Publications by authors named "Philip Friedlander"

31 Publications

Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

J Immunother Cancer 2021 Apr;9(4)

Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center, Baltimore, Maryland, USA.

Background: Merkel 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.

Methods: In 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.

Results: Overall 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.

Conclusions: This 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 Number: NCT02267603.
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http://dx.doi.org/10.1136/jitc-2021-002478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061836PMC
April 2021

A phase 1 study of NY-ESO-1 vaccine + anti-CTLA4 antibody Ipilimumab (IPI) in patients with unresectable or metastatic melanoma.

Oncoimmunology 2021 Mar 26;10(1):1898105. Epub 2021 Mar 26.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD ( = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67) CD8 T cells and decreases in RORγt CD4 T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8 T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. : Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events.
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http://dx.doi.org/10.1080/2162402X.2021.1898105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007150PMC
March 2021

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

Eur J Cancer 2021 Apr 9;147:170-181. Epub 2021 Mar 9.

Department of Dermatology, University Hospital Kiel, Kiel, Germany.

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes.

Patients And Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres.

Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis).

Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.
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http://dx.doi.org/10.1016/j.ejca.2021.01.013DOI Listing
April 2021

Current Melanoma Treatments: Where Do We Stand?

Cancers (Basel) 2021 Jan 9;13(2). Epub 2021 Jan 9.

The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.
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http://dx.doi.org/10.3390/cancers13020221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827568PMC
January 2021

Resolution of pembrolizumab-associated lichenoid dermatitis with a single dose of methotrexate.

Dermatol Online J 2020 May 15;26(5). Epub 2020 May 15.

Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

We present a 53-year-old woman with severe lichenoid dermatitis secondary to pembrolizumab therapy that was refractory to both topical and oral steroids. After almost three months without improvement, the rash was effectively combated with a single 15mg dose of methotrexate. We hope this case will help guide the management of the cutaneous adverse effects of anti-PD1 immunotherapy.
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May 2020

The use of baseline tumor size to prognosticate overall survival in stage IV melanoma patients treated with the PD-1 inhibitor pembrolizumab.

Ann Transl Med 2019 Mar;7(Suppl 1):S24

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.

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http://dx.doi.org/10.21037/atm.2019.01.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462599PMC
March 2019

A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab.

J Immunother Cancer 2018 09 18;6(1):90. Epub 2018 Sep 18.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.

Background: Anti-CTLA-4 immune checkpoint blockade is associated with immune-related adverse events (irAEs). Grade 3-4 diarrhea/colitis is the most frequent irAE requiring treatment discontinuation. Predicting high-risk diarrhea/colitis patients may facilitate early intervention, limit irAE severity, and extend treatment duration. No biomarkers currently predict for anti-CTLA-4 immunotherapy related severe diarrhea.

Methods: Whole-blood was collected pre-treatment and 30 days post-treatment initiation from patients with stage III or IV unresectable melanoma who received 15 mg/kg tremelimumab at 90 day intervals in two clinical trials. The discovery dataset was a phase II study that enrolled 150 patients between December 2005 and November 2006. The validation dataset was a phase III study that enrolled 210 patients between March 2006 and July 2007. RT-PCR was performed for 169 genes associated with inflammation, immunity, CTLA-4 pathway and melanoma. Gene expression was correlated with grade 0-1 versus grade 2-4 diarrhea/colitis development.

Results: Pre-treatment blood obtained from the discovery dataset (N = 150) revealed no gene predictive of diarrhea/colitis development (p < 0.05). A 16-gene signature (CARD12, CCL3, CCR3, CXCL1, F5, FAM210B, GADD45A, IL18bp, IL2RA, IL5, IL8, MMP9, PTGS2, SOCS3, TLR9 and UBE2C) was identified from 30 days post-tremelimumab initiation blood that discriminated patients developing grade 0-1 from grade 2-4 diarrhea/colitis. The 16-gene signature demonstrated an AUC of 0.814 (95% CI 0.743 to 0.873, p < 0.0001), sensitivity 42.9%, specificity 99.2%, positive predictive value (PPV) 90.0%, and negative predictive value (NPV) 91.4%. In the validation dataset (N = 210), the 16-gene signature discriminated patients developing grade 0-1 from grade 2-4 diarrhea/colitis with an AUC 0.785 (95% CI 0.723 to 0.838, p < 0.0001), sensitivity 57.1%, specificity 84.4%, PPV 57.1% and NPV 84.4%.

Conclusion: This study identifies a whole-blood mRNA signature predictive of a clinically relevant irAE in patients treated with immune checkpoint blockade. We hypothesize that immune system modulation induced by immune checkpoint blockade results in peripheral blood gene expression changes that are detectable prior to clinical onset of severe diarrhea. Assessment of peripheral blood gene expression changes in patients receiving anti-PD-1/PD-L1 immunotherapy, or combination anti-CTLA4 and anti-PD-1/PD-L1 immunotherapy, is warranted to provide early on-treatment mechanistic insights and identify clinically relevant predictive biomarkers.

Trial Registration: Clinicaltrials.gov , NCT00257205 , registered 22 November 2005.
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http://dx.doi.org/10.1186/s40425-018-0408-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145108PMC
September 2018

Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial.

Clin Cancer Res 2018 10 27;24(20):4937-4948. Epub 2018 Jun 27.

Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York.

Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells. In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood. Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191332PMC
October 2018

RAPID EVOLUTION OF THYROID DYSFUNCTION IN PATIENTS TREATED WITH NIVOLUMAB.

Endocr Pract 2017 Oct;23(10):1223-1231

Objective: To describe the evolution of thyroid dysfunction in a series of patients with cancer treated with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) monoclonal antibody, nivolumab.

Methods: Cases of thyroid dysfunction after initiation of checkpoint inhibitor treatment were identified from the Division of Endocrinology clinical practice at Mount Sinai Hospital, New York from April 2016 to February 2017. Charts were reviewed to identify patients treated with nivolumab with new onset of thyroid dysfunction.

Results: Nine cases of thyroid function in patients who were treated with nivolumab were identified. There were 4 male and 5 female patients, with a mean age of 66 years (range 50-76 years). Seven patients ultimately developed hypothyroidism. Five of the 7 patients developed abnormal thyroid function tests within the first 90 days of starting therapy (range 21-84 days), 3 of whom had transient hyperthyroidism. Transient hyperthyroidism evolved rapidly to hypothyroidism; elevated thyroid-stimulating hormone (TSH) levels were detected within 16 to 32 days of the last documented low TSH. In the 2 patients without a hyperthyroid phase, TSH levels >50 were found 18 to 28 days after the last normal TSH value.

Conclusion: As the use of immune checkpoint inhibitor therapy increases, the need for prompt diagnosis and treatment of drug-induced thyroid disease will become more important. As illustrated in this case series, in contrast to other causes of auto-immune thyroiditis, hypothyroidism can develop rapidly within 3 months of treatment. Close monitoring is necessary to detect the development of thyroid dysfunction and avoid preventable morbidity.

Abbreviations: Anti-TPO Abs = anti-thyroglobulin antibodies; CT = computed tomography; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; FDA = U.S. Food & Drug Administration; FDG-PET = fluorodeoxyglucose-positron emission tomography; PD-1 = programmed cell death protein-1; PD-L1 = programmed death-ligand 1; T3 = triiodothyronine; T4 = thyroxine; TG = thyroglobulin; TPO = thyroperoxidase; TSH = thyroid-stimulating hormone.
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http://dx.doi.org/10.4158/EP171832.ORDOI Listing
October 2017

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma.

J Clin Oncol 2018 06 5;36(17):1658-1667. Epub 2017 Oct 5.

Jason Chesney, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY; Igor Puzanov, Roswell Park Cancer Institute, Buffalo; Philip Friedlander, Mt Sinai School of Medicine, New York, NY; Frances Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Parminder Singh, Mayo Clinic, Phoenix, AZ; Mohammed M. Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA; John Glaspy, University of California Los Angeles School of Medicine; Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles; Lisa Chen, Jenny J. Kim, and Jennifer Gansert, Amgen, Thousand Oaks, CA; Merrick Ross, MD Anderson Cancer Center, Houston, TX; Claus Garbe, University Hospital Tuebingen, Tuebingen; Axel Hauschild, University of Kiel, Kiel, Germany; Theodore F. Logan, Indiana University Simon Cancer Center, Indianapolis, IN; Celeste Lebbé, Assistance Publique-Hôpital De Paris Dermatology and CIC Hôpital Saint Louis University Paris Diderot Sorbonne, Institut National de la Santé et de la Recherche Médicale U976, Paris, France; Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT; and Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.
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http://dx.doi.org/10.1200/JCO.2017.73.7379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075852PMC
June 2018

Development of Bell's Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report.

J Immunother 2018 01;41(1):39-41

Division of Hematology/Oncology, Tisch Cancer Institute, One Gustave L. Levy Place, New York, NY.

Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face. We report a case of Bell's palsy in a 45-year-old male patient who received 1 dose of both ipilimumab and nivolumab for the treatment of metastatic melanoma. After the resolution of symptoms, ipilimumab was permanently discontinued and single-agent nivolumab administered. The patient has remained free of neurological symptoms. This case suggests that Bell's palsy is an irAE induced by ipilimumab.
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http://dx.doi.org/10.1097/CJI.0000000000000184DOI Listing
January 2018

Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab.

J Immunother Cancer 2017 08 15;5(1):67. Epub 2017 Aug 15.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA.

Background: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions.

Methods: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset). A central panel of radiologists determined objective response using RECIST criteria. Gene expression for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene pre-treatment response-predictive classifier model was identified. An independent population (N = 150) of refractory melanoma patients receiving tremelimumab after chemotherapy enrolled in a worldwide phase II study (validation dataset). The classifier model, using the same genes, coefficients and constants for objective response and one-year survival after treatment, was applied to the validation dataset.

Results: A 15-gene pre-treatment classifier model (containing ADAM17, CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC, TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set. This model was validated in the validation set with AUCs of 0.62 (95% confidence interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year survival (95% confidence interval 0.59 to 0.75 p = 0.0002).

Conclusions: To our knowledge, this is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response. The data suggest that the model captures a biological signature representative of genes needed for a robust anti-cancer immune response. It also identifies non-responders to tremelimumab at baseline prior to treatment.
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http://dx.doi.org/10.1186/s40425-017-0272-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557000PMC
August 2017

Systemic Therapies for Late-stage Melanoma.

J Clin Aesthet Dermatol 2016 Oct 1;9(10):36-40. Epub 2016 Oct 1.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.

Late-stage melanoma is associated with high morbidity and mortality. Classic treatment methods relied on cytotoxic chemotherapy, which is limited by low response rates and significant adverse effects. Recent advances in immunogenetics have led to the advent of important new systemictreatments.Thisarticle reviews the latest therapy options for advanced melanoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104310PMC
October 2016

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.

N Engl J Med 2016 Jun 19;374(26):2542-52. Epub 2016 Apr 19.

From the University of Washington Medical Center (P.T.N., S. Bhatia, N.J.M., E.M.S., M.M.S., J.A.T., M.A.C.), Fred Hutchinson Cancer Research Center (P.T.N., S. Bhatia, S.P.F., L.L., J.A.T., M.A.C.), Cancer Immunotherapy Trials Network (S.P.F., L.L., M.A.C.), and Cancer Research and Biostatistics (A.M., L.R.S.) - all in Seattle; Johns Hopkins University School of Medicine and Kimmel Cancer Center, Baltimore (E.J.L., S. Berry, D.M.P., W.H.S., J.C.S., J.M.T., S.L.T.), and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda. (E.S.) - both in Maryland; Winship Cancer Institute of Emory University, Atlanta (R.R.K.); Merck Research Laboratories, Kenilworth, NJ (L.A., E.K.C., S.M.T., J.H.Y.); University of California, San Francisco, San Francisco (A.D.), and Stanford University, Stanford (H.E.K., K.M., S.A.R.) - both in California; Mt. Sinai Medical Center, New York (P.A.F.); Yale University, New Haven, CT (H.M.K.); and Ohio State University, Columbus (T.O.).

Background: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1.

Methods: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing.

Results: A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.

Conclusions: In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).
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http://dx.doi.org/10.1056/NEJMoa1603702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927341PMC
June 2016

Impact of inpatient radiation on length of stay and health care costs.

J Community Support Oncol 2015 Nov;13(11):399-404

Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Medical Center, Tisch Cancer Institute, New York, New York, USA.

Background: Health care costs are rising. Identifying areas for health care utilization savings may reduce costs.

Objective: To identify oncology patients receiving inpatient radiotherapy with the purpose of measuring length of stay (LoS) and hospital charges.

Methods: During July 2013 the oncology service physicians at Mount Sinai Medical Center in New York City were surveyed daily to identify patients receiving inpatient radiation. Actual LoS, acuity LoS were determined from the chart review. Expected LoS was calculated using the University Healthsystem Consortium database. Charges associated with actual LoS, acuity LoS, and expected LoS were then reported. Actual and expected LoS were compared for inpatient radiotherapy and nonradiotherapy groups.

Results: 7 patients were identified as having remained in the hospital to receive radiation treatment. In that cohort, the average actual LoS and charges per patient were 40.1 and $48,724, compared with acuity LoS and charges of 25.6 days and $34,089 and expected LoS and charges of 7.7 days and $10,028. Mean LoS and charges attributed to radiation alone amounted to 11 days and $12,514. The mean actual LoS of oncology patients admitted during the same time period who did not receive radiation was 6.7 days, compared with 40.1 days for patients who received radiation (𝑃 < .0001).

Limitations: Inability to access actual reimbursement data prevented exact cost calculations, small sample size, and single-institution focus.

Conclusions: Delivery of radiation therapy during inpatient hospitalization extends LoS and contributes to higher health care costs. Methods to facilitate the delivery of outpatient radiotherapy may result in cost savings.
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http://dx.doi.org/10.12788/jcso.0183DOI Listing
November 2015

Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.

J Am Acad Dermatol 2015 Jun;72(6):1021-6.e8

Universitätsklinikum Schleswig-Holstein, Kiel, Germany.

Background: Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation.

Objective: An efficacy and safety analysis was conducted 12 months after primary analysis.

Methods: This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility.

Results: After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration.

Limitations: Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations.

Conclusion: The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.
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http://dx.doi.org/10.1016/j.jaad.2015.03.021DOI Listing
June 2015

Bevacizumab plus ipilimumab in patients with metastatic melanoma.

Cancer Immunol Res 2014 Jul 21;2(7):632-42. Epub 2014 Apr 21.

Beth Israel-Deaconess Medical Center, Boston;

Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306338PMC
July 2014

Blood mRNA expression profiling predicts survival in patients treated with tremelimumab.

Clin Cancer Res 2014 Jun 10;20(12):3310-8. Epub 2014 Apr 10.

Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, CanadaAuthors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.

Purpose: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade.

Experimental Design: Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab.

Results: Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A four-gene model, including cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P < 0.0001).

Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2906DOI Listing
June 2014

Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

J Invest Dermatol 2014 Aug 12;134(8):2202-2211. Epub 2014 Feb 12.

Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.
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http://dx.doi.org/10.1038/jid.2014.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291112PMC
August 2014

Sweet's syndrome in a patient with metastatic melanoma after ipilimumab therapy.

Melanoma Res 2013 Dec;23(6):498-501

Departments of aHematology and Medical Oncology bPathology, Mount Sinai School of Medicine, New York, New York, USA.

Sweet's syndrome, a neutrophilic dermatosis, is a known paraneoplastic complication occurring with various malignancies. It has been infrequently reported in association with melanoma. Ipilimumab is an antibody against an inhibitory cytotoxic T-lymphocyte-associated antigen 4 receptor on T cells. It is associated with a range of immune-related toxicities. Sweet's syndrome in association with ipilimumab has been reported only briefly in the literature. However, neutrophilic infiltration has been seen in biopsies of patients with ipilimumab-associated enterocolitis. We report, in detail, the case of a woman with metastatic melanoma undergoing ipilimumab therapy. After the second cycle of immunotherapy, the patient presented with high-grade fever followed by a rash on her hands. No infectious etiology was elucidated after an extensive workup. Pathologic examination of the skin biopsy from the hands confirmed neutrophilic dermatosis. The patient was treated with systemic steroids achieving complete remission of the skin lesions. Physicians should be aware of Sweet's syndrome as a possible cutaneous side effect of ipilimumab therapy and be familiar with its management.
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http://dx.doi.org/10.1097/CMR.0000000000000017DOI Listing
December 2013

Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.

J Clin Oncol 2013 Sep 17;31(26):3182-90. Epub 2013 Jun 17.

F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute; Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital; Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA; Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR; Philip Friedlander, Mount Sinai Medical Center, New York, NY; Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO; Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Thomas F. Gajewski, University of Chicago, Chicago, IL; Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA; Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX; Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH.

Purpose: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.

Patients And Methods: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy.

Results: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment.

Conclusion: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.
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http://dx.doi.org/10.1200/JCO.2012.47.7836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878082PMC
September 2013

Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma.

J Clin Oncol 2013 Mar 11;31(9):1211-8. Epub 2013 Feb 11.

Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA.

Purpose: Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma.

Patients And Methods: Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m(2) either alone or in combination with elesclomol 213 mg/m(2) administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS.

Results: The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH.

Conclusion: The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.
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http://dx.doi.org/10.1200/JCO.2012.44.5585DOI Listing
March 2013

Oncolytic virus therapy for cancer.

Oncolytic Virother 2013 23;2:31-46. Epub 2013 Sep 23.

Department of Immunology & Microbiology, Rush University Medical Center, Chicago IL, USA; Department of Surgery, Rush University Medical Center, Chicago IL, USA.

The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers.
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http://dx.doi.org/10.2147/OV.S38901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918352PMC
August 2016

Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma.

Melanoma Res 2013 Feb;23(1):47-54

Departments of Dermatology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Melanoma is the deadliest form of skin cancer. Ipilimumab, a novel immunotherapy, is the first treatment shown to improve survival in patients with metastatic melanoma in large randomized controlled studies. The most concerning side effects reported in clinical studies of ipilimumab fall into the category of immune-related adverse events, which include enterocolitis, dermatitis, thyroiditis, hepatitis, hypophysitis, uveitis, and others. During the course of routine clinical care at Mount Sinai Medical Center, frequent hepatotoxicity was noted when ipilimumab was administered at a dose of 3 mg/kg according to Food and Drug Administration (FDA) guidelines. To better characterize these adverse events, we conducted a retrospective review of the first 11 patients with metastatic melanoma treated with ipilimumab at the Mount Sinai Medical Center after FDA approval. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, each occurred in six of 11 cases (≥grade 1), a notably higher frequency than could be expected on the basis of the FDA licensing study where elevations were reported in 0.8 and 1.5% of patients for AST and ALT, respectively. Grade 3 elevations in AST occurred in three of 11 patients as compared with 0% in the licensing trial. All cases of transaminitis resolved when ipilimumab was temporarily withheld without administration of immunosuppressive medication. During routine clinical care of late-stage melanoma patients with ipilimumab, physicians should monitor patients closely for hepatotoxicity and be aware that toxicity rates may differ across populations during ipilimumab therapy.
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http://dx.doi.org/10.1097/CMR.0b013e32835c7e68DOI Listing
February 2013

Efficacy and safety of vismodegib in advanced basal-cell carcinoma.

N Engl J Med 2012 Jun;366(23):2171-9

Mayo Clinic, Scottsdale, AZ 85259, USA.

Background: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.

Methods: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.

Results: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.

Conclusions: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).
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http://dx.doi.org/10.1056/NEJMoa1113713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278761PMC
June 2012

Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells.

Sci Transl Med 2011 Apr;3(80):80ra34

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.
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http://dx.doi.org/10.1126/scitranslmed.3002207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861895PMC
April 2011

Advances in targeted therapy for melanoma.

Clin Adv Hematol Oncol 2010 Sep;8(9):619-27

Instructor of Medicine, Department of Medical Oncology at Dana Farber Cancer Institute in Boston, Massachusetts 02115, USA.

Metastatic melanoma remains an aggressive malignancy conferring a very poor prognosis, and standard chemotherapeutic and immunologic treatments have not demonstrated an overall survival benefit. No molecularly targeted therapy is approved for the treatment of advanced melanoma. Melanoma is a molecularly heterogeneous malignancy, and optimal treatment in a given patient is likely to depend on the presence of specific molecular abnormalities. Aberrations in components of signal transduction pathways have been identified that modulate melanoma proliferation and survival. Mutations that activate the mitogen activated protein kinase (MAPK) pathway via BRAF or NRAS are present in the majority of melanomas arising on skin intermittently exposed to the sun. Mutations that activate the KIT oncogene are more commonly present in melanomas arising from mucosal, acral, or chronic sun-damaged sites. Inhibitors of the MAPK pathway and of KIT are currently undergoing clinical investigation. In this article, we review advances in targeted strategies to treat different subgroups of patients with melanoma.
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September 2010

Major response to imatinib mesylate in KIT-mutated melanoma.

J Clin Oncol 2008 Apr;26(12):2046-51

The Melanoma Program, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1200/JCO.2007.14.0707DOI Listing
April 2008

Gemcitabine-related radiation recall preferentially involves internal tissue and organs.

Cancer 2004 May;100(9):1793-9

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Radiation recall refers to inflammatory reactions triggered by cytotoxic agents and develops in previously irradiated areas. Most reactions develop cutaneously. The most common chemotherapeutic agents implicated are anthracyclines and taxanes. Gemcitabine, a nucleotide analog, recently was implicated in several cases. The authors performed a literature search using PubMed and the search terms "gemcitabine" and "radiation recall" to find prior cases of radiation recall attributed to gemcitabine. These cases were compared with those attributed to anthracyclines and taxanes. The literature search found 12 cases of radiation recall caused by gemcitabine. The authors also determined that their case of myositis developing in the rectus abdominus muscle of a patient with pancreatic adenocarcinoma was the manifestation of radiation recall, thereby bringing the number of patients who developed radiation recall to gemcitabine and were discussed in the current study to 13. Approximately 70% of the cases manifested as inflammation of internal organs or tissues and 30% manifested as a dermatitis or mucositis. This finding differs from other common agents, in which 63% of the radiation recall events are reported to manifest as a dermatitis. Compared with anthracyclines and taxanes, the interval from the completion of radiation therapy to the initiation of chemotherapy is less for gemcitabine (median time of 56 days for gemcitabine, compared with 218 days for the taxanes and 646 days for doxorubicin). The majority of radiation recall reactions attributed to gemcitabine are reported to affect internal tissue or organs. In contrast, other common agents for the most part trigger cutaneous inflammation. The development of internal tissue inflammation is reportedly correlated with a shorter interval from the time of completion of radiation therapy to the initiation of chemotherapy.
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http://dx.doi.org/10.1002/cncr.20229DOI Listing
May 2004