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Melanoma: HELP
Articles by Roxana S. Dronca
Based on 30 articles published since 2010
(Why 30 articles?)
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Between 2010 and 2020, R. S. Dronca wrote the following 30 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial BCL-2-interacting mediator of cell death (Bim) is a novel biomarker for response to anti-PD-1 therapy in patients with advanced melanoma. 2016

Dronca, Roxana S / Mansfield, Aaron S / Park, Sean S / Dong, Haidong. ·Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA. · Division of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. · Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Urology, Mayo Clinic, Rochester, MN, USA. ·Immunotherapy · Pubmed #27784186.

ABSTRACT: -- No abstract --

2 Editorial The dynamic human immune response to cancer: it might just be rocket science. 2011

Holtan, Shernan G / Dronca, Roxana S / Nevala, Wendy K / Porrata, Luis F / Mansfield, Aaron S / Block, Matthew S / Leontovich, Alexey A / Grotz, Travis E / Turner, James D / Frisch, Harold P / Markovic, Svetomir N. · ·Immunotherapy · Pubmed #21913823.

ABSTRACT: -- No abstract --

3 Review Immune Checkpoint Inhibitor Toxicities. 2019

Marin-Acevedo, Julian A / Chirila, Razvan M / Dronca, Roxana S. ·Division of General Internal Medicine, Mayo Clinic, Jacksonville, FL. · Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL. Electronic address: dronca.roxana@mayo.edu. ·Mayo Clin Proc · Pubmed #31272574.

ABSTRACT: Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.

4 Review Immunomodulatory effects of sex hormones: requirements for pregnancy and relevance in melanoma. 2014

Enninga, Elizabeth Ann L / Holtan, Shernan G / Creedon, Douglas J / Dronca, Roxana S / Nevala, Wendy K / Ognjanovic, Simona / Markovic, Svetomir N. ·Mayo Graduate School, Mayo Clinic, Rochester, MN. · Oregon Health and Science University, Portland. · Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN. · Department of Oncology, Mayo Clinic, Rochester, MN. · Department of Oncology, Mayo Clinic, Rochester, MN; Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address: Markovic.svetomir@mayo.edu. ·Mayo Clin Proc · Pubmed #24684874.

ABSTRACT: Similarities between the pathologic progression of cancer and the physiologic process of placentation (eg, proliferation, invasion, and local/systemic tolerance) have been recognized for many years. Sex hormones such as human chorionic gonadotropin, estrogens, progesterone, and others contribute to induction of immunologic tolerance at the beginning of gestation. Sex hormones have been shown to play contributory roles in the growth of cancers such as breast cancer, prostrate cancer, endometrial cancer, and ovarian cancer, but their involvement as putative mediators of the immunologic escape of cancer is still being elucidated. Herein, we compare the emerging mechanism by which sex hormones modulate systemic immunity in pregnancy and their potentially similar role in cancer. To do this, we conducted a PubMed search using combinations of the following keywords: "immune regulation," "sex hormones," "pregnancy," "melanoma," and "cancer." We did not limit our search to specific publication dates. Mimicking the maternal immune response to pregnancy, especially in late gestation, might aid in design of better therapies to reconstitute endogenous antitumor immunity and improve survival.

5 Review Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma. 2014

Shah, Darshil J / Dronca, Roxana S. ·Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Beaumont Health System, Royal Oak, MI. Electronic address: darshil@gmail.com. · Division of Medical Oncology, Mayo Clinic, Rochester, MN. ·Mayo Clin Proc · Pubmed #24684873.

ABSTRACT: Melanoma is the most dangerous form of skin cancer owing to its metastatic potential and is an important public health concern. The melanoma incidence has been increasing worldwide. Although potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blocking antibodies, as well as combination strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review was to summarize the evolution of and recent advances in the treatment of metastatic melanoma. Therefore, we conducted a comprehensive PubMed search between January 1, 1960, and February 1, 2014, using the search term melanoma or metastatic melanoma combined with terms such as chemotherapy, immunotherapy, CTLA-4, PD-1, PD-L1, adoptive T cell, targeted therapy, MAPK, molecular biology, and survival.

6 Review Rare presentations of primary melanoma and special populations: a systematic review. 2014

Kottschade, Lisa A / Grotz, Travis E / Dronca, Roxana S / Salomao, Diva R / Pulido, Jose S / Wasif, Nabil / Jakub, James W / Bagaria, Sanjay P / Kumar, Riten / Kaur, Judith S / Morita, Shane Y / Moran, Steven L / Nguyen, Jesse T / Nguyen, Emily C / Hand, Jennifer L / Erickson, Lori A / Brewer, Jerry D / Baum, Christian L / Miller, Robert C / Swanson, David L / Lowe, Val / Markovic, Svetomir N. ·Departments of *Oncology †Surgery ‡Laboratory Medicine and Pathology §Ophthalmology #Dermatology ‡‡Radiation Oncology **Pediatrics §§Radiology ∥∥Hematology ¶¶Immunology ††Medical Genetics, Mayo Clinic, Rochester, MN ∥Department of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada ¶The Queen's Medical Center/Queen's Cancer Center, University of Hawaii/John A. Burns School of Medicine, Honolulu, HI. ·Am J Clin Oncol · Pubmed #23563206.

ABSTRACT: A subset of patients with melanoma present in rare and unique clinical circumstances requiring specific considerations with respect to diagnostic and therapeutic interventions. Herein, we present our review of patients with: (1) primary mucosal melanoma of the head and neck, gastrointestinal, and genitourinary tracts; (2) primary melanoma of the eye; (3) desmoplastic melanoma; (4) subungual melanoma; (5) melanoma in special populations: children, nonwhites, as well as a discussion of familial melanoma.

7 Review Personalized therapy for metastatic melanoma: could timing be everything? 2012

Dronca, Roxana S / Leontovich, Alexey A / Nevala, Wendy K / Markovic, Svetomir N. ·Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA. dronca.roxana@mayo.edu ·Future Oncol · Pubmed #23148614.

ABSTRACT: There is ample evidence that immune-related processes in humans are under temporal regulation. The circadian variation of humoral and cellular immunity is well documented and appears to be hormonally modulated via the hypothalamic-pituitary-adrenal axis. In advanced melanoma, it has recently been demonstrated that systemic immunity is repolarized toward a global state of chronic inflammation (Th2 dominance) and appears to be governed by infradian biorhythms of cytokines and immune cell subsets, which extend beyond the 24-h circadian variability reported in healthy volunteers. It is suggested that synchronizing administration of lymphodepleting chemotherapy (temozolomide) with these endogenous (individualized) immune dynamics (biorhythms) in patients with advanced/metastatic melanoma improves clinical outcomes compared with temozolomide used in a conventional 'random delivery' fashion.

8 Clinical Trial Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. 2018

Robert, Caroline / Ribas, Antoni / Hamid, Omid / Daud, Adil / Wolchok, Jedd D / Joshua, Anthony M / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Joseph, Richard W / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Kefford, Richard / Hersey, Peter / Zhang, Jin / Anderson, James / Diede, Scott J / Ebbinghaus, Scot / Hodi, F Stephen. ·Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Adil Daud, University of California, San Francisco, San Francisco, CA · Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY · Anthony M. Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Jeffrey S. Weber, H Lee Moffitt Cancer Center, Tampa · Richard W. Joseph, Mayo Clinic Cancer Center-Florida, Jacksonville, FL · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead · Melanoma Institute Australia, Wollstonecraft · and Macquarie University, MQ Health, Health Sciences Centre · Peter Hersey, University of Sydney, Sydney, New South Wales, Australia · Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA. ·J Clin Oncol · Pubmed #29283791.

ABSTRACT: Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.

9 Clinical Trial NCCTG N0879 (Alliance): A randomized phase 2 cooperative group trial of carboplatin, paclitaxel, and bevacizumab ± everolimus for metastatic melanoma. 2018

McWilliams, Robert R / Allred, Jacob B / Slostad, Jessica A / Katipamula, Rajini / Dronca, Roxana S / Rumilla, Kandelaria M / Erickson, Lori A / Bryce, Alan H / Joseph, Richard W / Kottschade, Lisa A / King, David M / Leitch, John M / Markovic, Svetomir N. ·Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Medicine, Mayo Clinic, Rochester, Minnesota. · Minnesota Oncology, Coon Rapids, Minnesota. · Division of Molecular Genetics, Mayo Clinic, Rochester, Minnesota. · Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota. · Division of Hematology/Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona. · Division of Hematology/Oncology, Mayo Clinic in Florida, Jacksonville, Florida. · Unity Hospital, Metro Minnesota Community Oncology Research Consortium, Saint Louis Park, Minnesota. · Sanford Clinic North-Fargo, Fargo, North Dakota. ·Cancer · Pubmed #29044496.

ABSTRACT: BACKGROUND: Despite the success of immune checkpoint and targeted therapy, many patients with melanoma ultimately require further treatment. The combination of carboplatin, paclitaxel, and bevacizumab (CPB) has demonstrated promising activity in a single-arm study. In the current study, the authors performed a randomized phase 2 study to confirm efficacy and to determine whether adding everolimus would increase the activity of the combination. METHODS: Through the North Central Cancer Treatment Group, a total of 149 patients with unresectable AJCC 6th edition stage IV melanoma were randomized from May 2010 to May 2014 to either CPB or CPB with everolimus (CPBE). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate, and tolerability. RESULTS: The CPB and CPBE treatment arms were balanced with regard to age (median age: 59 years vs 58 years) and high lactate dehydrogenase (48% vs 51%), but were unbalanced with regard to sex (male sex: 72% vs 55%; P = .03). Overall, there was no difference noted with regard to PFS, with a median PFS of 5.6 months for CPB versus 5.1 months for CPBE (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.81-1.62 [P = .44]), or for OS, with a median OS of 14.5 months for CPB versus 10.8 months for CPBE (HR, 1.16; 95% CI, 0.84-1.84). The confirmed response rate was 13% for CPB and 23% for CPBE (P = .13). Toxicity was higher for CPBE compared with CPB (83% for grade 3 + and 14% for grade 4 + vs 63% for grade 3 + and 11% for grade 4+, respectively) (toxicities were graded using the Cancer Therapy Evaluation Program of the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Common grade 3 + toxicities were neutropenia, leukopenia, and fatigue, which occurred in both treatment arms with comparable frequency. CONCLUSIONS: Both experimental arms demonstrated activity, with a PFS of >5 months. However, the addition of everolimus to CPB failed to improve outcomes, with increased toxicity noted. These findings replicate the moderate antitumor activity of CPB, with future development possibly in combination with targeted or immunotherapy. Cancer 2018;124:537-45. © 2017 American Cancer Society.

10 Clinical Trial Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program. 2017

Gangadhar, Tara C / Hwu, Wen-Jen / Postow, Michael A / Hamid, Omid / Daud, Adil / Dronca, Roxana / Joseph, Richard / O'Day, Steven J / Hodi, F S / Pavlick, Anna C / Kluger, Harriet / Oxborough, Romina P / Yang, Aiming / Gazdoiu, Mihaela / Kush, Debra A / Ebbinghaus, Scot / Salama, April K S. ·*Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA †The University of Texas MD Anderson Cancer Center, Houston, TX ‡Memorial Sloan Kettering Cancer Center §Weill Cornell Medical College §§NYU Clinical Cancer Center, New York, NY ∥The Angeles Clinic and Research Institute, Los Angeles ¶Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco ††The John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA #Mayo Clinic, Rochester, MN **Mayo Clinic, Jacksonville, FL ‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥Yale Cancer Center, New Haven, CT ¶¶Clinigen, Weybridge, UK ##Merck & Co. Inc., Kenilworth, NJ ***Duke Cancer Institute, Durham, NC. ·J Immunother · Pubmed #29028788.

ABSTRACT: KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%-25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

11 Clinical Trial Effect of the lymphocyte-to-monocyte ratio on the clinical outcome of chemotherapy administration in advanced melanoma patients. 2017

Leontovich, Alexey A / Dronca, Roxana S / Nevala, Wendy K / Thompson, Michael A / Kottschade, Lisa A / Ivanov, Leonid V / Markovic, Svetomir N / Anonymous9750886. ·aDepartment of Health Science Research, Division of Biomedical Statistics and Informatics bDepartment of Medical Oncology cDepartment of Hematology, Mayo Clinic, Rochester, Minnesota, USA. ·Melanoma Res · Pubmed #27824739.

ABSTRACT: Skin cancer affects more individuals in the USA than any other malignancy and malignant melanoma is particularly deadly because of its metastatic potential. Melanoma has been recognized as one of the most immunogenic malignancies; therefore, understanding the mechanisms of tumor-immune interaction is key for developing more efficient treatments. As the tumor microenvironment shows an immunosuppressive action, immunotherapeutic agents promoting endogenous immune response to cancer have been tested (interleukin-2, anticytotoxic-T-lymphocyte-associated antigen 4, and antiprogrammed cell death protein 1 monoclonal antibodies) as well as combinations of cytotoxic chemotherapy agents and inhibitors of angiogenesis (taxol/carboplatin/avastin). However, clinical outcomes are variable, with only a minority of patients achieving durable complete responses. The variability of immune homeostasis, which may be more active or more tolerant at any given time, in cancer patients and the interaction of the immune system with the tumor could explain the inconsistency in clinical outcomes among these patients. Recently, the role of the lymphocyte-to-monocyte-ratio (LMR) in the peripheral blood has been investigated and has been proven to be an independent predictor of survival in different hematological malignancies and in solid tumors. In melanoma, our group has validated the significance of LMR as a predictor of relapse after resection of advanced melanoma. In this study, we examined the dynamics in the immune system of patients with advanced melanoma by performing serial multiday concentration measurements of cytokines and immune cell subsets in the peripheral blood. The analysis of outcomes of chemotherapy administration as related to LMR on the day of treatment initiation showed that progression-free survival was improved in the patients who received chemotherapy on the day when LMR was elevated.

12 Clinical Trial Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. 2016

Daud, Adil I / Wolchok, Jedd D / Robert, Caroline / Hwu, Wen-Jen / Weber, Jeffrey S / Ribas, Antoni / Hodi, F Stephen / Joshua, Anthony M / Kefford, Richard / Hersey, Peter / Joseph, Richard / Gangadhar, Tara C / Dronca, Roxana / Patnaik, Amita / Zarour, Hassane / Roach, Charlotte / Toland, Grant / Lunceford, Jared K / Li, Xiaoyun Nicole / Emancipator, Kenneth / Dolled-Filhart, Marisa / Kang, S Peter / Ebbinghaus, Scot / Hamid, Omid. ·Adil I. Daud, University of California, San Francisco, San Francisco · Antoni Ribas, University of California, Los Angeles · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Charlotte Roach and Grant Toland, Dako North America, Carpinteria, CA · Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia · Hassane Zarour, University of Pittsburgh, Pittsburgh, PA · Roxana Dronca, Mayo Clinic, Rochester, MN · Jared K. Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S. Peter Kang, and Scot Ebbinghaus, Merck & Co, Kenilworth, NJ · Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif, France · Anthony M. Joshua, Princess Margaret Cancer Centre, Toronto, ON, Canada · Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia · Richard Kefford, Macquarie University · and Richard Kefford and Peter Hersey, University of Sydney, Sydney, NSW, Australia. ·J Clin Oncol · Pubmed #27863197.

ABSTRACT: Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

13 Clinical Trial Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. 2016

Ribas, Antoni / Hamid, Omid / Daud, Adil / Hodi, F Stephen / Wolchok, Jedd D / Kefford, Richard / Joshua, Anthony M / Patnaik, Amita / Hwu, Wen-Jen / Weber, Jeffrey S / Gangadhar, Tara C / Hersey, Peter / Dronca, Roxana / Joseph, Richard W / Zarour, Hassane / Chmielowski, Bartosz / Lawrence, Donald P / Algazi, Alain / Rizvi, Naiyer A / Hoffner, Brianna / Mateus, Christine / Gergich, Kevin / Lindia, Jill A / Giannotti, Maxine / Li, Xiaoyun Nicole / Ebbinghaus, Scot / Kang, S Peter / Robert, Caroline. ·Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles. · Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California. · Department of Hematology/Oncology, University of California-San Francisco, San Francisco. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia7Department of Clinical Medicine, Macquarie University, Sydney, Australia. · Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio. · Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia. · Department of Medicine, University of Sydney, Sydney, Australia. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology/Oncology, Massachusetts General Hospital, Boston. · Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France. · Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey. · BARDS, Merck & Co, Inc, Kenilworth, New Jersey. ·JAMA · Pubmed #27092830.

ABSTRACT: IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

14 Clinical Trial Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab. 2016

Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Weber, Jeffrey S / Daud, Adil / Hamid, Omid / Patnaik, Amita / Ribas, Antoni / Robert, Caroline / Gangadhar, Tara C / Joshua, Anthony M / Hersey, Peter / Dronca, Roxana / Joseph, Richard / Hille, Darcy / Xue, Dahai / Li, Xiaoyun Nicole / Kang, S Peter / Ebbinghaus, Scot / Perrone, Andrea / Wolchok, Jedd D. ·F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston · Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX · Richard Kefford, Westmead Hospital, Melanoma Institute Australia, and Macquarie University · Peter Hersey, University of Sydney, Sydney, Australia · Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa · Richard Joseph, Mayo Clinic, Jacksonville, FL · Adil Daud, University of California San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute · Antoni Ribas, University of California Los Angeles, Los Angeles, CA · Caroline Robert, Gustave-Roussy and Paris-Sud University, Villejuif-Paris-Sud, France · Tara C. Gangadhar, Abramson Cancer Center, Philadelphia, PA · Anthony M. Joshua, Princess Margaret Hospital, Toronto, Ontario, Canada · Roxana Dronca, Mayo Clinic, Rochester, MN · Darcy Hille, Dahai Xue, Xiaoyun Nicole Li, S. Peter Kang, Scot Ebbinghaus, and Andrea Perrone, Merck, Kenilworth, NJ · and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #26951310.

ABSTRACT: PURPOSE: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). PATIENTS AND METHODS: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. RESULTS: Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). CONCLUSION: Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

15 Clinical Trial Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. 2014

Robert, Caroline / Ribas, Antoni / Wolchok, Jedd D / Hodi, F Stephen / Hamid, Omid / Kefford, Richard / Weber, Jeffrey S / Joshua, Anthony M / Hwu, Wen-Jen / Gangadhar, Tara C / Patnaik, Amita / Dronca, Roxana / Zarour, Hassane / Joseph, Richard W / Boasberg, Peter / Chmielowski, Bartosz / Mateus, Christine / Postow, Michael A / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Li, Xiaoyun Nicole / Iannone, Robert / Ebbinghaus, Scot W / Kang, S Peter / Daud, Adil. ·Gustave Roussy and INSERM U981, Paris-Sud, France. Electronic address: caroline.robert@gustaveroussy.fr. · University of California Los Angeles, Los Angeles, CA, USA. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia. · H Lee Moffitt Cancer Center, Tampa, FL, USA. · Princess Margaret Cancer Centre, Toronto, ON, Canada. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · South Texas Accelerated Research Therapeutics, San Antonio, TX, USA. · Mayo Clinic, Rochester, MN, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Mayo Clinic, Jacksonville, FL, USA. · Gustave Roussy and INSERM U981, Paris-Sud, France. · Merck, Whitehouse Station, NJ, USA. · University of California San Francisco, San Francisco, CA, USA. ·Lancet · Pubmed #25034862.

ABSTRACT: BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. METHODS: In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. FUNDING: Merck Sharp and Dohme.

16 Clinical Trial Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. 2014

Dronca, Roxana S / Allred, Jacob B / Perez, Domingo G / Nevala, Wendy K / Lieser, Elizabeth A T / Thompson, Michael / Maples, William J / Creagan, Edward T / Pockaj, Barbara A / Kaur, Judith S / Moore, Timothy D / Marchello, Benjamin T / Markovic, Svetomir N. ·*Mayo Clinic Rochester, Rochester †Metro-Minnesota Community Clinical Oncology Program, St. Louis Park, MN ‡Mayo Clinic Arizona, Scottsdale, AZ §Columbus CCOP, Columbus, OH ∥Montana Cancer Consortium, Billings, MT. ·Am J Clin Oncol · Pubmed #23357973.

ABSTRACT: OBJECTIVE: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. METHODS: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. RESULTS: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). CONCLUSIONS: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.

17 Clinical Trial Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. 2013

Hamid, Omid / Robert, Caroline / Daud, Adil / Hodi, F Stephen / Hwu, Wen-Jen / Kefford, Richard / Wolchok, Jedd D / Hersey, Peter / Joseph, Richard W / Weber, Jeffrey S / Dronca, Roxana / Gangadhar, Tara C / Patnaik, Amita / Zarour, Hassane / Joshua, Anthony M / Gergich, Kevin / Elassaiss-Schaap, Jeroen / Algazi, Alain / Mateus, Christine / Boasberg, Peter / Tumeh, Paul C / Chmielowski, Bartosz / Ebbinghaus, Scot W / Li, Xiaoyun Nicole / Kang, S Peter / Ribas, Antoni. ·Angeles Clinic and Research Institute, Los Angeles, CA, USA. ·N Engl J Med · Pubmed #23724846.

ABSTRACT: BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).

18 Article Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal? 2019

Duma, Narjust / Abdel-Ghani, Azzouqa / Yadav, Siddhartha / Hoversten, Katherine P / Reed, Clay T / Sitek, Andrea N / Enninga, Elizabeth Ann L / Paludo, Jonas / Aguilera, Jesus Vera / Leventakos, Konstantinos / Lou, Yanyan / Kottschade, Lisa A / Dong, Haidong / Mansfield, Aaron S / Manochakian, Rami / Adjei, Alex A / Dronca, Roxana S. ·Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, Florida, USA. · Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Division of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, Florida, USA dronca.roxana@mayo.edu. ·Oncologist · Pubmed #31036771.

ABSTRACT: BACKGROUND: Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy. MATERIALS AND METHODS: All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis. RESULTS: In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. CONCLUSION: Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. IMPLICATIONS FOR PRACTICE: The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

19 Article Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine. 2019

Vera, Jesus / Paludo, Jonas / Kottschade, Lisa / Brandt, Jessica / Yan, Yiyi / Block, Matthew / McWilliams, Robert / Dronca, Roxana / Loprinzi, Charles / Grothey, Axel / Markovic, Svetomir N. ·Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. · Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Markovic.svetomir@mayo.edu. ·Support Care Cancer · Pubmed #30767130.

ABSTRACT: The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

20 Article CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. 2018

Yan, Yiyi / Cao, Siyu / Liu, Xin / Harrington, Susan M / Bindeman, Wendy E / Adjei, Alex A / Jang, Jin Sung / Jen, Jin / Li, Ying / Chanana, Pritha / Mansfield, Aaron S / Park, Sean S / Markovic, Svetomir N / Dronca, Roxana S / Dong, Haidong. ·Division of Medical Oncology. · Department of Urology. · Mayo Clinic Cancer Center Early Therapeutic Program. · Mayo Clinic Center of Individualized Medicine. · Department of Biomedical Statistics and Informatics. · Department of Radiation Oncology, and. · Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. ·JCI Insight · Pubmed #29669928.

ABSTRACT: Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.

21 Article Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011. 2017

Enninga, Elizabeth Ann L / Moser, Justin C / Weaver, Amy L / Markovic, Svetomir N / Brewer, Jerry D / Leontovich, Alexey A / Hieken, Tina J / Shuster, Lynne / Kottschade, Lisa A / Olariu, Ariadna / Mansfield, Aaron S / Dronca, Roxana S. ·Department of Oncology, Division of Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, France. · Huntsman Cancer Institute, Divisions of Hematology and Oncology, University of Utah, 30 N 1900 E, Salt Lake City, Utah, 84132, France. · Biomedical Statistics and Informatics, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, France. · Department of Dermatology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, France. · Department of Surgery, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, France. · Department of Surgery, Notre Dame des Aydes, Notre Dame des Aydes 11 Rue Franciade, Blois, 41000, France. ·Cancer Med · Pubmed #28879661.

ABSTRACT: Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18-45, 46-54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.

22 Article Association between the use of surveillance PET/CT and the detection of potentially salvageable occult recurrences among patients with resected high-risk melanoma. 2017

Leon-Ferre, Roberto A / Kottschade, Lisa A / Block, Matthew S / McWilliams, Robert R / Dronca, Roxana S / Creagan, Edward T / Allred, Jacob B / Lowe, Val J / Markovic, Svetomir N. ·Departments of aOncology bRadiology cDepartment of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota, USA. ·Melanoma Res · Pubmed #28296712.

ABSTRACT: The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III-IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I-II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68-6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94-93.31%), specificity (90%, 95% CI=88.56-91.56%), and negative predictive value (99%, 95% CI=98.46-99.52%). However, the positive predictive value was only 37% (95% CI=31.32-43.68%). In patients with resected stage III-IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities.

23 Article The use of pembrolizumab for the treatment of metastatic uveal melanoma. 2016

Kottschade, Lisa A / McWilliams, Robert R / Markovic, Svetomir N / Block, Matthew S / Villasboas Bisneto, Jose / Pham, Anthony Q / Esplin, Brandt L / Dronca, Roxana S. ·Departments of aOncology bHematology cImmunology, Mayo Clinic, Rochester, Minnesota, USA. ·Melanoma Res · Pubmed #26848796.

ABSTRACT: Uveal melanoma is a rare type of melanoma, with only five to seven cases per one million persons diagnosed each year. Patients with metastatic melanoma of uveal origin tend to have lower response rates on traditional therapies. Herein we report our experience with 10 patients with metastatic uveal melanoma (MUM) who received pembrolizumab. Eligible patients were more than or equal to 18 years old, had unresectable MUM, progressed on prior ipilimumab therapy, had good performance status (Eastern Cooperative Oncology Group of 0 or 1), and adequate organ and marrow function. Patients could have central nervous system disease, but needed to be clinically stable. Patients were treated with 2 mg/kg pembrolizumab intravenously over 30 min every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years. Between April 2014 and October 2014, we treated a total of 10 patients with MUM with pembrolizumab. Median age was 65 years, with 70% being female. As of the data cutoff date of 14 May 2015, median progression-free survival was 18 weeks (range 3.14-49.3 weeks), with four patients still currently receiving therapy. Of eight evaluable patients, there was one complete response, two partial responses, and one patient with stable disease. Four patients had rapidly progressive disease. Toxicities were as expected and were usually grade 1/2 in nature. Although this cohort of patients was small, to our knowledge this is the first such report of outcomes in uveal melanoma patients being treated with anti-PD1 therapy. In the absence of a clinical trial, treatment with pembrolizumab appears to be a viable option for patients with MUM.

24 Article A gender factor in shaping T-cell immunity to melanoma. 2015

Dronca, Roxana S / Dong, Haidong. ·Division of Medical Oncology, College of Medicine, Mayo Clinic , Rochester, MN , USA. · Department of Urology, College of Medicine, Mayo Clinic , Rochester, MN , USA ; Department of Immunology, College of Medicine, Mayo Clinic , Rochester, MN , USA. ·Front Oncol · Pubmed #25699234.

ABSTRACT: -- No abstract --

25 Article The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab, bevacizumab, and local therapies in the treatment of metastatic uveal melanoma. 2015

Moser, Justin C / Pulido, Jose S / Dronca, Roxana S / McWilliams, Robert R / Markovic, Svetomir N / Mansfield, Aaron S. ·Departments of aInternal Medicine bOphthalmology cOncology, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA. ·Melanoma Res · Pubmed #25396683.

ABSTRACT: Uveal melanoma is the most common neoplasm of the adult eye. Many patients will develop metastatic disease, for which there is no standard of care. Therefore, we sought to review our experience with treating this neoplasm. We retrospectively reviewed all of the cases of metastatic uveal melanoma seen at the Mayo Clinic, Rochester, Minnesota, USA, between 1 January 2000 and 1 August 2013. Overall survival rates were compared among patients treated with local therapies (LTs), ipilumumab, bevacizumab, or kinase inhibitors. A total of 101 patients were included in the study, among whom 59% were male; the median age was 62 years (interquartile range 54-71), and 92% had an Eastern Cooperative Oncology Group performance status of 0-1. Treatment with LT was associated with increased median overall survival: 26 months (n=46; interquartile range 20-44) versus 9.1 months (n=55; 4.1-20, P<0.0001). No significant survival benefit was seen with the use of bevacizumab (25 vs. 12 months; P=0.09), ipilimumab (28 vs. 13 months; P=0.07), or kinase inhibitors (24 vs. 13 months; P=0.06). Multivariate analysis showed LT as the only therapy to significantly improve survival (risk ratio 0.23, P=0.0003). However, these patients had better markers of prognosis at the time of treatment. These data suggest that survival was improved in patients who were amenable to LTs; however, they had better prognostic markers at diagnosis of metastatic disease. Ongoing prospective clinical trials will define the roles of these novel agents in this patient population.

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