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Melanoma: HELP
Articles by Thomas F. Gajewski
Based on 49 articles published since 2010
(Why 49 articles?)
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Between 2010 and 2020, T. Gajewski wrote the following 49 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

2 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

3 Review Molecular profiling of melanoma and the evolution of patient-specific therapy. 2011

Gajewski, Thomas F. ·Department of Pathology, The University of Chicago, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu ·Semin Oncol · Pubmed #21421113.

ABSTRACT: It recently has become clear that multiple molecular subtypes of melanoma likely exist that may be associated with clinical response to defined therapeutic modalities. Gene expression profiling has revealed a signature that is associated with clinical benefit to melanoma vaccines, with preliminary work suggesting a correlation with response to other immunotherapy agents as well. Activating mutations in B-Raf and c-kit are associated with clinical response to the specific kinase inhibitors PLX4032 and imatinib, respectively. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Together, these emerging data suggest the evolution of a new paradigm in melanoma therapy in which molecular analysis of the tumor will be used to assign the most appropriate therapeutic modality for each individual patient, to maximize therapeutic success.

4 Review Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. 2010

Gajewski, Thomas F / Louahed, Jamila / Brichard, Vincent G. ·University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu ·Cancer J · Pubmed #20693853.

ABSTRACT: Immunotherapeutic approaches for melanoma and other cancers can impart profound clinical benefit but only for a subset of patients. Interpatient heterogeneity could, in principle, be due to somatic differences in the tumor between individuals or alternatively be accounted for distinct germline polymorphisms in immunoregulatory genes of the host. Analysis of these possibilities has been initiated by investigating gene expression profiling of the tumor microenvironment in the context of clinical trials of cancer vaccines. Distinct gene expression profiles have been identified on pretreatment biopsies that are associated with a positive or negative clinical outcome. These observations suggest that such profiling might be useful as a predictive biomarker for clinical benefit from vaccines and other immunotherapy approaches, and analysis of specific gene products has begun to suggest new therapeutic interventions to overcome mechanisms of tumor resistance.

5 Clinical Trial Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. 2019

Stein, J E / Soni, A / Danilova, L / Cottrell, T R / Gajewski, T F / Hodi, F S / Bhatia, S / Urba, W J / Sharfman, W H / Wind-Rotolo, M / Edwards, R / Lipson, E J / Taube, J M. ·Departments of Dermatology. · Biostatistics, Johns Hopkins University SOM, Baltimore; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins, Baltimore. · Department of Pathology, Johns Hopkins University SOM, Baltimore. · Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland. · The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins, Baltimore; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore. · Bristol-Myers Squibb, Princeton, USA. · Departments of Dermatology; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins, Baltimore; Department of Pathology, Johns Hopkins University SOM, Baltimore; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore. Electronic address: jtaube1@jhmi.edu. ·Ann Oncol · Pubmed #30689736.

ABSTRACT: BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

6 Clinical Trial Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. 2017

Ribas, Antoni / Dummer, Reinhard / Puzanov, Igor / VanderWalde, Ari / Andtbacka, Robert H I / Michielin, Olivier / Olszanski, Anthony J / Malvehy, Josep / Cebon, Jonathan / Fernandez, Eugenio / Kirkwood, John M / Gajewski, Thomas F / Chen, Lisa / Gorski, Kevin S / Anderson, Abraham A / Diede, Scott J / Lassman, Michael E / Gansert, Jennifer / Hodi, F Stephen / Long, Georgina V. ·University of California at Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · University Hospital of Zurich, Zurich, Switzerland. · Roswell Park Cancer Institute, Buffalo, NY, USA. · The West Clinic, Memphis, TN, USA. · University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Fox Chase Cancer Center, Philadelphia, PA, USA. · Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Hopitaux Universitaires de Genève, Geneva, Switzerland. · University of Pittsburgh Cancer Institute and Hillman UPMC Cancer Center, Pittsburgh, PA, USA. · The University of Chicago School of Medicine, Chicago, IL, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Amgen Inc., South San Francisco, CA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Cell · Pubmed #28886381.

ABSTRACT: Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8

7 Clinical Trial Safety and efficacy of the antiganglioside GD3 antibody ecromeximab (KW2871) combined with high-dose interferon-α2b in patients with metastatic melanoma. 2017

Tarhini, Ahmad A / Moschos, Stergios J / Lin, Yan / Lin, Hui-Min / Sander, Cindy / Yin, Yan / Venhaus, Ralph / Gajewski, Thomas F / Kirkwood, John M. ·aDepartment of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania bLudwig Institute for Cancer Research Ltd, New York, New York cDepartment of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA. ·Melanoma Res · Pubmed #28489678.

ABSTRACT: This study evaluated the safety and clinical benefit of ecromeximab (KW2871) combined with high-dose interferon-α2b (HDI) in patients with metastatic melanoma. We also carried out pharmacokinetic and immune monitoring studies of this combination. This was an open-label, phase 1/2 study of ecromeximab plus HDI in patients with measurable metastatic melanoma. Eligible patients received ecromeximab-HDI combination therapy: ecromeximab administered intravenously once every 2 weeks and HDI at a dose of 20 million units (MU)/m administered intravenously for 5 consecutive days per week for the first 4 weeks (induction phase) and then at 10 MU/m subcutaneously thrice weekly through week 14 (maintenance phase). Patients were treated with combination therapy until disease progression or limiting toxicity. Three dose-escalation cohorts (5, 10, and 20 mg/m) of ecromeximab were planned. Thirty-six evaluable patients were enrolled including six in each of cohorts 1 and 2, and 24 in cohort 3. Median progression-free survival was 2.53 months [95% confidence interval (CI):1.93-3.83] and it was 1.93 months (95% CI: 1.00-3.80) in cohort 3. The median overall survival was 10.28 months (95% CI: 6.93-16.77) and 7.78 months (95% CI: 6.03-13.97) in cohort 3. There was no significant difference in progression-free survival or overall survival by BRAF mutation status. The response rate was 5.6% (95% CI: 0.68-18.7), with two patients showing an objective response (one complete response and one partial response), and the clinical benefit rate was 78% (95% CI: 61-90). Stable disease as best response was observed in 26 (72%) patients including five in each of cohorts 1 and 2, and 16 in cohort 3. Treatment-emergent adverse events considered related to ecromeximab treatment occurred in four (66.7%) patients in cohort 1, five (83.3%) patients in cohort 2, and seven (29.2%) patients in cohort 3. Among TEAEs with a maximum severity of grade 3 or 4, those that occurred only in cohort 3 were related to pain, electrolyte imbalance, blood cell decreases, and allergic reaction. Safety and efficacies considered related to ecromeximab occurred in cohort 3 and included grade 3 hypersensitivity [one (4.2%)] and grade 2 hypotension [one (4.2%)]. Regimen-limiting toxicities occurred in two (8.3%) patients in cohort 3: hypersensitivity (with hypertension, supraventricular tachycardia, bronchospasm, chills, and dyspnea) and hypotension. One patient out of 31 examined showed a low-level transient positivity for human antichimeric antibodies against ecromeximab. Pharmacokinetic measurements by enzyme-linked immunosorbent assay determined that administration of HDI does not influence serum levels of ecromeximab at 5, 10, and 20 mg/m dose levels. Ecromeximab in combination with HDI was generally well tolerated in patients with metastatic melanoma and has shown low immunogenicity. However, the clinical activity was limited, suggesting that future development of this combination should be deprioritized and that other combinations, such as with immune checkpoint inhibitors, should be considered.

8 Clinical Trial Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. 2017

Atkinson, Thomas M / Hay, Jennifer L / Shoushtari, Alexander / Li, Yuelin / Paucar, Daniel J / Smith, Sloane C / Kudchadkar, Ragini R / Doyle, Austin / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Schwartz, Gary K / Carvajal, Richard D. ·Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. atkinsot@mskcc.org. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. · Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. · Mayo Clinic, Rochester, MN, USA. · University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Princess Margaret Hospital University Health Network, Toronto, ON, Canada. · Penn Medicine, Philadelphia, PA, USA. · University of Chicago, Chicago, IL, USA. · Mount Sinai Medical Center, Miami Beach, FL, USA. · University of Michigan, Ann Arbor, MI, USA. · Minnesota Oncology, Woodbury, MN, USA. · Univeristy of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · University of Colorado - Denver, Denver, CO, USA. · Columbia University Medical Center, New York, NY, USA. ·J Cancer Res Clin Oncol · Pubmed #27921276.

ABSTRACT: PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

9 Clinical Trial A phase II study of cediranib, an oral VEGF inhibitor, in previously untreated patients with metastatic or recurrent malignant melanoma. 2016

McWhirter, Elaine / Quirt, Ian / Gajewski, Thomas / Pond, Gregory / Wang, Lisa / Hui, June / Oza, Amit. ·Department of Medical Oncology, Juravinski Cancer Centre, Hamilton Health Sciences Centre, Hamilton, ON, Canada. emcwhirt@hhsc.ca. · Department of Medical Oncology, Princess Margaret Cancer Centre, Drug Development Program, Toronto, ON, Canada. · University of Chicago Medical Centre, Chicago, IL, USA. · Ontario Clinical Oncology Group, McMaster University, Hamilton, ON, Canada. ·Invest New Drugs · Pubmed #26841902.

ABSTRACT: PURPOSE: A two stage multi-institution Phase II study was undertaken by the Princess Margaret Hospital Consortium to evaluate the efficacy and toxicity of oral cediranib, an inhibitor of vascular endothelial growth factor receptors 1 and 2, in patients with previously untreated advanced malignant melanoma. PATIENTS AND METHODS: Between May 2006 and April 2008, 24 patients (median age 65 years) with advanced malignant melanoma were treated with oral cediranib. Cediranib was given on a continuous, oral once daily schedule of 45 mg, on a 28 day cycle. RESULTS: Of the 17 patients evaluable for response, there was stable disease in 8 patients, and progressive disease in 9 patients, with no objective responses seen. Only 2 patients had stable disease >/= 6 months, thus the study was terminated at the end of stage 1 accrual. The overall median survival was 9.9 months, and the median time to progression was 3.5 months. The most frequent non-hematologic adverse events were hypertension (78%), fatigue (69%), diarrhea (69%) and anorexia and nausea (each 57%). CONCLUSIONS: Although 2 patients had stable disease at 6 months, the short median time to progression and lack of any objective responses indicate that single agent cediranib at this dose and schedule is not sufficiently active to warrant study continuation.

10 Clinical Trial Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. 2015

Carvajal, Richard D / Lawrence, Donald P / Weber, Jeffrey S / Gajewski, Thomas F / Gonzalez, Rene / Lutzky, Jose / O'Day, Steven J / Hamid, Omid / Wolchok, Jedd D / Chapman, Paul B / Sullivan, Ryan J / Teitcher, Jerrold B / Ramaiya, Nikhil / Giobbie-Hurder, Anita / Antonescu, Cristina R / Heinrich, Michael C / Bastian, Boris C / Corless, Christopher L / Fletcher, Jonathan A / Hodi, F Stephen. ·Memorial Sloan Kettering Cancer Center, New York, New York. Weill Medical College of Cornell University, New York, New York. · Massachusetts General Hospital, Boston, Massachusetts. · H. Lee Moffitt Cancer Center, Tampa, Florida. · The University of Chicago, Chicago, Illinois. · The University of Colorado Cancer Center, Aurora, Colorado. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Beverly Hills Cancer Center, Beverly Hills, California. · Angeles Clinic and Research Institute, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Dana Farber Cancer Institute, Boston, Massachusetts. · Oregon Health and Science University, Portland, Oregon. · The University of California San Francisco, San Francisco, California. · Dana Farber Cancer Institute, Boston, Massachusetts. Stephen_hodi@dfci.harvard.edu. ·Clin Cancer Res · Pubmed #25695690.

ABSTRACT: PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

11 Clinical Trial Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. 2015

Lee, Sylvia M / Moon, James / Redman, Bruce G / Chidiac, Tarek / Flaherty, Lawrence E / Zha, Yuanyuan / Othus, Megan / Ribas, Antoni / Sondak, Vernon K / Gajewski, Thomas F / Margolin, Kim A. ·Seattle Cancer Care Alliance/University of Washington, Seattle, WA. · SWOG Statistical Center, Seattle, WA. · University of Michigan, Ann Arbor, MI. · Columbus CCOP/Mid-Ohio Onc/Hem Inc, Columbus, OH. · Wayne State University/Karmanos Cancer Institute, Detroit, MI. · University of Chicago, Chicago, IL. · UCLA Medical Center, Los Angeles, CA. · H. Lee Moffitt Cancer Center, Tampa, FL. ·Cancer · Pubmed #25250858.

ABSTRACT: BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS: Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.

12 Clinical Trial Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma. 2014

Zukotynski, Katherine / Yap, Jeffrey T / Giobbie-Hurder, Anita / Weber, Jeffrey / Gonzalez, Rene / Gajewski, Thomas F / O'Day, Steven / Kim, Kevin / Hodi, F Stephen / Van den Abbeele, Annick D. · ·Cancer Imaging · Pubmed #25609545.

ABSTRACT: BACKGROUND: In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population. METHODS: Baseline and 4-week follow-up 18F-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months. RESULTS: Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR. CONCLUSIONS: Metabolic response by 18F-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. 18F-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this. CLINICAL TRIAL REGISTRATION: NCT00424515.

13 Clinical Trial Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. 2014

Ribas, Antoni / Gonzalez, Rene / Pavlick, Anna / Hamid, Omid / Gajewski, Thomas F / Daud, Adil / Flaherty, Lawrence / Logan, Theodore / Chmielowski, Bartosz / Lewis, Karl / Kee, Damien / Boasberg, Peter / Yin, Ming / Chan, Iris / Musib, Luna / Choong, Nicholas / Puzanov, Igor / McArthur, Grant A. ·Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · New York University Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Chicago, Chicago, IL, USA. · Hematology/Oncology Division, University of California, San Francisco, CA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. · Genentech, South San Francisco, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org. ·Lancet Oncol · Pubmed #25037139.

ABSTRACT: BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

14 Clinical Trial Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. 2014

Carvajal, Richard D / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Kudchadkar, Ragini R / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Doyle, Austin / Ancell, Kristin / Panageas, Katherine S / Bluth, Mark / Hedvat, Cyrus / Erinjeri, Joseph / Ambrosini, Grazia / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Wolchok, Jedd D / Chapman, Paul B / Schwartz, Gary K. ·Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York. · Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee. · Mayo Clinic, Rochester, Minnesota. · University of Iowa Hospital and Clinics, Iowa City. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · H. Lee Moffitt Cancer Center, Tampa, Florida. · Washington University, St Louis, Missouri. · University of Chicago, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · University of Michigan, Ann Arbor. · Metro Minnesota Community Clinical Oncology Program, St Louis Park. · University of Wisconsin, Madison. · Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · University of Colorado, Aurora. · Investigational Drug Branch, National Cancer Institute, Rockville, Maryland. · Memorial Sloan-Kettering Cancer Center, New York, New York. ·JAMA · Pubmed #24938562.

ABSTRACT: IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

15 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·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. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: 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.

16 Clinical Trial Phase II study of the Src kinase inhibitor saracatinib (AZD0530) in metastatic melanoma. 2013

Gangadhar, Tara C / Clark, Joseph I / Karrison, Theodore / Gajewski, Thomas F. ·Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA. ·Invest New Drugs · Pubmed #23151808.

ABSTRACT: BACKGROUND: Src kinases are activated in melanoma, and inhibition of Src kinase activity has pre-clinical anti-tumor effects. Targeting this pathway could therefore have therapeutic activity in patients with metastatic melanoma. PATIENTS AND METHODS: We conducted a multi-center, open-label study of the Src kinase inhibitor saracatanib (AZD0530) in patients with metastatic melanoma. Twenty-three patients received saracatanib at a dose of 175 mg daily. The primary objectives were to determine whether this agent had clinical activity in patients with advanced melanoma and whether it increased progression free survival. Functional effects on circulating T cells were also assessed. RESULTS: Twenty-three patients received oral saracatanib on a continuous daily dosing regimen. There were no objective clinical responses. Saracatanib was generally well tolerated with few grade 3-4 adverse events. T cell function was inhibited in most patients, based on decreased superantigen-induced IL-2 production in post- versus pre-treatment samples. CONCLUSIONS: Saracatanib has minimal clinical activity as a single agent in an unselected population of patients with advanced melanoma, as evidenced by a lack of objective responses in this study. Reduced T cell cytokine production in most treated patients suggests potential immune suppressive activity by this agent.

17 Clinical Trial Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). 2012

Gajewski, Thomas F / Salama, April K S / Niedzwiecki, Donna / Johnson, Jeffrey / Linette, Gerald / Bucher, Cynthia / Blaskovich, Michelle A / Sebti, Said M / Haluska, Frank / Anonymous3900744. ·The University of Chicago, Section of Hematology/Oncology, 5841 S, Maryland Ave, MC2115, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu ·J Transl Med · Pubmed #23228035.

ABSTRACT: BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0-1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT00060125.

18 Clinical Trial Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. 2010

O'Day, S J / Maio, M / Chiarion-Sileni, V / Gajewski, T F / Pehamberger, H / Bondarenko, I N / Queirolo, P / Lundgren, L / Mikhailov, S / Roman, L / Verschraegen, C / Humphrey, R / Ibrahim, R / de Pril, V / Hoos, A / Wolchok, J D. ·The Angeles Clinic and Research Institute, Santa Monica, CA, USA.SODay@theangelesclinic.org ·Ann Oncol · Pubmed #20147741.

ABSTRACT: BACKGROUND: This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS: BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

19 Article Perspectives in melanoma: meeting report from the Melanoma Bridge (November 29th-1 December 1st, 2018, Naples, Italy). 2019

Ascierto, Paolo A / Agarwala, Sanjiv S / Botti, Gerardo / Budillon, Alfredo / Davies, Michael A / Dummer, Reinhard / Ernstoff, Marc / Ferrone, Soldano / Formenti, Silvia / Gajewski, Thomas F / Garbe, Claus / Hamid, Omid / Lo, Roger S / Luke, Jason J / Michielin, Oliver / Palmieri, Giuseppe / Zitvogel, Laurence / Marincola, Francesco M / Masucci, Giuseppe / Caracò, Corrado / Thurin, Magdalena / Puzanov, Igor. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Medical Oncology and Hematology, St. Luke's University Hospital and Temple University, Bethlehem, PA, USA. · Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Experimental Pharmacology Unit, Department of Translational Research, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland. · Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. · Department of Pathology and Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL, USA. · Division of Dermatologic Oncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. · The Angeles Clinic, Experimental Therapeutics Cedars Sinai Foundation, Los Angeles, CA, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · University of Chicago Medical Center, Chicago, IL, USA. · Oncology Department, UNIL-CHUV, Lausanne, Switzerland. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Institut de Cancérologie, Gustave Roussy Cancer Campus, Villejuif, Paris, France. · Refuge Biotechnologies, Menlo Park, CA, USA. · Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. · Division of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, 9609 Medical Center Drive, Bethesda, MD, 20892-7420, USA. thurinm@mail.nih.gov. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ·J Transl Med · Pubmed #31331337.

ABSTRACT: Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report.

20 Article Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. 2019

Gibney, Geoffrey T / Hamid, Omid / Lutzky, Jose / Olszanski, Anthony J / Mitchell, Tara C / Gajewski, Thomas F / Chmielowski, Bartosz / Hanks, Brent A / Zhao, Yufan / Newton, Robert C / Maleski, Janet / Leopold, Lance / Weber, Jeffrey S. ·Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Present Address: Lombardi Comprehensive Cancer Center, Medstar-Georgetown University Hospital, 3800 Reservoir Road NW, Podium A, Washington, DC, 20007, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Melanoma and Skin Cancers Center, The Angeles Clinic and Research Institute, 11818 Wilshire Blvd, Suite #200, Los Angeles, CA, USA. · Division of Hematology & Oncology, Mount Sinai Medical Center, 4306 Alton Rd, Miami Beach, FL, USA. · Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, USA. · Division of Hematology Oncology, Abramson Cancer Center, Hospital of the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, USA. · Department of Hematology/Oncology, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL, USA. · Jonsson Comprehensive Medical Center, University of California, Los Angeles, 10945 Le Conte Ave #2339, Los Angeles, CA, USA. · Department of Medicine, Duke University Medical Center, 20 Duke Medicine Cir, Durham, NC, USA. · Incyte Corporation, 1801 Augustine Cutoff, Wilmington, DE, USA. · Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA. · Present Address: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA. ·J Immunother Cancer · Pubmed #30894212.

ABSTRACT: BACKGROUND: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). METHODS: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. RESULTS: Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. CONCLUSIONS: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.

21 Article WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers. 2019

Luke, Jason J / Bao, Riyue / Sweis, Randy F / Spranger, Stefani / Gajewski, Thomas F. ·Department of Medicine, The University of Chicago, Chicago, Illinois. · Center for Research Informatics, The University of Chicago, Chicago, Illinois. · Department of Pediatrics, The University of Chicago, Chicago, Illinois. · Department of Pathology, The University of Chicago, Chicago, Illinois. · Department of Medicine, The University of Chicago, Chicago, Illinois. tgajewsk@medicine.bsd.uchicago.edu. ·Clin Cancer Res · Pubmed #30635339.

ABSTRACT: PURPOSE: The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-T-cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/β-catenin signaling mediates immune exclusion in melanoma, but association with the non-T-cell-inflamed tumor microenvironment in other tumor types is not well understood. EXPERIMENTAL DESIGN: Using The Cancer Genome Atlas (TCGA), a T-cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/β-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in β-catenin signaling elements including RESULTS: Across TCGA, 3,137/9,244 (33.9%) tumors were non-T-cell-inflamed, whereas 3,161/9,244 (34.2%) were T-cell-inflamed. Non-T-cell-inflamed tumors demonstrated significantly lower expression of T-cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of β-catenin signaling molecules in non-T-cell-inflamed tumors were enriched three-fold relative to T-cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated β-catenin signaling in the non-T-cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of β-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased β-catenin protein levels (20 tumors, 65%). CONCLUSIONS: Activation of tumor-intrinsic WNT/β-catenin signaling is enriched in non-T-cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy.

22 Article Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity. 2018

Ishihara, Jun / Ishihara, Ako / Potin, Lambert / Hosseinchi, Peyman / Fukunaga, Kazuto / Damo, Martina / Gajewski, Thomas F / Swartz, Melody A / Hubbell, Jeffrey A. ·Institute for Molecular Engineering, University of Chicago, Chicago, Illinois. · Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. · Department of Pathology, University of Chicago, Chicago, Illinois. · Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois. · Institute for Molecular Engineering, University of Chicago, Chicago, Illinois. jhubbell@uchicago.edu. ·Mol Cancer Ther · Pubmed #30097487.

ABSTRACT: CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2

23 Article Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab. 2018

Hantel, Andrew / Gabster, Brooke / Cheng, Jason X / Golomb, Harvey / Gajewski, Thomas F. ·Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA. · Pritzker School of Medicine, The University of Chicago, Chicago, USA. · Department of Pathology, The University of Chicago, Chicago, USA. · Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA. tgajewsk@medicine.bsd.uchicago.edu. ·J Immunother Cancer · Pubmed #30012206.

ABSTRACT: BACKGROUND: Treatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Side effects are due to immune activation, can affect virtually all organ systems, and are occasionally severe. Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis (HLH) due to immune checkpoint inhibitor therapy. CASE PRESENTATION: A patient with metastatic melanoma was treated with one course of ipilimumab + nivolumab and presented 3 weeks later with severe anemia and hyperferritinemia. A bone marrow biopsy revealed necrotic tumor cells, infiltrating T cells, and hemophagocytosis. The patient was treated with high-dose steroids; 12 months later, the patient remains off all therapy and in complete remission of both HLH and metastatic melanoma. CONCLUSIONS: The hemophagocytic syndromes are attributable to dysregulated immune activation and share pathophysiologic mechanisms with immune activation from checkpoint inhibitors. Increasing use of regimens that include immune checkpoint inhibition require vigilant monitoring for immune-activating side effects as they can occasionally be life threatening, as in this case of HLH.

24 Article The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. 2018

Matson, Vyara / Fessler, Jessica / Bao, Riyue / Chongsuwat, Tara / Zha, Yuanyuan / Alegre, Maria-Luisa / Luke, Jason J / Gajewski, Thomas F. ·Department of Pathology, University of Chicago, Chicago, IL 60637, USA. · Center for Research Informatics, University of Chicago, IL 60637, USA. · Department of Pediatrics, University of Chicago, IL 60637, USA. · Department of Medicine, University of Chicago, Chicago, IL 60637, USA. ·Science · Pubmed #29302014.

ABSTRACT: Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16

25 Article Intratumoral CD8 2018

Horton, Brendan L / Williams, Jason B / Cabanov, Alexandra / Spranger, Stefani / Gajewski, Thomas F. ·Department of Pathology, University of Chicago, Chicago, Illinois. · The Committee on Immunology, University of Chicago, Chicago, Illinois. · Department of Pathology, University of Chicago, Chicago, Illinois. tgajewsk@medicine.bsd.uchicago.edu. · Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois. ·Cancer Immunol Res · Pubmed #29097422.

ABSTRACT: Subsets of human tumors are infiltrated with tumor antigen-specific CD8

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