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Melanoma: HELP
Articles by Alain P. Algazi
Based on 24 articles published since 2009
(Why 24 articles?)
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Between 2009 and 2019, A. Algazi wrote the following 24 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline NCCN Guidelines Insights: Melanoma, Version 3.2016. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Fields, Ryan C / Fleming, Martin D / Gastman, Brian / Gonzalez, Rene / Guild, Valerie / Johnson, Douglas / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ott, Patrick / Gupta, Aparna Priyanath / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. ·From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27496110.

ABSTRACT: The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

2 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

3 Review Melanoma immunotherapy. 2014

Sanlorenzo, Martina / Vujic, Igor / Posch, Christian / Dajee, Akshay / Yen, Adam / Kim, Sarasa / Ashworth, Michelle / Rosenblum, Michael D / Algazi, Alain / Osella-Abate, Simona / Quaglino, Pietro / Daud, Adil / Ortiz-Urda, Susanna. ·University of California San Francisco; San Francisco, CA USA; Department of Medical Sciences; Section of Dermatology; University of Turin; Turin, Italy. · University of California San Francisco; San Francisco, CA USA; The Rudolfstiftung Hospital; Vienna, Austria. · University of California San Francisco; San Francisco, CA USA. · Department of Medical Sciences; Section of Dermatology; University of Turin; Turin, Italy. ·Cancer Biol Ther · Pubmed #24651672.

ABSTRACT: Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment.

4 Clinical Trial Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. 2018

Tawbi, Hussein A / Forsyth, Peter A / Algazi, Alain / Hamid, Omid / Hodi, F Stephen / Moschos, Stergios J / Khushalani, Nikhil I / Lewis, Karl / Lao, Christopher D / Postow, Michael A / Atkins, Michael B / Ernstoff, Marc S / Reardon, David A / Puzanov, Igor / Kudchadkar, Ragini R / Thomas, Reena P / Tarhini, Ahmad / Pavlick, Anna C / Jiang, Joel / Avila, Alexandre / Demelo, Sheena / Margolin, Kim. ·From the University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.) · Moffitt Cancer Center and Research Institute, Tampa, FL (P.A.F., N.I.K.) · University of California-San Francisco, San Francisco (A. Algazi), the Angeles Clinic and Research Institute, Los Angeles (O.H.), Stanford University Hospital, Palo Alto (R.P.T.), and the Department of Medical Oncology, City of Hope, Duarte (K.M.) - all in California · Dana-Farber Cancer Institute, Boston (F.S.H., D.A.R.) · University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (S.J.M.) · University of Colorado Comprehensive Cancer Center, Aurora (K.L.) · University of Michigan, Ann Arbor (C.D.L.) · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.A.P.), Roswell Park Cancer Institute, Buffalo (M.S.E., I.P.), and New York University, Lake Success (A.C.P.) - all in New York · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · Winship Cancer Institute of Emory University, Atlanta (R.R.K.) · University of Pittsburgh Medical Center, Pittsburgh (A.T.) · Bristol-Myers Squibb, Princeton, NJ (J.J., A. Avila, S.D.) · and Cleveland Clinic-Taussig Cancer Institute, Cleveland (A.T.). ·N Engl J Med · Pubmed #30134131.

ABSTRACT: BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

5 Clinical Trial Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. 2018

Algazi, Alain P / Esteve-Puig, Rosaura / Nosrati, Adi / Hinds, Brian / Hobbs-Muthukumar, Adele / Nandoskar, Prachi / Ortiz-Urda, Susana / Chapman, Paul B / Daud, Adil. ·UCSF Melanoma Oncology, San Francisco, CA, USA. · UCSF Dermatology, San Francisco, CA, USA. · UCSD Dermatopathology, La Jolla, CA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. ·Pigment Cell Melanoma Res · Pubmed #28921907.

ABSTRACT: Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS-mutant and BRAF

6 Clinical Trial Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. 2017

Tumeh, Paul C / Hellmann, Matthew D / Hamid, Omid / Tsai, Katy K / Loo, Kimberly L / Gubens, Matthew A / Rosenblum, Michael / Harview, Christina L / Taube, Janis M / Handley, Nathan / Khurana, Neharika / Nosrati, Adi / Krummel, Matthew F / Tucker, Andrew / Sosa, Eduardo V / Sanchez, Phillip J / Banayan, Nooriel / Osorio, Juan C / Nguyen-Kim, Dan L / Chang, Jeremy / Shintaku, I Peter / Boasberg, Peter D / Taylor, Emma J / Munster, Pamela N / Algazi, Alain P / Chmielowski, Bartosz / Dummer, Reinhard / Grogan, Tristan R / Elashoff, David / Hwang, Jimmy / Goldinger, Simone M / Garon, Edward B / Pierce, Robert H / Daud, Adil. ·University of California, Los Angeles, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Angeles Clinic, Los Angeles, California. · University of California, San Francisco, San Francisco, California. · Johns Hopkins University, Baltimore, Maryland. · OncoSec Inc., San Diego, California. · University of California, San Francisco, San Francisco, California. adil.daud@ucsf.edu. ·Cancer Immunol Res · Pubmed #28411193.

ABSTRACT: We explored the association between liver metastases, tumor CD8

7 Clinical Trial Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. 2017

Nosrati, Adi / Tsai, Katy K / Goldinger, Simone M / Tumeh, Paul / Grimes, Barbara / Loo, Kimberly / Algazi, Alain P / Nguyen-Kim, Thi Dan Linh / Levesque, Mitchell / Dummer, Reinhard / Hamid, Omid / Daud, Adil. ·Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco, Mount Zion A-743, 1600 Divisadero Street, San Francisco, CA 94143, USA. · Department of Dermatology, University Hospital of Zurich (USZ), University of Zurich, Gloriastrasse 31, Zürich 8091, Switzerland. · Division of Dermatology, Department of Medicine, University of California Los Angeles (UCLA), 200 Medical Plaza Driveway, Los Angeles, CA 90024, USA. · Department of Epidemiology & Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA 94158, USA. · Department of Interventional Radiology, University of Zurich, Rämistrasse 100, Zürich, 8091, Switzerland. · The Angeles Clinic and Research Institute (TACRI), 11818 Wilshire Boulevard #200, Los Angeles, CA 90025, USA. ·Br J Cancer · Pubmed #28324889.

ABSTRACT: BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg RESULTS: The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.

8 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.

9 Clinical Trial Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. 2016

Long, Georgina V / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Daud, Adil / Gonzalez, Rene / Sosman, Jeffrey A / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Kefford, Richard F / Lawrence, Donald / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Puzanov, Igor / Ibrahim, Nageatte / Sun, Peng / Cunningham, Elizabeth / Kline, Amy S / Del Buono, Heather / McDowell, Diane Opatt / Patel, Kiran / Flaherty, Keith T. ·Georgina V. Long, Melanoma Institute Australia · The University of Sydney · Richard F. Kefford, Melanoma Institute Australia · The University of Sydney · Macquarie University, Sydney · Westmead Hospital, Westmead · Jonathan Cebon, Austin Health, Melbourne, Victoria, Australia · Jeffrey S. Weber and Ragini Kudchadkar, Moffitt Cancer Center, Tampa, FL · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute/Tennessee Oncology · Kevin B. Kim, California Pacific Medical Center · Adil Daud, Alain Algazi, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, Karl Lewis, University of Colorado · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Jeffrey A. Sosman, Igor Puzanov, Vanderbilt University Medical Center, Nashville, TN · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Elizabeth Cunningham, Merck · Peng Sun, Amy S. Kline, Heather Del Buono, Diane Opatt McDowell, GlaxoSmithKline, Philadelphia, PA · Donald Lawrence and Kiran Patel, Incyte Corporation, Wilmington, DE · and Keith T. Flaherty, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #26811525.

ABSTRACT: PURPOSE: To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. METHODS: BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. RESULTS: For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. CONCLUSION: Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

10 Clinical Trial The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial. 2015

Algazi, A P / Cha, E / Ortiz-Urda, S M / McCalmont, T / Bastian, B C / Hwang, J / Pampaloni, M H / Behr, S / Chong, K / Cortez, B / Quiroz, A / Coakley, F / Liu, S / Daud, A I. ·Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA. · Department of Dermatology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA. · Department of Nuclear Medicine, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA. · Department of Radiology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA. ·Br J Cancer · Pubmed #25867272.

ABSTRACT: BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

11 Clinical Trial Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. 2014

Johnson, Douglas B / Flaherty, Keith T / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Kefford, Richard F / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William H / McWilliams, Robert R / Sznol, Mario / Lawrence, Donald P / Gibney, Geoffrey T / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Long, Georgina V / Patel, Kiran / Ibrahim, Nageatte / Sun, Peng / Little, Shonda / Cunningham, Elizabeth / Sosman, Jeffrey A / Daud, Adil / Gonzalez, Rene. ·Douglas B. Johnson and Jeffrey A. Sosman, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN · Keith T. Flaherty and Donald P. Lawrence, Massachusetts General Hospital Cancer Center, Boston MA · Jeffrey S. Weber and Geoffrey T. Gibney, Moffitt Cancer Center, Tampa, FL · Kevin B. Kim and Gerald S. Falchook, University of Texas MD Anderson Cancer Center, Houston, TX · Richard F. Kefford and Georgina V. Long, Melanoma Institute Australia, University of Sydney and Westmead Hospital, Sydney, New South Wales · Jonathan Cebon, Joint Ludwig-Austin Oncology Unit, Austin Health, Melbourne, Victoria, Australia · Omid Hamid, Angeles Clinic and Research Institute, Los Angeles · Alain Algazi and Adil Daud, University of California, San Francisco, San Francisco, CA · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Peng Sun, Shonda Little, and Elizabeth Cunningham, GlaxoSmithKline, Philadelphia, PA · William H. Sharfman, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD · Robert R. McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · Karl Lewis and Rene Gonzalez, University of Colorado, Denver, CO · and Kiran Patel, Incyte, Wilmington, DE. ·J Clin Oncol · Pubmed #25287827.

ABSTRACT: PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

12 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.).

13 Clinical Trial Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. 2012

Long, Georgina V / Trefzer, Uwe / Davies, Michael A / Kefford, Richard F / Ascierto, Paolo A / Chapman, Paul B / Puzanov, Igor / Hauschild, Axel / Robert, Caroline / Algazi, Alain / Mortier, Laurent / Tawbi, Hussein / Wilhelm, Tabea / Zimmer, Lisa / Switzky, Julie / Swann, Suzanne / Martin, Anne-Marie / Guckert, Mary / Goodman, Vicki / Streit, Michael / Kirkwood, John M / Schadendorf, Dirk. ·Melanoma Institute Australia, Westmead Institute for Cancer Research, and Westmead Hospital, The University of Sydney, Sydney, NSW, Australia. georgina.long@sydney.edu.au ·Lancet Oncol · Pubmed #23051966.

ABSTRACT: BACKGROUND: Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. METHODS: We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (≥5 mm and ≤40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01266967. FINDINGS: Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39·2%, 95% CI 28·0-51·2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30·8%, 19·9-43·4) of 65 in cohort B. One (6·7%, 0·2-31·9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22·2%, 6·4-47·6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). INTERPRETATION: Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. FUNDING: GlaxoSmithKline.

14 Clinical Trial Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. 2012

Flaherty, Keith T / Infante, Jeffery R / Daud, Adil / Gonzalez, Rene / Kefford, Richard F / Sosman, Jeffrey / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Ibrahim, Nageatte / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald / Algazi, Alain / Lewis, Karl / Long, Georgina V / Puzanov, Igor / Lebowitz, Peter / Singh, Ajay / Little, Shonda / Sun, Peng / Allred, Alicia / Ouellet, Daniele / Kim, Kevin B / Patel, Kiran / Weber, Jeffrey. ·Massachusetts General Hospital Cancer Center, Boston, USA. ·N Engl J Med · Pubmed #23020132.

ABSTRACT: BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

15 Clinical Trial Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma. 2012

Algazi, A P / Weber, J S / Andrews, S C / Urbas, P / Munster, P N / DeConti, R C / Hwang, J / Sondak, V K / Messina, J L / McCalmont, T / Daud, A I. ·University of California, San Francisco, MTZ-A741, 1600 Divisadero Street, San Francisco, CA 94143, USA. ·Br J Cancer · Pubmed #22127285.

ABSTRACT: BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

16 Clinical Trial Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma. 2010

DeConti, R C / Algazi, A P / Andrews, S / Urbas, P / Born, O / Stoeckigt, D / Floren, L / Hwang, J / Weber, J / Sondak, V K / Daud, A I. ·Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA. ·Br J Cancer · Pubmed #20924376.

ABSTRACT: BACKGROUND: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. METHODS: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). CONCLUSION: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

17 Article High response rate to PD-1 blockade in desmoplastic melanomas. 2018

Eroglu, Zeynep / Zaretsky, Jesse M / Hu-Lieskovan, Siwen / Kim, Dae Won / Algazi, Alain / Johnson, Douglas B / Liniker, Elizabeth / Ben Kong, ? / Munhoz, Rodrigo / Rapisuwon, Suthee / Gherardini, Pier Federico / Chmielowski, Bartosz / Wang, Xiaoyan / Shintaku, I Peter / Wei, Cody / Sosman, Jeffrey A / Joseph, Richard W / Postow, Michael A / Carlino, Matteo S / Hwu, Wen-Jen / Scolyer, Richard A / Messina, Jane / Cochran, Alistair J / Long, Georgina V / Ribas, Antoni. ·University of California Los Angeles, Los Angeles, California, USA. · Moffitt Cancer Center and University of South Florida, Tampa, Florida, USA. · The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA. · University of California San Francisco, San Francisco, California, USA. · Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Weill Cornell Medical College, New York, New York, USA. · Georgetown Lombardi Cancer Center, Washington DC, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. · Mayo Clinic, Jacksonville, Florida, USA. · The University of Sydney, Sydney, New South Wales, Australia. · Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Nature · Pubmed #29320474.

ABSTRACT: Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

18 Article Melanoma treatment with intratumoral electroporation of tavokinogene telseplasmid (pIL-12, tavokinogene telseplasmid). 2017

Canton, David A / Shirley, Shawna / Wright, Jocelyn / Connolly, Richard / Burkart, Christoph / Mukhopadhyay, Anandaroop / Twitty, Chris / Qattan, Kristen E / Campbell, Jean S / Le, Mai H / Pierce, Robert H / Gargosky, Sharron / Daud, Adil / Algazi, Alain. ·OncoSec Medical Incorporated, 5820 Nancy Ridge Dr, San Diego, CA 92121, USA. · Fred Hutchinson Cancer Research Center, Clinical Research Division, 1100 Fairview Ave. N. Seattle, WA 98109, USA. · UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St, San Francisco, CA 94115, USA. ·Immunotherapy · Pubmed #29064334.

ABSTRACT: Tumors evade detection and/or clearance by the immune system via multiple mechanisms. IL-12 is a potent immunomodulatory cytokine that plays a central role in immune priming. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. We developed an electroporation technique to produce highly localized IL-12 expression within tumors leading to regression of both treated and untreated lesions in animal models and in patients with a favorable safety profile. Furthermore, intratumoral tavokinogene telseplasmid electroporation can drive cellular immune responses, converting 'cold' tumors into 'hot' tumors. Clinical trials are ongoing to determine whether intratumoral tavokinogene telseplasmid electroporation synergizes with checkpoint blockade therapy in immunologically cold tumors predicted not to respond to PD-1 antibody monotherapy.

19 Article The efficacy of anti-PD-1 agents in acral and mucosal melanoma. 2016

Shoushtari, Alexander N / Munhoz, Rodrigo R / Kuk, Deborah / Ott, Patrick A / Johnson, Douglas B / Tsai, Katy K / Rapisuwon, Suthee / Eroglu, Zeynep / Sullivan, Ryan J / Luke, Jason J / Gangadhar, Tara C / Salama, April K S / Clark, Varina / Burias, Clare / Puzanov, Igor / Atkins, Michael B / Algazi, Alain P / Ribas, Antoni / Wolchok, Jedd D / Postow, Michael A. ·Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York. shoushta@mskcc.org. · Weill Cornell Medical College, New York, New York. shoushta@mskcc.org. · Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. · Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. · Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia. · Moffitt Cancer Center, Tampa, Florida. · Massachussetts General Hospital, Harvard Medical School, Boston, Massachusetts. · University of Chicago Comprehensive Cancer Center Chicago, Illinois. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. · Duke University School of Medicine, Durham, North Carolina. · Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. · Weill Cornell Medical College, New York, New York. ·Cancer · Pubmed #27533633.

ABSTRACT: BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS: Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society.

20 Article Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. 2016

Algazi, Alain P / Tsai, Katy K / Shoushtari, Alexander N / Munhoz, Rodrigo R / Eroglu, Zeynep / Piulats, Josep M / Ott, Patrick A / Johnson, Douglas B / Hwang, Jimmy / Daud, Adil I / Sosman, Jeffrey A / Carvajal, Richard D / Chmielowski, Bartosz / Postow, Michael A / Weber, Jeffrey S / Sullivan, Ryan J. ·Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. alain.algazi@ucsf.edu. · Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. · Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York. · Moffitt Cancer Center, Tampa, Florida. · Spanish Melanoma Multidisciplinary Group, Barcelona, Spain. · Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. · Columbia University Medical Center, New York, New York. · Johansson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California. · Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York. · Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Cancer · Pubmed #27533448.

ABSTRACT: BACKGROUND: Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS: Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. RESULTS: Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. CONCLUSIONS: PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society.

21 Article Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. 2016

Daud, Adil I / Loo, Kimberly / Pauli, Mariela L / Sanchez-Rodriguez, Robert / Sandoval, Priscila Munoz / Taravati, Keyon / Tsai, Katy / Nosrati, Adi / Nardo, Lorenzo / Alvarado, Michael D / Algazi, Alain P / Pampaloni, Miguel H / Lobach, Iryna V / Hwang, Jimmy / Pierce, Robert H / Gratz, Iris K / Krummel, Matthew F / Rosenblum, Michael D. · ·J Clin Invest · Pubmed #27525433.

ABSTRACT: BACKGROUND: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. METHODS: We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype. RESULTS: Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs. CONCLUSIONS: Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition. FUNDING: This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.

22 Article Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. 2015

Moriceau, Gatien / Hugo, Willy / Hong, Aayoung / Shi, Hubing / Kong, Xiangju / Yu, Clarissa C / Koya, Richard C / Samatar, Ahmed A / Khanlou, Negar / Braun, Jonathan / Ruchalski, Kathleen / Seifert, Heike / Larkin, James / Dahlman, Kimberly B / Johnson, Douglas B / Algazi, Alain / Sosman, Jeffrey A / Ribas, Antoni / Lo, Roger S. ·Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Division of Oncology, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. · Discovery Oncology, Merck Research Laboratories, Boston, MA 02115, USA. · Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Department of Medicine, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. · Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. · Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. · Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. · Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. · Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rlo@mednet.ucla.edu. ·Cancer Cell · Pubmed #25600339.

ABSTRACT: Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

23 Article Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. 2014

Sanlorenzo, Martina / Choudhry, Aditi / Vujic, Igor / Posch, Christian / Chong, Kim / Johnston, Katia / Meier, Melissa / Osella-Abate, Simona / Quaglino, Pietro / Daud, Adil / Algazi, Alain / Rappersberger, Klemens / Ortiz-Urda, Susana. ·University of California-San Francisco, Mt Zion Cancer Research Center, San Francisco, California; Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy. Electronic address: martina.sanlorenzo@hotmail.it. · University of California-San Francisco, Mt Zion Cancer Research Center, San Francisco, California. · University of California-San Francisco, Mt Zion Cancer Research Center, San Francisco, California; Department of Dermatology, Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria. · Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy. · Department of Dermatology, Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria. ·J Am Acad Dermatol · Pubmed #25440439.

ABSTRACT: BACKGROUND: BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events. OBJECTIVE: We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens. METHODS: We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described. RESULTS: The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not. LIMITATIONS: There were a limited number of patients. CONCLUSION: Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.

24 Minor NRAS-mutant melanoma: response to chemotherapy. 2011

Soon, Christopher W M / Algazi, Alain P / Cha, Edward N / Webb, Emma M / Daud, Adil I. · ·Arch Dermatol · Pubmed #21576590.

ABSTRACT: -- No abstract --