 67%. The ORR at the RP2D of 10 mg is 55% (12/22). Responses were observed in PD-L1 negative pts and those with elevated LDH. Comprehensive transcriptome and immune cell profiling of peripheral blood mononuclear cells and tumor biopsies obtained from local lesions at baseline and 24 hours post sotigalimab injection demonstrate that sotigalimab effectively engaged CD40 pathway. In comparison to anti-PD1 monotherapy, the combination therapy significantly increased expression of genes associated with antigen presentation and effector T cells in local lesions accompanied by an increase in T cell activation genes at distant lesions. Additionally, T cell repertoire analysis demonstrated a significant increase in T cell clonality with expansion of new clones shared between local and distant tumors. Importantly, these immunologic changes were correlated with clinical response. Collectively, this combination therapy is well tolerated and has a notable clinical response rate, accompanied by broad innate and adaptive immune activation at both local and distant lesions. Citation Format: Salah-Eddine Bentebibel, Daniel Johnson, Rodabe Amariae, Daniel McGrail, Srisuda Lecagoonporn, Cara Haymaker, Dzifa Duose, Khalida Wani, Houssein Safa, Isabella Claudia Glitza, Sapna Pradyuman Patel, Michael K. Wong, Hussein Tawbi, Jared Burks, Xiaodong Yang, Patrick Hwu, Cassian Yee, Michael A. Davies, Ravi Murthy, Chantale Bernatchez, Suhendan Ekmekcioglu, Adi Diab, Gregory Lizée. Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT039.

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses over adjuvant treatment1; however, optimal regimens have not been defined. Herein, we report results from a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs), and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results are the first to describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

Background Anti‐programmed cell death protein 1 (PD‐1) antibodies are a standard treatment for metastatic melanoma patients. However, the understanding of the efficacy of anti‐PD‐1 for acral melanoma (AM) and mucosal melanoma (MM) is limited as these subtypes are relatively rare compared to cutaneous melanoma (CM). Methods This single institution, retrospective cohort study included patients with advanced AM and MM who underwent anti‐PD‐1 therapy for metastatic melanoma between 2012 and 2018. Objective responses were determined using the investigator‐assessed Response Evaluation Criteria in Solid Tumors version 1.1. Progression‐free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier method. A Cox regression analysis was performed to identify the factors associated with survival outcomes. Results Ninety‐seven patients were identified, 38 (39%) with AM and 59 (61%) with MM. The objective response rates (ORRs) were 21.0% and 15.2% in patients with AM and MM, respectively. The median PFS and OS were 3.6 and 25.7 months for AM patients, and 3.0 and 20.1 months for MM patients, respectively. Elevated serum lactate dehydrogenase (LDH) (AM: hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06–0.87; p = 0.03, MM: HR, 0.20; 95% CI, 0.08–0.53; p = 0.001) was significantly associated with shorter OS for both subtypes. Conclusions The ORR, PFS, and OS with anti‐PD‐1 therapy were poor in patients with AM and MM compared to those previously reported clinical trials for nonacral CM. High serum LDH was associated with significantly shorter OS.

Background The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN). Methods Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival. Results Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score. Conclusions Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy.

Background Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has shown great benefit in patients with melanoma.1,2 It was suggested that long term tumor immunosurveillance is provided by TIL persisting after transfer. Dendritic cells (DC) are professional antigen presenting cells and have the ability to optimally activate T lymphocytes.3 We hypothesized that the combination of autologous TIL containing a population of HLA-A0201 restricted MART-1 reactive CD8+ TIL with autologous MART-1 antigen-pulsed DCs will result in enhanced proliferation and prolonged survival of the transferred antigen-specific T cells in vivo, thus leading to improved clinical responses. Methods This is a randomized phase II trial of lymphodepleting chemotherapy followed by autologous TILs ± DC vaccine and high dose Interleukin-2 (IL-2) for patients with metastatic melanoma. Patients were randomized to receive TIL alone or TIL + DCs pulsed with MART-1 peptide. The primary objective was to determine whether patients receiving TIL + DCs have sustained persistence of infused T cells compared to patients treated with TIL alone. Secondary endpoints included evaluation of tumor response and survival. Results A total of 18 patients with stage IV melanoma were treated; 89% with stage M1c, including 56% with brain metastasis; 17% had high LDH level. All but one patient were checkpoint naive prior to TIL. Ten patients received TIL alone and eight received TIL + DC. Treatments were well tolerated with no grade 5 adverse events. There were no toxicities conferred by the DC vaccination. The ORR was 63% (5/8) in TIL + DC arm (1 CR, 4 PR) and 40% (4/10) in TIL arm alone (1 CR, 3 PR) (P=0.64). There was no statistically significant difference in survival between the arms. The median progression-free survival (PFS) was 3.6 months in the TIL arm and 7.2 months in the TIL+DC arm, while the median overall survival (OS) was 4.1 years in the TIL arm and 2 years in the TIL+DC arm. Tracking of the infused MART-1 reactive CD8+ T cells in the blood over time by flow cytometry showed no difference in persistence between the two arms. Conclusions ACT with TILs has robust response in checkpoint naive advanced melanoma patients. Despite numerically higher response rate in the TIL+DC arm, due to small patient number there was no statistically significant difference between the arms. Further testing of this approach in a prospective trial post-ICI is warranted. Trial Registration All metastatic melanoma TIL lines were derived from tumor tissue obtained from patients enrolled on the TIL ACT clinical trial [institutional review board (IRB)-approved protocol# 2004-0069, NCT00338377] at The University of Texas MD Anderson Cancer Center. Ethics Approval The United States Food and Drug Administration and the Institutional Review Board at MD Anderson Cancer Center approved the study. This study was conducted according to the principles from the Declaration of Helsinki. Consent All study participants granted a written informed consent prior to treatment initiation. References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62–8. Forget MA, Haymaker C, Hess KR, Meng YJ, Creasy C, Karpinets T, et al. Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome. Clin Cancer Res. 2018;24(18):4416–28. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma–specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus–negative subgroup. Combining SDom with CD3+ or CD8+ T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3+ or CD8+ T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3+ or CD8+ T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3+ or CD8+ had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.

Summary Background Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. Methods We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775. Findings Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6–23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2–not estimable] vs 2·9 months [95% CI 1·7–not estimable]; hazard ratio 0·016, 95% CI 0·00012–0·14, p Interpretation Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III–IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. Funding Novartis Pharmaceuticals Corporation.

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Background Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. Methods Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. Results Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14–79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92–32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3–22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. Conclusions SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0585-1) contains supplementary material, which is available to authorized users.

Background Melanoma brain metastases (MBM) occur in up to 50% of patients with metastatic melanoma (MM) and represent a frequent site of systemic treatment failure for targeted therapies. However, to the authors' knowledge, little is known regarding the incidence, patterns of disease progression, and outcomes of MBM in patients treated with anti-PD-1 immunotherapy. Methods A total of 320 patients with MM who were treated with anti-PD-1 at The University of Texas MD Anderson Cancer Center in Houston were reviewed. Analyses were performed to identify factors associated with brain metastasis-free survival and overall survival (OS) using Cox regression models. Results The median age of the patients was 63.3 years. OS from the initiation of anti-PD-1 therapy was not significantly different between patients without MBM prior to anti-PD-1 compared with patients with prior MBM (P = .359). Among patients without prior MBM, 21 patients (8.6%) developed MBM during anti-PD-1 therapy, 12 of whom (4.9%) presented with disease progression in the central nervous system (CNS) only. Developing MBM during or after therapy with anti-PD-1 (hazard ratio, 4.70; 95% CI, 3.18-6.93) was associated with shorter OS. Among patients with MBM prior to anti-PD-1 treatment, 15 (20.0%) progressed in the CNS only and 19 (25.3%) progressed both intracranially and extracranially; at the time of the last data cutoff, 27 patients (36.0%) had not developed disease progression. Radiation necrosis occurred in 11.3% of patients (7 of 62 patients) in the group with a prior MBM who received stereotactic radiosurgery. Conclusions Anti-PD-1 therapy may change the natural history of patients with preexisting MBM. However, CNS failure during treatment with anti-PD-1 is predictive of a worse prognosis compared with extracranial progression. The results of the current study support the activity of anti-PD-1 in patients with MBM, although routine CNS imaging during therapy is warranted.

In the U.S., prospective clinical trial data regarding nivolumab plus ipilimumab for metastatic uveal melanoma have yet to be reported. Here we present clinical data regarding responders to nivolumab plus ipilimumab that occurred in the context of a prospective clinical trial. NCT01585194 is an open-label, phase II study of nivolumab in combination with ipilimumab for the treatment of metastatic uveal melanoma. Patients with confirmed metastatic uveal melanoma received nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by up to 2 years of nivolumab maintenance. Response was evaluated using irRC beginning at week 12 and every 12 weeks thereafter. Responses were rare, but were seen in 3 patients, all female, with a mean age of 48. These subjects had hepatic M1b metastases (67%) and extrahepatic M1a metastasis (33%), and all three patients experienced a partial response at the first restaging, after 4 doses of Nivo/Ipi. Two additional patients, who came off study after two doses prior to response evaluation, one due to protocol-limiting hyperglycemia, and the other due to hyperuricemia and AKI, with M1b and M1a hepatic metastases, respectively, experienced partial responses. The first of these patients continued on additional Nivo/Ipi and developed a partial response 6 months after clinical trial initiation. The second patient never resumed additional treatment for metastatic disease. Her restaging scans 2 months after clinical trial initiation showed partial response; five months after initiation, her response continues with >70% reduction in tumor burden. Responders to Nivo/Ipi had the following immune-mediated toxicities: endocrinopathy, vitiligo, diarrhea, pneumonitis, transaminitis, hyperglycemia, and nephritis. Baseline tissue analysis on one of the responders showed sheets of cytotoxic T lymphocytes invading the tumor in a biopsy specimen. Responses to Nivo/Ipi in metastatic uveal melanoma are not confined to extrahepatic sites. In our study, 4 of 5 (80%) responses were seen in hepatic metastases. Durability of responses and impact on overall survival remain to be seen, and tissue-based exploratory correlative studies are under way. Citation Format: Michael Paul Shephard, Maura Glover, Gener Balmes, Suzanne Cain, Anna Vardeleon, Rosalind Mouton, Liberty Posada, Rinata Simien, Patrick Hwu, Michael Davies, Cassian Yee, Michael Wong, Hussein Tawbi, Scott Woodman, Rodabe Amaria, Adi Diab, Isabella Glitza, Wen-Jen Hwu, Sapna Patel. Clinical characteristics of responders to nivolumab plus ipilimumab (Nivo/Ipi) in metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A13.

In contrast to cutaneous melanoma, central nervous system (CNS) metastasis from uveal melanoma are uncommon, occurring in less than 5% of uveal patients. There is no published literature describing the features or survival of this unique population. Here we describe the clinical characteristics and outcomes of uveal melanoma CNS metastasis patients. We performed an MD Anderson Cancer Center institutional database review from 1999–2017 for consecutive uveal melanoma patients with CNS metastasis. Excluding dural-based metastases, 19 patients were identified. Ethnic makeup was 84% White, 11% Hispanic, 5% other, and median age at diagnosis was 52.4 years. The gender distribution was 12 (63%) female and 7 (37%) male. Primary tumor location in the uveal tract was 26% choroid, 11% iridociliary, 5% chiliochoroidal, and 58% not otherwise specified. Seven of 19 (37%) patients were treated with enucleation; 63% received radiation therapy for primary uveal melanoma. Median interval from diagnosis of uveal melanoma to diagnosis of CNS metastasis was 5 years. Only 7 patients had molecular testing for mutations. Of these, all had G-alpha mutations: 4 (57%) with GNAQ, and 3 (43%) with GNA11 hotspot mutations in Q209. At the time of data cutoff, 14 of 19 (74%) patients were deceased. Additional clinical information regarding treatment for CNS metastasis, histopathologic evaluation, and overall survival will be presented at the meeting. Citation Format: Sapna P. Patel, Patrick Hwu, Michael Davies, Michael Wong, Hussein Tawbi, Rodabe Amaria, Adi Diab, Dan Gombos, Isabella C. Glitza. Characteristics of uveal melanoma patients with central nervous system metastases [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A09.

10067 Background: Metastatic melanoma pt outcomes have been revolutionized by targeted therapy (TT) and immune checkpoint blockade (ICB), which are now being evaluated in the neoadjuvant (neoadj) setting. While tumor-based biomarkers may help predict response, predictors of response obtained by less invasive strategies could greatly benefit pt care and allow real-time treatment response monitoring. Radiomic signatures derived from computerized tomography (CT) images have recently been shown to predict response to ICB in stage IV pts. However, the association of radiomic features with pathological response following neoadj therapy has not been assessed. We sought to determine if radiomic assessment predicts pCR in pts receiving neoadj TT and ICB. Methods: We collected data for a cohort of melanoma pts with locoregional metastases who were treated with neoadj TT (n = 33) or ICB (n = 30). Pts received systemic therapy for 8-10 weeks prior to planned surgical resection. Responses were evaluated radiographically (RECIST 1.1) and via pathological assessment (evaluating for pathologic complete response; (pCR) versus < pCR). Thirty two pts (19 ICB; 13 TT) were included in the radiomics analysis based on the availability of appropriate CT imaging. A total of 310 unique radiomic features (10 histogram-based and 300 second-order texture features) were calculated from each extracted volume of interest (VOI). Feature extraction was performed on baseline and initial on-treatment pre-operative CT scans. Features associated with pCR were assessed using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of pCR to ICB or TT. Leave-One-Out Cross-Validation was performed to evaluate the robustness of the estimates. Results: Out of 310 radiomic features, three features measured at baseline were able to predict a pCR to neoadj ICB or TT with sensitivity, specificity and accuracy of 100%, though these signatures were non-overlapping. In the on-treatment pre-operative scans, 3 distinct features (also non-overlapping and distinct from the predictive pre-treatment signatures) also predicted pCR to ICB and TT with 100% sensitivity, specificity and accuracy. Conclusions: Radiomic signatures in baseline and on-treatment CT scans accurately predict pCR in melanoma pts with locoregional metastases treated with neoadj TT or ICB. These provocative findings warrant further investigation in larger, independent cohorts.

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

INTRODUCTION: There is evidence that the combination of ipilimumab and stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We investigated clinical outcomes, radiation toxicity, and impact of ipilimumab timing in patients treated with SRS for melanoma brain metastases. METHODS: We retrospectively identified 91 patients treated with SRS at our institution for melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration was defined as within ±4 weeks of SRS procedure. Acute and late toxicities were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain failure, and failure-free survival were analyzed with the Kaplan–Meier method. OS was analyzed with Cox regression. RESULTS: Twenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. The median age was 62 years and 91% had KPS ≥ 80. The median follow-up time was 7.4 months. Patients who received ipilimumab had a median OS of 15.1 months compared to 7.8 months in patients who did not (p = 0.02). In multivariate analysis, ipilimumab (p = 0.02) and diagnosis-specific graded prognostic assessment (p = 0.02) were associated with OS. There were no differences in intracranial control by ipilimumab administration or timing. The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab. CONCLUSIONS: Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.

Objectives Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis, with a median survival measured in weeks, and few treatment options. Outcomes of a retrospective cohort of patients with LMD that were treated with intrathecal interleukin-2 (IT IL-2) were reviewed to assess the long-term efficacy of this therapy. Methods The records of metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug study were reviewed. IL-2 (1.2 mIU) was administered intrathecally via Ommaya reservoir up to five times per week in the inpatient setting for 4 weeks; patients with good tolerance and clinical benefit received maintenance IT IL-2 every 1–3 months thereafter. Results The cohort included 43 patients. The median age of the patients was 47 years (range 18–71), and 32 (74%) were male. 23 patients (53%) had positive cerebrospinal fluid (CSF) cytology and radiographic evidence of LMD, 8 (19%) had positive CSF cytology only, 9 (21%) had radiographic evidence only and 3 (7%) were diagnosed based on pathology review after craniotomy. The median overall survival (OS) from initiation of IT IL-2 was 7.8 months (range, 0.4–90.8 months), with 1-year, 2-year and 5-year OS rates of 36%, 26% and 13%. The presence of neurological symptoms (HR 2.1, P=0.03), positive baseline CSF cytology (HR 4.1, P=0.001) and concomitant use of targeted therapy (HR 3.0, P=0.02) was associated with shorter OS on univariate analysis. All patients developed symptoms due to increased intracranial pressure which was managed with supportive medications and/or CSF removal, and there were no treatment-related deaths. Conclusion These results demonstrate that despite their historically dismal prognosis a subset of metastatic melanoma patients with LMD treated with IT IL-2 can achieve long-term survival, but these data need to be verified in a prospective trial setting.

Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in‐frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5′ fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall‐cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p, What's new? New results may help target a rare genetic alteration that promotes cancer. Activation of the BRAF gene is already known to spur tumor growth, and usually that activation results from a single amino acid substitution. BRAF‐inhibiting treatments, then, target that mutation. However, in some cases, BRAF gets revved up by a gene fusion. In our study, the authors tested 20,000 tumors and identified 55 BRAF gene fusions in 12 different tumor types. They found the gene fusions occurred more frequently in certain histologic subtypes, information which will help guide treatment strategies for patients with these tumor subtypes.

Background: There is a growing appreciation for the GM in response to melanoma therapy. Recent work identified a favorable (T1) GM signature associated with checkpoint benefit. However, little is known about how lifestyle factors may influence features of the GM or about the influence of the GM on therapeutic outcomes to other common melanoma therapies. Methods: We prospectively collected fecal samples melanoma patients at MD Anderson Cancer Center and characterized the GM via 16S rRNA sequencing (n=146). In a subset initiating systemic therapy (n= 113), we also collected baseline diet information via the NCI dietary screener questionnaire, and probiotic and antibiotic use and followed for response (RECISTv1.1). We compared GM beta diversity (BD)(Bray-Curtis) with ANOSIM and descriptive statistics and Wilcoxon tests were applied to alpha diversity (AD)(Chao1) among treatment response groups. Spearman correlation was used to test relationships of dietary groups and GM composition. Univariate and multivariate logistic regression models were used to determine the individual and joint effects of lifestyle factors on response. Receiver operating characteristic (ROC) curves were constructed for area under the curve (AUC) quantification. Results: Considering all treatment groups, baseline AD was highest in patients with complete/partial response (mean=355), compared to patients with stable (mean=330) and progressive disease (mean=318). The GM did not significantly differ by age, sex or BMI. Report of probiotic (42%) and antibiotic (29%) use at baseline was associated with lower AD (p=0.02). Whole grains and overall diet quality correlated positively with pro-response bacteria, added sugars and processed meat negatively correlated. GM community structure (BD) differed by high and low fiber intake (p Conclusion: AD of the GM varies by response regardless of treatment type. While preliminary, this data points to the idea that the GM in melanoma patients may be negatively influenced by probiotics and could be targeted by dietary manipulation. Larger prospective and interventional studies are needed to assess the relationships between host lifestyle factors, the GM and response to melanoma therapies. Citation Format: Christine N. Spencer, Vancheswaran Gopalakrishnan, Jennifer McQuade, Miles C. Andrews, Beth Helmink, M.A. Wadud Khan, Elizabeth Sirmans, Lauren Haydu, Alexandria Cogdill, Elizabeth Burton, Rodabe Amaria, Sapna Patel, Isabella Glitza, MIchael Davies, Eliza Posada, Wen-Jen Hwu, Adi Diab, Kelly Nelson, Hussein Tawbi, Michael Wong, Robert R. Jenq, Lorenzo Cohen, Carrie Daniel-MacDougall, Jennifer A. Wargo. The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2838.

Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT.Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs.Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14-79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92-32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3-22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs.SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.

Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX.Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints.Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p 0.001), median times to diarrhea resolution (3 vs. 9 days; p 0.001) and to steroid titration (4 vs. 13 days; p 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group.Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.

To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US.Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments.A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib.Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected.In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820–9. ©2012 AACR.

Background: It is unclear whether anti-PD and BRAFi therapy should be administered sequentially or concurrently in patients (pts) with BMMM, although clinical trials using varying strategies are ongoing. We performed a retrospective, single-center analysis of BMMM pts who received anti-PD therapy either sequentially or concurrent with BRAFi therapy. Methods: A total of 457 metastatic melanoma pts (excluding uveal) were treated with anti-PD therapy at MD Anderson Cancer Center from 11/2009-12/2015. Of those, 148 pts had BMMM and were categorized into 4 treatment groups: BRAFi-naïve treated with anti-PD alone (group 1) N=39 (26%); BRAFi-naive treated with combination therapy (group 2) N=30 (20%); BRAFi-refractory treated with anti-PD alone (group 3) N=45 (31%); and BRAFi-refractory treated with combination therapy (group 4) N=34 (23%). Clinical outcomes were analyzed and tabulated for each group. Pretreatment tissue samples were obtained for correlative biomarker immunohistochemistry (IHC) analyses. Results: BMMM pts with elevated LDH are more likely to receive upfront combination therapy. BRAFi-refractory pts have a higher incidence of brain metastases than BRAFi-naïve pts. The clinical outcomes of overall responses, median PFS and OS are provided in the table. Preliminary biomarker IHC analyses in 11 pts showed PD-L1 expression on the tumor cells correlated with median PFS and OS : 15 mo and 22 mo, respectively in 7 pts with PD-L1 >1%, vs. 6.5 mo and 12 mo in 4 pts with PD-L1 GroupLDH > upper limit normal (%)Prior CNS metastases (%)Prior anti CLTA-4 exposure (%)Number of anti PD-1 doses (#)Overall Responses CRs + PRs (%)Median PFS (mo)Median OS (mo)Group 1 BRAFi-naïve; anti-PD alone23.72317.912.530.8 + 25.6= 56.41021Group 2 BRAFi-naïve; combination37.9206.710.523.3 + 43.3 = 66.6 812.5Group 3 BRAFi- refractory; anti-PD alone254073.31637.8 + 17.8= 55.6925Group 4 BRAFi- refractory; combination17.644.172.711.529.4 + 5.9 = 35.3519 Citation Format: Rodabe N. Amaria, Van A. Trinh, Jun Gu, Susan McIntyre, Carlos Torres Cabala, Rinata Simien, Adi Diab, Hussein A. Tawbi, Michael A. Davies, Michael K. Wong, Patrick Hwu, Isabella C. Glitza, Sapna P. Patel, Wen Jen Hwu. Treatment strategies using anti-PD1/PD-L1 (anti-PD) and BRAF/MEK inhibitor (BRAFi) therapy: a retrospective study comparing sequential vs. concurrent administration in BRAF-mutated metastatic melanoma (BMMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3640.

Introduction: Although immune checkpoint inhibitors have improved survival for many with MM, most pts do not respond and median PFS is only 6 months for single agent therapy. Cancers subvert the cellular epigenetic machinery to facilitate immune escape. Epigenetic mechanisms of resistance are potentially reversible by DNA hypomethylating agents (HMA). Based on preclinical models, we hypothesized that CC-486, an oral HMA, will enhance response to PEMBRO in PD-1 naïve pts and reverse resistance in anti-PD-1 refractory pts. The aim of this study is to determine the safety, efficacy, and characterize the pharmacodynamic impact of CC-486 + PEMBRO on immune infiltrates in pts with MM. Experimental: NCT02816021 is an ongoing phase II study of CC-486 + PEMBRO in MM pts who are PD-1 naïve (Arm A) or who have progressed on prior PD-1 directed therapy (Arm B). Pts receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO q3 weeks. Serum and tumor biopsies are obtained at baseline, prior to cycles 3 and 5. Immune monitoring studies were performed by the Immunotherapy Platform at MD Anderson. Immune cell phenotyping by CyTOF was performed using 36 metal-conjugated antibodies targeting myeloid and T cell surface markers. FCS files were exported and manually gated for lymphocytes using FlowJo (version 10.1) and subjected to multidimensional phenographic analysis. Results: Thirteen pts (Arm A, n=6; Arm B, n=7) have been enrolled. Two of the 3 pts remaining on study are PD-1 naïve and have received 13 and 8 cycles of CC-496 + PEMBRO with partial responses by RECIST1.1 at 6 months, respectively. One pt on Arm B remains on study with stable disease after 4 cycles. The combination was considered safe after a run-in phase (6 pts/arm treated without DLTs) and the study is open to full accrual. The most common grade 3/4 AEs were leukopenia , neutropenia, vomiting, and diarrhea (2 each) with 1 grade 5 AE unrelated to treatment (hepatic rupture/bleeding due to progressive disease). Serum and tumor biopsies from 6 pts (3 per Arm) were available for interim analysis, with additional samples in process. Of these 6 pts, 1 pt (PD-1 naïve) responded to therapy by RECIST1.1. We evaluated the blood and tumor samples by CyTOF. In the tumor samples, we observed an increase in frequency of T cells in 2 PD-1 naïve patients but did not observe similar changes in PD-1 refractory patients in this small cohort. Similar data was found with immunohistochemistry. These changes were not observed in the blood samples. Conclusion: The regimen CC-486 + PEMBRO is not marrow suppressive and is well tolerated. Changes in the peripheral lymphocyte cell populations upon treatment are not necessarily concordant with changes occurring in the tumor. Analysis of collected samples is ongoing and will be presented at the meeting, and will help corroborate initial findings and yield further insight into the effect of this combination on the immune response. Citation Format: Emily Z. Keung, Isabella C. Glitza, Elizabeth Burton, Rodabe N. Amaria, Sapna P. Patel, Adi Diab, Cassian Yee, Michael K. Wong, Wen-Jen Hwu, Patrick Hwu, Scott E. Woodman, Michael T. Tetzlaff, Nallely Trujillo-Conley, Denai R. Milton, Michael A. Davies, Kunal Rai, Irina Fernandez, Jorge M. Blando, Luis M. Vence, Padmanee Sharma, James P. Allison, Jennifer A. Wargo, Hussein Tawbi. The impact of combination oral azacitidine (CC-486) + pembrolizumab (PEMBRO) on the immune infiltrate in metastatic melanoma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5711.

Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials.Two separate chart sets (2009 - 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI).Prognostic factors for OS have been identified and validated in separate samples.One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months - higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score80%, duration of mRCC1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 - 2 risk factors, 63% for 3 risk factors and 22% for 4 - 5 risk factors (log-rank p0.001).Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.

The most active metabolite of vitamin D, calcitriol, is growth inhibitory for various tumor types in vitro and in vivo and inhibits the growth of endothelial cells freshly isolated from tumors [tumor-derived endothelial cells (TDEC)]. We compared the effects of calcitriol on Matrigel-derived endothelial cells (MDEC) and TDEC isolated from Matrigel plugs and squamous cell carcinoma tumors, respectively. TDEC and MDEC expressed vitamin D receptor (VDR) and responded to calcitriol by increasing VDR protein expression. Although no mutations were found in VDR from either cell type, Scatchard plot analysis revealed a higher ligand-binding affinity in TDEC (Kd, 0.26 nmol/L) than MDEC (Kd, 0.65 nmol/L). The VDR signaling axis in both cells was intact as shown using nuclear translocation and 24-hydroxylase promoter-luciferase reporter assays. However, unlike TDEC, MDEC were resistant to calcitriol-induced growth inhibition. Calcitriol (10 nmol/L) resulted in a 12.3% growth inhibition of MDEC compared with 47% in TDEC. In TDEC, calcitriol resulted in induction of G0/G1 arrest (10.75%) and reduction of S-phase cells (6.8%) with induction of p27 and down-regulation of p21 protein expression. Apoptotic effects, determined by Annexin V staining were also observed in calcitriol-treated TDEC (38.6%). Calcitriol caused reduced expression of p-Erk and p-Akt and an increase of poly(ADP-ribose) polymerase and caspase-3 cleavage in TDEC. By contrast, none of these effects on cell cycle or apoptosis were seen in calcitriol-treated MDEC. These results show that TDEC were more sensitive than MDEC to the antiproliferative effects of calcitriol despite apparently normal VDR content and structure of signaling axis in both cell types. (Cancer Res 2006; 66(17): 8565-73)

9574 Background: Limited OS data, including prognostic and predictive factors of response, is available in mm pts treated with immune checkpoint inhibitors. Methods: A single-institution retrospective review was conducted on 696 mm pts treated with single-agent anti CTLA-4 or anti PD-1 on and off clinical trial between 2011-2015. Median OS was calculated from mm diagnosis. Results:Median age at mm diagnosis was 60 years old (range 15-86) and 65.2% were male. Subtypes were 63.2% non-acral cutaneous, 17.2% unknown primary, 7.8% mucosal, 6.5% acral, and 5.3% uveal. AJCC v7 staging at diagnosis was 7.9% M1a, 16.5% M1b, 33.0% M1c, and 42.5% not staged due to unknown LDH. LDH was elevated in 18.0% (400 pts). Mutation rates were 30.0% BRAF V600E/K (636 pts tested) and 24.5% NRAS (429 pts tested). First-line therapy for BRAF V600E/K mm pts included anti CTLA-4 (24.1%), BRAF/MEK targeted therapy (21.5%) and anti PD-1 (8.9%). First-line therapy for BRAF WT mm pts included anti CTLA-4 (28.1%) and anti PD-1 (12.8%). Median OS from mm for the cohort was 36.5 months (95% CI 33.3-44.9). Elevated LDH and staging correlated with OS (p < 0.001, p < 0.001, respectively) on univariate analysis. Age, gender, subtype and mutation status were not significantly associated with OS. Compared to BRAF WT, pts with BRAF V600E/K mutation were younger (median = 53 vs 62 yrs, p < 0.001), more likely to have non-acral cutaneous mm (83.2% vs 58.0%, p < 0.001) and have a diagnosis of brain metastasis during the disease course (57.0% vs 28.8%, p < 0.001). While adjusting for stage, there was no significant difference in OS based on first or second line therapy in pts with BRAF V600E/K mm or first line therapy in BRAF WT MM; however, BRAF WT pts treated second line with anti-PD1 were observed to have improved OS compared with pts receiving anti-CTLA 4 (HR 0.43 95% CI:0.23-0.84 p = 0.012). Conclusions: This study demonstrates that LDH and stage are prognostic of OS in all mm pts treated with single agent immune therapy. Second line therapy in BRAF WT pts treated with single agent immune therapy is also prognostic of OS thus prompting further investigation to determine advantageous therapy sequencing in MM.

TPS9594 Background: Immune checkpoint inhibitors have impressive response rates and improved survival for many pts with MM, offering durable responses in up to 35% of pts while others have short-lived or no response ( > 40%). A potentially targetable mechanism for immune escape is for cancers to subvert the cellular epigenetic machinery, affecting multiple aspects of the immune response from suppression of tumor antigen expression [such as Cancer Testis Antigens (CTA)] to antigen processing and presentation, thus allowing tumor proliferation to continue undetected. In preclinical models, decitabine (DAC), a DNA hypomethylating agent (HMA), has been able to revert heterogeneous CTA expression profiles, increasing cancer cell immunogenicity. HMAs also increased TH1-chemokine expression, T cell tumor infiltration, T cell-mediated tumor killing, and have been shown to be synergistic with checkpoint inhibitors in preclinical models. This suggests that epigenetic therapy with checkpoint inhibition is a rational combination to target MM. Clinical advantages of the HMA CC-486 over DAC include oral bioavailability and potential versatility in dosing and schedule. We hypothesize that CC-486 + PEMBRO will be tolerated at biologically relevant doses; enhance response to PEMBRO in pts with mm who are PD-1 naïve; and reverse resistance to immunotherapy in pts refractory/resistant to PD-1 directed therapy. Methods: This study will evaluate the safety and efficacy of CC-486 + PEMBRO defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. Pts who are PD-1 naïve (Arm A, n = 36) and pts who have progressed on prior PD-1 directed therapy (Arm B, n = 35) will be enrolled. Unlimited prior systemic therapies will be allowed. Pts will receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO every 3 weeks. Continuous monitoring for toxicity and futility will be performed and assumes an ORR of > 35% and > 15% for Arms A and B, respectively (95% power). Tumor biopsies at baseline and post treatment are required. Effects of CC-486 + PEMBRO on CTAs, MDSCs and Tregs, and correlation between mutation burden and response will be studied. This study is open for enrollment. Clinical trial information: NCT02816021.

To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM).Eligible patients received ramucirumab (10mg/kg) + dacarbazine (1000 mg/m(2)) (Arm A) or ramucirumab only (10mg/kg) (Arm B) every 3 weeks. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety.Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities.Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.

Cancer registries have proven valuable with respect to validating therapeutic safety and drug efficacy, uncovering real-world implementation practices, and their evolution over time. Modern cancer therapeutics are approved as single agents oftentimes compared to the least active approved standard agent in randomized trials. However, the burgeoning diversity and number of drugs introduces a complexity that quickly outstrips the knowledge provided by these pivotal trials. This gap in information is particularly relevant when survival is the primary therapeutic endpoint. In addition, the inherent complexity of the immune response will make registries a particularly important tool in expeditiously understanding solid tumor immunotherapy and patient outcomes.

Background. Continuous infusion of 2'-deoxy-5-fluorouridine (FUdR) has shown promise in its activity against metastatic renal cell carcinoma. Its side-effect profile is dominated by gastrointestinal toxicity ; there are no known adverse pulmonary reactions. To the authors' knowledge, this is the first report on the development of lung toxicity in three patients receiving FUdR-infusion chemotherapy for metastatic renal cell carcinoma. Methods. The hospital charts of three patients presenting with pulmonary symptoms during FUdR chemotherapy were reviewed. A literature search was performed regarding FUdR-related pulmonary toxicity. Results. Nonproductive cough, dyspnea, and fever appeared within the 10th chemotherapy cycle. Chest radiographs showed interstitial disease in each case, accompanied by a restrictive pattern by pulmonary-function testing. Lung biopsies were performed on two patients showing a pattern of interstitial inflammation. Discontinuing FUdR and instituting steroidal therapy invariably improved symptoms, as was evident by chest radiographs and pulmonary function tests. In one patient, resuming FUdR treatment resulted in a recurrence of the respiratory symptoms, which was controlled with an increased steroidal dose. All three patients required low dose steroids to maintain their baseline respiratory functions. Conclusion. 2'-deoxy-5-fluorouridine-related lung toxicity is an uncommon event and occurs late in the treatment course. It is rapidly symptomatic and responds readily to steroidal therapy. Cancer 1995 ; 75 :2558-64.

The aims of this study were to quantify and contrast patient preferences between second-line advanced renal cell carcinoma (RCC) medication profiles and their associated benefits and toxicities, and to help frame the doctor-patient discussion about selecting appropriate RCC therapies.Adult residents of the US with a diagnosis of RCC completed a Web-enabled choice-format conjoint survey consisting of a series of 10 treatment-choice questions, each of which included a pair of hypothetical RCC medication profiles. Each profile was described by various medication attributes (features or outcomes) with varying levels. The attributes included efficacy (progression-free survival [PFS]), tolerability (fatigue, stomach problems, mucositis or stomatitis, hand-foot syndrome [HFS]), serious but rare adverse events (pneumonitis, hepatic impairment), and mode of administration. Treatment-choice questions were based on an experimental design with known statistical properties. Random-parameters logit regression was used to estimate relative preference weights for each attribute level. Benefit equivalent measures (additional months of PFS in exchange for toxicities) were also calculated.Of the 272 patients who completed the survey, the majority were female (53%), white (92%), and had at least a college degree (66%). The mean age was 57 years (standard deviation: 10 years). Over the range of attributes and attribute levels included in the survey, PFS was the most important attribute, followed by fatigue, stomach problems, hepatic impairment, mucositis or stomatitis, HFS, pneumonitis, and mode of administration. To reduce severe fatigue to mild-to-moderate fatigue, patients on average would be willing to forego 4.4 months of PFS. To reduce hepatic impairment risk from 0.5% to 0.0%, patients on average would be willing to forego 1.0 month of PFS. The main study limitation was that patients answered hypothetical treatment-choice questions.This study provides information to physicians about patient priorities when reviewing and selecting RCC therapies with patients.

The use of specialty pharmacies is expanding in oncology pharmacy practice. Specialty pharmacies provide a channel for distributing drugs that, from the payor perspective, creates economies of scale and streamlines the delivery of expensive drugs. Proposed goals of specialty pharmacy include optimization of pharmaceutical care outcomes through ensuring appropriate medication use and maximizing adherence, and optimization of economic outcomes through avoiding unwarranted drug expenditure. In oncology practice, specialty pharmacies have become a distribution channel for various agents. The use of a specialty pharmacy, and the addition of the pharmacist from the specialty pharmacy to the health care team, may not only provide benefits for care but also present challenges in oncology practice. The NCCN Specialty Pharmacy Task Force met to identify and examine the impact of specialty pharmacy practice on the care of people with cancer, and to provide recommendations regarding issues discussed. This report provides recommendations within the following categories: education and training of specialty pharmacy practitioners who care for individuals with cancer, coordination of care, and patient safety. Areas for further evaluation are also identified.

Meeting abstracts Patients with stable disease (SD) following cancer treatment have traditionally not been considered responders. We, and others, have previously shown that SD is an important response criteria in cancer patients treated with HD IL-2 immunotherapy [[1][1]–[5][2]]. Here we

Gemcitabine is a commonly used chemotherapy for biliary tree carcinomas, achieving response rates of 10% to 60%. Preclinical studies indicate that fixed dose rate infusion optimizes accumulation of gemcitabine triphosphate and may enhance the clinical activity of gemcitabine. We conducted a phase II study of fixed dose rate gemcitabine in 15 chemotherapy-naive patients with advanced cholangiocarcinoma and gallbladder carcinoma. Gemcitabine was administered at a dose of 1500 mg/m2 over 150 minutes weekly for 3 weeks every 28 days. Fourteen patients were evaluable for response. No complete or partial responses were observed. Two patients (13%) had stable disease lasting a median of 9 weeks. The median time to progression was 9 weeks; median survival was 20 weeks. There was considerable grade 3/4 hematologic toxicity, including neutropenia in 49% of patients, leukopenia in 40%, anemia in 27%, and thrombocytopenia in 27%. Grade 3/4 nonhematologic toxicities were minimal. We conclude that fixed dose rate gemcitabine results in significant myelosuppression and has minimal activity in patients with biliary tree carcinoma.

practice pattern and expertise to support IL-2 patients through to the threshold dose density necessary for that individual to trigger a beneficial anti-tumor immune response. These data suggest that the site’s willingness to tolerate elevated creatinine, bilirubin, and thrombocytopenia, and to use vasopressors for hypotension allows for higher number of doses that optimizes outcomes for this group of patients. Conclusion Administering HD IL-2 to maximize the number of safely administered doses/cycle may be important in achieving optimal outcomes. Changes in IL-2 practice should await the analysis of an appropriately sized prospective cohort to test this hypothesis.

Melanoma is a highly invasive disease characterized by widespread lymphatic and systemic metastases. Although angiogenesis is critical for this to occur, the responsible mechanisms within melanoma cells remain unclear. The purpose of this study is to identify factors secreted by tumor-derived melanoma cells which can mediate these processes. Serum-free conditioned medium (CM) isolated from two melanoma cell lines and four newly derived melanoma cell strains promote both the growth in culture and angiogenic outgrowth activity of HUVEC and HMEC1 in 3-dimensional (3-D) collagen gel culture. Substantial amounts of both FGF1 (acidic) and FGF2 (basic) are found in the conditioned medium (CM). The addition of neutralizing antibodies to FGF1 (5 μg/ml) and FGF2 (3 μg/ml) to the melanoma CM significantly decreased the proliferation of HUVEC and HMEC1 by (20%) and (40%), respectively, and the angiogenic activity of HMEC1 by (20%). Amlexanox (AMX) is an anti-inflammatory agent that binds intracellular S100A13, one component of the putative FGF1-secretion complexes. AMX suppresses constitutive release of FGF1, but not FGF2, from these melanoma cells. AMX-treated melanoma-CM results in significant reduction of: HUVEC mitogenic activity, endothelial migration into 3-D collagen gel as well as melanoma cell proliferation. These AMX-mediated effects correlate with a concomitant decrease of FGFR1 phosphorylation in melanoma cells. The sum of these results point to the importance of the FGF-1 pathway and nominate AMX as a significant anti-melanoma agent by virtue of its impact on both paracrine and autocrine activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1375.