458 results on '"Atkins, MB"'
Search Results
2. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial
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Long, GV, Atkinson, V, Cebon, JS, Jameson, MB, Fitzharris, BM, McNeil, CM, Hill, AG, Ribas, A, Atkins, MB, Thompson, JA, Hwu, WJ, Hodi, FS, Menzies, AM, Guminski, AD, Kefford, R, Kong, BY, Tamjid, B, Srivastava, A, Lomax, AJ, Islam, M, Shu, X, Ebbinghaus, S, Ibrahim, N, Carlino, MS, Long, GV, Atkinson, V, Cebon, JS, Jameson, MB, Fitzharris, BM, McNeil, CM, Hill, AG, Ribas, A, Atkins, MB, Thompson, JA, Hwu, WJ, Hodi, FS, Menzies, AM, Guminski, AD, Kefford, R, Kong, BY, Tamjid, B, Srivastava, A, Lomax, AJ, Islam, M, Shu, X, Ebbinghaus, S, Ibrahim, N, and Carlino, MS
- Abstract
© 2017 Elsevier Ltd Background Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. Methods In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety
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- 2017
3. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.
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Jay, Raman, primary, McKay, RR, additional, Werner, L, additional, Atkins, MB, additional, Van Allen, EM, additional, Olivier, KM, additional, Song, J, additional, Signoretti, S, additional, McDermott, DF, additional, and Choueiri, TK, additional
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- 2017
- Full Text
- View/download PDF
4. The state of melanoma: challenges and opportunities
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Merlino, G, Herlyn, M, Fisher, DE, Bastian, BC, Flaherty, KT, Davies, MA, Wargo, JA, Curiel-Lewandrowski, C, Weber, MJ, Leachman, SA, Soengas, MS, McMahon, M, Harbour, JW, Swetter, SM, Aplin, AE, Atkins, MB, Bosenberg, MW, Dummer, R, Gershenwald, JE, Halpern, AC, Herlyn, D, Karakousis, GC, Kirkwood, JM, Krauthammer, M, Lo, RS, Long, GV, McArthur, G, Ribas, A, Schuchter, L, Sosman, JA, Smalley, KS, Steeg, P, Thomas, NE, Tsao, H, Tueting, T, Weeraratna, A, Xu, G, Lomax, R, Martin, A, Silverstein, S, Turnham, T, Ronai, ZA, Merlino, G, Herlyn, M, Fisher, DE, Bastian, BC, Flaherty, KT, Davies, MA, Wargo, JA, Curiel-Lewandrowski, C, Weber, MJ, Leachman, SA, Soengas, MS, McMahon, M, Harbour, JW, Swetter, SM, Aplin, AE, Atkins, MB, Bosenberg, MW, Dummer, R, Gershenwald, JE, Halpern, AC, Herlyn, D, Karakousis, GC, Kirkwood, JM, Krauthammer, M, Lo, RS, Long, GV, McArthur, G, Ribas, A, Schuchter, L, Sosman, JA, Smalley, KS, Steeg, P, Thomas, NE, Tsao, H, Tueting, T, Weeraratna, A, Xu, G, Lomax, R, Martin, A, Silverstein, S, Turnham, T, and Ronai, ZA
- Abstract
The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.
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- 2016
5. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015.
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Nanda, VGY, Peng, W, Hwu, P, Davies, MA, Ciliberto, G, Fattore, L, Malpicci, D, Aurisicchio, L, Ascierto, PA, Croce, CM, Mancini, R, Spranger, S, Gajewski, TF, Wang, Y, Ferrone, S, Vanpouille-Box, C, Wennerberg, E, Pilones, KA, Formenti, SC, Demaria, S, Tang, H, Fu, Y-X, Dummer, R, Puzanov, I, Tarhini, A, Chauvin, J-M, Pagliano, O, Fourcade, J, Sun, Z, Wang, H, Sanders, C, Kirkwood, JM, Chen, T-HT, Maurer, M, Korman, AJ, Zarour, HM, Stroncek, DF, Huber, V, Rivoltini, L, Thurin, M, Rau, T, Lugli, A, Pagès, F, Camarero, J, Sancho, A, Jommi, C, de Coaña, YP, Wolodarski, M, Yoshimoto, Y, Gentilcore, G, Poschke, I, Masucci, GV, Hansson, J, Kiessling, R, Scognamiglio, G, Sabbatino, F, Marino, FZ, Anniciello, AM, Cantile, M, Cerrone, M, Scala, S, D’alterio, C, Ianaro, A, Cirin, G, Liguori, G, Bott, G, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Ribas, A, Hogg, D, Hamid, O, Testori, A, Lorigan, P, Sosman, JA, Flaherty, KT, Yue, H, Coleman, S, Caro, I, Hauschild, A, McArthur, GA, Sznol, M, Callahan, MK, Kluger, H, Postow, MA, Gordan, R, Segal, NH, Rizvi, NA, Lesokhin, A, Atkins, MB, Burke, MM, Ralabate, A, Rivera, A, Kronenberg, SA, Agunwamba, B, Ruisi, M, Horak, C, Jiang, J, Wolchok, J, Liszkay, G, Maio, M, Mandalà, M, Demidov, L, Stoyakovskiy, D, Thomas, L, de la Cruz-Merino, L, Atkinson, V, Dutriaux, C, Garbe, C, Wongchenko, M, Chang, I, Koralek, DO, Rooney, I, Yan, Y, Dréno, B, Sullivan, R, Patel, M, Hodi, S, Amaria, R, Boasberg, P, Wallin, J, He, X, Cha, E, Richie, N, Ballinger, M, Smith, DC, Bauer, TM, Wasser, JS, Luke, JJ, Balmanoukian, AS, Kaufman, DR, Zhao, Y, Maleski, J, Leopold, L, Gangadhar, TC, Long, GV, Michielin, O, VanderWalde, A, Andtbacka, RHI, Cebon, J, Fernandez, E, Malvehy, J, Olszanski, AJ, Gause, C, Chen, L, Chou, J, Stephen Hodi, F, Brady, B, Mortier, L, Hassel, JC, Rutkowski, P, McNeil, C, Kalinka-Warzocha, E, Lebbé, C, Ny, L, Chacon, M, Queirolo, P, Loquai, C, Cheema, P, Berrocal, A, Eizmendi, KM, Bar-Sela, G, Hardy, H, Weber, JS, Grob, J-J, Marquez-Rodas, I, Schmidt, H, Briscoe, K, Baurain, J-F, Wolchok, JD, Pinto, R, De Summa, S, Garrisi, VM, Strippoli, S, Azzariti, A, Guida, G, Guida, M, Tommasi, S, Jacquelot, N, Enot, D, Flament, C, Pitt, JM, Vimond, N, Blattner, C, Yamazaki, T, Roberti, M-P, Vetizou, M, Daillere, R, Poirier-Colame, V, la Semeraro, M, Caignard, A, Slingluff, CL, Sallusto, F, Rusakiewicz, S, Weide, B, Marabelle, A, Kohrt, H, Dalle, S, Cavalcanti, A, Kroemer, G, Di Giacomo, AM, Wong, P, Yuan, J, Umansky, V, Eggermont, A, Zitvogel, L, Anna, P, Marco, T, Stefania, S, Francesco, M, Mariaelena, C, Gabriele, M, Antonio, AP, Franco, S, Roberti, MP, Enot, DP, Semeraro, M, Jégou, S, Flores, C, Kwon, BS, Anderson, AC, Borg, C, Aubin, F, Ayyoub, M, De Presbiteris, AL, Cordaro, FG, Camerlingo, R, Fratangelo, F, Mozzillo, N, Pirozzi, G, Patriarca, EJ, Caputo, E, Motti, ML, Falcon, R, Miceli, R, Capone, M, Madonna, G, Mallardo, D, Carrier, MV, Panza, E, De Cicco, P, Armogida, C, Ercolano, G, Botti, G, Cirino, G, Sandru, A, Blank, M, Balatoni, T, Olasz, J, Farkas, E, Szollar, A, Savolt, A, Godeny, M, Csuka, O, Horvath, S, Eles, K, Shoenfeld, Y, Kasler, M, Costantini, S, Capone, F, Moradi, F, Berglund, P, Leandersson, K, Linnskog, R, Andersson, T, Prasad, CP, Nigro, CL, Lattanzio, L, Proby, C, Syed, N, Occelli, M, Cauchi, C, Merlano, M, Harwood, C, Thompson, A, Crook, T, Bifulco, K, Ingangi, V, Minopoli, M, Ragone, C, Pessi, A, Mannavola, F, D’Oronzo, S, Felici, C, Tucci, M, Doronzo, A, Silvestris, F, Ferretta, A, Guida, S, Maida, I, Cocco, T, Passarelli, A, Quaresmini, D, Franzese, O, Palermo, B, Di Donna, C, Sperduti, I, Foddai, M, Stabile, H, Gismondi, A, Santoni, A, Nisticò, P, Sponghini, AP, Platini, F, Marra, E, Rondonotti, D, Alabiso, O, Fierro, MT, Savoia, P, Stratica, F, Quaglino, P, Di Monta, G, Corrado, C, Di Marzo, M, Ugo, M, Di Cecilia, ML, Nicola, M, Fusciello, C, Marra, A, Guarrasi, R, Baldi, C, Russo, R, Di Giulio, G, Faiola, V, Zeppa, P, Pepe, S, Gambale, E, Carella, C, Di Paolo, A, De Tursi, M, Marra, L, De Murtas, F, Sorrentino, V, Voinea, S, Panaitescu, E, Bolovan, M, Stanciu, A, Cinca, S, Botti, C, Aquino, G, Anniciello, A, Fortes, C, Mastroeni, S, Caggiati, A, Passarelli, F, Zappalà, A, Capuano, M, Bono, R, Nudo, M, Marino, C, Michelozzi, P, De Biasio, V, Battarra, VC, Formenti, S, Ascierto, ML, McMiller, TL, Berger, AE, Danilova, L, Anders, RA, Netto, GJ, Xu, H, Pritchard, TS, Fan, J, Cheadle, C, Cope, L, Drake, CG, Pardoll, DM, Taube, JM, Topalian, SL, Gnjatic, S, Nataraj, S, Imai, N, Rahman, A, Jungbluth, AA, Pan, L, Venhaus, R, Park, A, Lehmann, FF, Lendvai, N, Cohen, AD, Cho, HJ, Daniel, S, Hirsh, V, Nanda, VGY, Peng, W, Hwu, P, Davies, MA, Ciliberto, G, Fattore, L, Malpicci, D, Aurisicchio, L, Ascierto, PA, Croce, CM, Mancini, R, Spranger, S, Gajewski, TF, Wang, Y, Ferrone, S, Vanpouille-Box, C, Wennerberg, E, Pilones, KA, Formenti, SC, Demaria, S, Tang, H, Fu, Y-X, Dummer, R, Puzanov, I, Tarhini, A, Chauvin, J-M, Pagliano, O, Fourcade, J, Sun, Z, Wang, H, Sanders, C, Kirkwood, JM, Chen, T-HT, Maurer, M, Korman, AJ, Zarour, HM, Stroncek, DF, Huber, V, Rivoltini, L, Thurin, M, Rau, T, Lugli, A, Pagès, F, Camarero, J, Sancho, A, Jommi, C, de Coaña, YP, Wolodarski, M, Yoshimoto, Y, Gentilcore, G, Poschke, I, Masucci, GV, Hansson, J, Kiessling, R, Scognamiglio, G, Sabbatino, F, Marino, FZ, Anniciello, AM, Cantile, M, Cerrone, M, Scala, S, D’alterio, C, Ianaro, A, Cirin, G, Liguori, G, Bott, G, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Ribas, A, Hogg, D, Hamid, O, Testori, A, Lorigan, P, Sosman, JA, Flaherty, KT, Yue, H, Coleman, S, Caro, I, Hauschild, A, McArthur, GA, Sznol, M, Callahan, MK, Kluger, H, Postow, MA, Gordan, R, Segal, NH, Rizvi, NA, Lesokhin, A, Atkins, MB, Burke, MM, Ralabate, A, Rivera, A, Kronenberg, SA, Agunwamba, B, Ruisi, M, Horak, C, Jiang, J, Wolchok, J, Liszkay, G, Maio, M, Mandalà, M, Demidov, L, Stoyakovskiy, D, Thomas, L, de la Cruz-Merino, L, Atkinson, V, Dutriaux, C, Garbe, C, Wongchenko, M, Chang, I, Koralek, DO, Rooney, I, Yan, Y, Dréno, B, Sullivan, R, Patel, M, Hodi, S, Amaria, R, Boasberg, P, Wallin, J, He, X, Cha, E, Richie, N, Ballinger, M, Smith, DC, Bauer, TM, Wasser, JS, Luke, JJ, Balmanoukian, AS, Kaufman, DR, Zhao, Y, Maleski, J, Leopold, L, Gangadhar, TC, Long, GV, Michielin, O, VanderWalde, A, Andtbacka, RHI, Cebon, J, Fernandez, E, Malvehy, J, Olszanski, AJ, Gause, C, Chen, L, Chou, J, Stephen Hodi, F, Brady, B, Mortier, L, Hassel, JC, Rutkowski, P, McNeil, C, Kalinka-Warzocha, E, Lebbé, C, Ny, L, Chacon, M, Queirolo, P, Loquai, C, Cheema, P, Berrocal, A, Eizmendi, KM, Bar-Sela, G, Hardy, H, Weber, JS, Grob, J-J, Marquez-Rodas, I, Schmidt, H, Briscoe, K, Baurain, J-F, Wolchok, JD, Pinto, R, De Summa, S, Garrisi, VM, Strippoli, S, Azzariti, A, Guida, G, Guida, M, Tommasi, S, Jacquelot, N, Enot, D, Flament, C, Pitt, JM, Vimond, N, Blattner, C, Yamazaki, T, Roberti, M-P, Vetizou, M, Daillere, R, Poirier-Colame, V, la Semeraro, M, Caignard, A, Slingluff, CL, Sallusto, F, Rusakiewicz, S, Weide, B, Marabelle, A, Kohrt, H, Dalle, S, Cavalcanti, A, Kroemer, G, Di Giacomo, AM, Wong, P, Yuan, J, Umansky, V, Eggermont, A, Zitvogel, L, Anna, P, Marco, T, Stefania, S, Francesco, M, Mariaelena, C, Gabriele, M, Antonio, AP, Franco, S, Roberti, MP, Enot, DP, Semeraro, M, Jégou, S, Flores, C, Kwon, BS, Anderson, AC, Borg, C, Aubin, F, Ayyoub, M, De Presbiteris, AL, Cordaro, FG, Camerlingo, R, Fratangelo, F, Mozzillo, N, Pirozzi, G, Patriarca, EJ, Caputo, E, Motti, ML, Falcon, R, Miceli, R, Capone, M, Madonna, G, Mallardo, D, Carrier, MV, Panza, E, De Cicco, P, Armogida, C, Ercolano, G, Botti, G, Cirino, G, Sandru, A, Blank, M, Balatoni, T, Olasz, J, Farkas, E, Szollar, A, Savolt, A, Godeny, M, Csuka, O, Horvath, S, Eles, K, Shoenfeld, Y, Kasler, M, Costantini, S, Capone, F, Moradi, F, Berglund, P, Leandersson, K, Linnskog, R, Andersson, T, Prasad, CP, Nigro, CL, Lattanzio, L, Proby, C, Syed, N, Occelli, M, Cauchi, C, Merlano, M, Harwood, C, Thompson, A, Crook, T, Bifulco, K, Ingangi, V, Minopoli, M, Ragone, C, Pessi, A, Mannavola, F, D’Oronzo, S, Felici, C, Tucci, M, Doronzo, A, Silvestris, F, Ferretta, A, Guida, S, Maida, I, Cocco, T, Passarelli, A, Quaresmini, D, Franzese, O, Palermo, B, Di Donna, C, Sperduti, I, Foddai, M, Stabile, H, Gismondi, A, Santoni, A, Nisticò, P, Sponghini, AP, Platini, F, Marra, E, Rondonotti, D, Alabiso, O, Fierro, MT, Savoia, P, Stratica, F, Quaglino, P, Di Monta, G, Corrado, C, Di Marzo, M, Ugo, M, Di Cecilia, ML, Nicola, M, Fusciello, C, Marra, A, Guarrasi, R, Baldi, C, Russo, R, Di Giulio, G, Faiola, V, Zeppa, P, Pepe, S, Gambale, E, Carella, C, Di Paolo, A, De Tursi, M, Marra, L, De Murtas, F, Sorrentino, V, Voinea, S, Panaitescu, E, Bolovan, M, Stanciu, A, Cinca, S, Botti, C, Aquino, G, Anniciello, A, Fortes, C, Mastroeni, S, Caggiati, A, Passarelli, F, Zappalà, A, Capuano, M, Bono, R, Nudo, M, Marino, C, Michelozzi, P, De Biasio, V, Battarra, VC, Formenti, S, Ascierto, ML, McMiller, TL, Berger, AE, Danilova, L, Anders, RA, Netto, GJ, Xu, H, Pritchard, TS, Fan, J, Cheadle, C, Cope, L, Drake, CG, Pardoll, DM, Taube, JM, Topalian, SL, Gnjatic, S, Nataraj, S, Imai, N, Rahman, A, Jungbluth, AA, Pan, L, Venhaus, R, Park, A, Lehmann, FF, Lendvai, N, Cohen, AD, Cho, HJ, Daniel, S, and Hirsh, V
- Abstract
MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunosc
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- 2016
6. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014
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Dutcher, JP, Schwartzentruber, DJ, Kaufman, HL, Agarwala, SS, Tarhini, AA, Lowder, JN, Atkins, MB, Dutcher, JP, Schwartzentruber, DJ, Kaufman, HL, Agarwala, SS, Tarhini, AA, Lowder, JN, and Atkins, MB
- Abstract
Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient Selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.
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- 2014
7. Defining the critical hurdles in cancer immunotherapy
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Fox, BA, Schendel, DJ, Butterfield, LH, Aamdal, S, Allison, JP, Ascierto, PA, Atkins, MB, Bartunkova, J, Bergmann, L, Berinstein, N, Bonorino, CC, Borden, E, Bramson, JL, Britten, CM, Cao, X, Carson, WE, Chang, AE, Characiejus, D, Raja Choudhury, A, Coukos, G, de Gruijl, T, Dillman, RO, Dolstra, H, Dranoff, G, Durrant, LG, Finke, JH, Galon, J, Gollob, JA, Gouttefangeas, C, Grizzi, F, Guida, M, Håkansson, L, Hege, K, Herberman, RB, Stephen Hodi, F, Hoos, A, Huber, C, Hwu, P, Imai, K, Jaffee, EM, Janetzki, S, June, CH, Kalinski, P, Kaufman, HL, Kawakami, K, Kawakami, Y, Keilholtz, U, Khleif, SN, Kiessling, R, Kotlan, B, Kroemer, G, Lapointe, R, Levitsky, HI, Lotze, MT, Maccalli, C, Maio, M, Marschner, JP, Mastrangelo, MJ, Masucci, G, Melero, I, Melief, C, Murphy, WJ, Nelson, B, Nicolini, A, Nishimura, MI, Odunsi, K, Ohashi, PS, O'Donnell-Tormey, J, Old, LJ, Ottensmeier, C, Papamichail, M, Parmiani, G, Pawelec, G, Proietti, E, Qin, S, Rees, R, Ribas, A, Ridolfi, R, Ritter, G, Rivoltini, L, Romero, PJ, Salem, ML, Scheper, RJ, Seliger, B, Sharma, P, Shiku, H, Singh-Jasuja, H, Song, W, Straten, PT, Tahara, H, Tian, Z, van der Burg, SH, von Hoegen, P, Wang, E, Welters, MJP, Winter, H, Withington, T, Wolchok, JD, Xiao, W, Zitvogel, L, Fox, BA, Schendel, DJ, Butterfield, LH, Aamdal, S, Allison, JP, Ascierto, PA, Atkins, MB, Bartunkova, J, Bergmann, L, Berinstein, N, Bonorino, CC, Borden, E, Bramson, JL, Britten, CM, Cao, X, Carson, WE, Chang, AE, Characiejus, D, Raja Choudhury, A, Coukos, G, de Gruijl, T, Dillman, RO, Dolstra, H, Dranoff, G, Durrant, LG, Finke, JH, Galon, J, Gollob, JA, Gouttefangeas, C, Grizzi, F, Guida, M, Håkansson, L, Hege, K, Herberman, RB, Stephen Hodi, F, Hoos, A, Huber, C, Hwu, P, Imai, K, Jaffee, EM, Janetzki, S, June, CH, Kalinski, P, Kaufman, HL, Kawakami, K, Kawakami, Y, Keilholtz, U, Khleif, SN, Kiessling, R, Kotlan, B, Kroemer, G, Lapointe, R, Levitsky, HI, Lotze, MT, Maccalli, C, Maio, M, Marschner, JP, Mastrangelo, MJ, Masucci, G, Melero, I, Melief, C, Murphy, WJ, Nelson, B, Nicolini, A, Nishimura, MI, Odunsi, K, Ohashi, PS, O'Donnell-Tormey, J, Old, LJ, Ottensmeier, C, Papamichail, M, Parmiani, G, Pawelec, G, Proietti, E, Qin, S, Rees, R, Ribas, A, Ridolfi, R, Ritter, G, Rivoltini, L, Romero, PJ, Salem, ML, Scheper, RJ, Seliger, B, Sharma, P, Shiku, H, Singh-Jasuja, H, Song, W, Straten, PT, Tahara, H, Tian, Z, van der Burg, SH, von Hoegen, P, Wang, E, Welters, MJP, Winter, H, Withington, T, Wolchok, JD, Xiao, W, and Zitvogel, L
- Abstract
Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. © 2011 Fox et al; licensee BioMed Central Ltd.
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- 2011
8. Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial
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Gogas, H, Dafni, U, Koon, H, Spyropoulou-Vlachou, M, Metaxas, Y, Buchbinder, E, Pectasides, E, Tsoutsos, D, Polyzos, A, Stratigos, A, Markopoulos, C, Panagiotou, P, Fountzilas, G, Castana, O, Skarlos, P, Atkins, MB, Kirkwood, JM, Gogas, H, Dafni, U, Koon, H, Spyropoulou-Vlachou, M, Metaxas, Y, Buchbinder, E, Pectasides, E, Tsoutsos, D, Polyzos, A, Stratigos, A, Markopoulos, C, Panagiotou, P, Fountzilas, G, Castana, O, Skarlos, P, Atkins, MB, and Kirkwood, JM
- Abstract
Purpose: Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.Experimental design: 286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.Results: No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.Conclusion: No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients. © 2010 Gogas et al; licensee BioMed Central Ltd.
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- 2010
9. Treatment of BRAF-Mutant Melanoma: The Role of Vemurafenib and Other Therapies.
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Jang, S and Atkins, MB
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GENETIC mutation ,MELANOMA ,MITOGEN-activated protein kinases ,IMMUNOTHERAPY ,GENE therapy - Abstract
The discovery of activating BRAF mutations in melanomas has led to the investigation of small molecular inhibitors targeting BRAF mutation and MEK, a downstream protein within the mitogen-activated protein kinase (MAPK) pathway. This article reviews the role of mutant BRAF in melanoma and summarizes the results of clinical trials evaluating inhibitors of BRAF and MEK in BRAF-mutant melanoma. We further describe recent findings on the mechanisms of resistance to BRAF inhibitors and discuss ongoing efforts to combine BRAF inhibitors with other targeted agents. Finally, we review the results of immunotherapy in BRAF-mutant melanoma and address the current status of efforts to either combine or determine the optimal sequence of these two distinct treatment approaches. Although the recent advances in melanoma therapy have been dramatic, greater understanding of melanoma biology coupled with the successful development of several new treatments and combination regimens will further improve patient outcomes in the future.Clinical Pharmacology & Therapeutics (2013); 95 1, 24-31 advance online publication 27 November 2013. doi:10.1038/clpt.2013.197 [ABSTRACT FROM AUTHOR]
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- 2014
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10. PP34. Economic analysis of adjuvant interferon-ALFA 2B (IFN) in high risk melanoma using projections from ECOG (E) 1684
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Hillner, BE, primary, Kirkwood, JM, additional, Atkins, MB, additional, Johnson, ER, additional, and Smith, TJ, additional
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- 1997
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11. Interleukin-6-associated anemia: determination of the underlying mechanism
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Atkins, MB, primary, Kappler, K, additional, Mier, JW, additional, Isaacs, RE, additional, and Berkman, EM, additional
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- 1995
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12. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55
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Tilg, H, primary, Trehu, E, additional, Atkins, MB, additional, Dinarello, CA, additional, and Mier, JW, additional
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- 1994
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13. Complement activation in cancer patients undergoing immunotherapy with interleukin-2 (IL-2): binding of complement and C-reactive protein by IL-2-activated lymphocytes
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Vachino, G, primary, Gelfand, JA, additional, Atkins, MB, additional, Tamerius, JD, additional, Demchak, P, additional, and Mier, JW, additional
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- 1991
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14. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
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Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, and Choueiri TK
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- 2009
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15. Treatment selection for patients with metastatic renal cell carcinoma: identification of features favoring upfront IL-2-based immunotherapy.
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Atkins MB and Atkins, Michael B
- Abstract
The availability of approved agents with distinct mechanisms of action (immunotherapy, vascular endothelial growth factor pathway, and mTOR inhibitors) has complicated treatment decisions for patients with advanced kidney cancer. High-dose IL-2 therapy is the only treatment that can produce durable complete responses; however, it has significant side effects and the vast majority of patients do not benefit. Thus, identifying the optimal patients to receive first-line IL-2 therapy is a priority. Past studies have identified some clinical features that might be associated with benefit from IL-2-based immunotherapy. Subsequent investigations of tumors from patients treated with IL-2 suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into two groups of roughly equal size, with 96% of long-term responding patients being in the favorable prognostic group. This model is currently undergoing prospective validation. More recent studies involving gene expression profiling and array CGH have begun to identify additional features that might predict response to IL-2 therapy. Taken together, these data offer the possibility to limit the use of this toxic therapy to those most likely to benefit. [ABSTRACT FROM AUTHOR]
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- 2009
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16. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial...
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Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM, Atkins, Michael B, Hsu, Jessie, Lee, Sandra, Cohen, Gary I, Flaherty, Lawrence E, Sosman, Jeffrey A, Sondak, Vernon K, Kirkwood, John M, and Eastern Cooperative Oncology Group
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- 2008
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17. Immunotherapy of metastatic renal cell carcinoma.
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McDermott DF and Atkins MB
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In 1992, high-dose bolus interleukin (IL)-2 was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma (RCC). However, the substantial toxicity and limited efficacy that is associated with IL-2 has narrowed its application to highly selected patients treated at specialized centers. In recent years, the relative merits of low- and high-dose cytokine regimens have been clarified by the results of 4 randomized trials. Taken together, these studies suggest that high-dose IV bolus IL-2 is superior in terms of response rate and possibly response quality to regimens that involve either low-dose IL-2 and interferon-alpha, intermediate- or low-dose IL-2 alone, or low-dose interferon-alpha alone. More significantly, investigations associated with these trials suggest that the potential exists for identifying predictors of response (or resistance) and limiting IL-2 therapy to those most likely to benefit. The Cytokine Working Group has launched the high-dose IL-2 'select' trial to determine, in a prospective fashion, if the predictive model proposed by Atkins et al. can identify a group of patients with advanced RCC who are significantly more likely to respond to high dose IL-2-based therapy ('good' risk) than a historical, unselected patient population. For patients unlikely to benefit from IL-2, are unable to receive it or who progress after IL-2, the emergence of molecularly targeted therapies offers hope for improved clinical outcome. As the list of effective therapies for metastatic RCC grows, improvements in patient selection and more 'targeted' approaches will be required to optimize the benefits of cytokine therapy in metastatic RCC. [ABSTRACT FROM AUTHOR]
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- 2008
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18. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib.
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Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, Garbe C, Hauschild A, Puzanov I, Alexandrescu DT, Anderson RT, Wood L, and Dutcher JP
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The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown benefit in patients with renal cell carcinoma, hepatocellular carcinoma (sorafenib), and gastrointestinal stromal tumor (sunitinib). Their efficacy in other malignancies is currently being investigated because of their broad range of activity. The effectiveness of these drugs is somewhat diminished by the development of a variety of toxicities, most notably hand-foot skin reaction (HFSR). Although HFSR does not appear to directly affect survival, it can impact quality of life and lead to MKI dose modification or interruption, potentially limiting the antitumor effect. Currently, no standard guidelines exist for the prevention and management of MKI-associated HFSR. To address this issue, an international, interdisciplinary panel of experts gathered in January 2008 to discuss and evaluate the best-practice management of these reactions. Based on these proceedings, recommendations for the management of HFSR have been provided to offer patients the best possible quality of life while taking these drugs and to optimize the patient benefit associated with MKI therapy. [ABSTRACT FROM AUTHOR]
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- 2008
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19. Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma.
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Sosman JA, Carrillo C, Urba WJ, Flaherty L, Atkins MB, Clark JI, Dutcher J, Margolin KA, Mier J, Gollob J, Kirkwood JM, Panka DJ, Crosby NA, O'Boyle K, LaFleur B, Ernstoff MS, Sosman, Jeffrey A, Carrillo, Carole, Urba, Walter J, and Flaherty, Lawrence
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- 2008
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20. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma.
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Mitchell MS, Abrams J, Thompson JA, Kashani-Sabet M, DeConti RC, Hwu WJ, Atkins MB, Whitman E, Ernstoff MS, Haluska FG, Jakowatz JG, Das Gupta TK, Richards JM, Samlowski WE, Costanzi JJ, Aronson FR, Deisseroth AB, Dudek AZ, Jones VE, and Mitchell, Malcolm S
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- 2007
21. Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects [see comments]
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Mier, JW, primary, Vachino, G, additional, Klempner, MS, additional, Aronson, FR, additional, Noring, R, additional, Smith, S, additional, Brandon, EP, additional, Laird, W, additional, and Atkins, MB, additional
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- 1990
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22. Management of cutaneous melanoma.
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Tsao H, Atkins MB, Sober AJ, Tsao, Hensin, Atkins, Michael B, and Sober, Arthur J
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- 2004
23. More support for the judicious use of high-dose interleukin-2 in patients with advanced melanoma.
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McDermott DF and Atkins MB
- Published
- 2007
24. Targeted therapies: sunitinib in RCC-expanded access equals expanded benefit?
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Choueiri TK, Atkins MB, Choueiri, Toni K, and Atkins, Michael B
- Abstract
Sunitinib is a standard first-line therapy for patients with advanced or metastatic clear-cell renal cell carcinoma. in an expanded-access study, sunitinib has demonstrated clinical benefit with an acceptable safety profile in a population of patients that is representative of those seen in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2009
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25. Symptomatic exacerbation of Crohn disease after treatment with high-dose interleukin-2.
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Sparano JA, Brandt LJ, Dutcher JP, DuBois JS, Atkins MB, Sparano, J A, Brandt, L J, Dutcher, J P, DuBois, J S, and Atkins, M B
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- 1993
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26. Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.
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Ribas A, Kirkwood JM, Atkins MB, Whiteside TL, Gooding W, Kovar A, Gillies SD, Kashala O, Morse MA, Ribas, Antoni, Kirkwood, John M, Atkins, Michael B, Whiteside, Theresa L, Gooding, William, Kovar, Andreas, Gillies, Stephen D, Kashala, Oscar, and Morse, Michael A
- Abstract
Background: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.Methods: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.Results: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.Conclusion: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine. [ABSTRACT FROM AUTHOR]- Published
- 2009
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27. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
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Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, and Taube JM
- Abstract
Background: Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.Methods: We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.Results: A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).Conclusions: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.). [ABSTRACT FROM AUTHOR]- Published
- 2012
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28. Management of cutaneous melanoma.
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de Giorgi V, Carli P, Giannotti B, Sampsel JW, Barbera-Guillem E, Miranda EP, Tsao H, Atkins MB, and Sober AJ
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- 2004
29. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.
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Agarwal N, Brugarolas J, Ghatalia P, George S, Haanen JB, Gurney H, Ravilla R, Van der Veldt A, Beuselinck B, Pokataev I, Suelmann BBM, Tuthill MH, Vaena D, Zagouri F, Wu J, Perini RF, Liu Y, Merchan J, and Atkins MB
- Abstract
Background: Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear., Patients and Methods: The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P = 0.5312; -0.5%, 95% confidence interval (CI) -14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group., Conclusions: The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan., (Copyright © 2024. Published by Elsevier Ltd.)
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- 2024
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30. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial.
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Tannir NM, Albigès L, McDermott DF, Burotto M, Choueiri TK, Hammers HJ, Barthélémy P, Plimack ER, Porta C, George S, Donskov F, Atkins MB, Gurney H, Kollmannsberger CK, Grimm MO, Barrios C, Tomita Y, Castellano D, Grünwald V, Rini BI, Jiang R, Desilva H, Fedorov V, Lee CW, and Motzer RJ
- Abstract
Background: Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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31. A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.
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Chang E, Zhou J, Song C, Gittleman H, Fernandes L, Weinstock C, Atkins MB, Agrawal S, Sridhara R, Gormley N, Tang S, Suzman DL, Amiri-Kordestani L, Kluetz PG, Pazdur R, Rini BI, McDermott DF, and Regan MM
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- Humans, Male, Female, Middle Aged, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Randomized Controlled Trials as Topic, Kaplan-Meier Estimate, Adult, Sunitinib therapeutic use, Sunitinib administration & dosage, Sunitinib adverse effects, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell pathology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors administration & dosage, Kidney Neoplasms drug therapy, Kidney Neoplasms mortality, Kidney Neoplasms pathology
- Abstract
Purpose: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC)., Experimental Design: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times, defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death., Results: Three trials met criteria for analysis; 1,183 patients received IO-TKI versus 1,184 on control arms receiving TKI alone (sunitinib, SUN). IO-TKI and SUN groups spent 9% {2.7 months [95% confidence interval (CI), 1.8-3.5]} and 10% [2.9 months (95% CI, 2.1-3.8)] of the 30-month period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively., Conclusions: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared with the SUN group. These findings may reflect contin-uation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in two trials. See related commentary by Stadler and Karrison, p. 3098., (©2024 American Association for Cancer Research.)
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- 2024
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32. Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214.
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Mantia CM, Jegede OA, Plimack ER, Powles T, Motzer RJ, Tannir NM, Lee CH, Tomita Y, Voss MH, Choueiri TK, Rini BI, Hammers HJ, Escudier B, Albigès L, Rosenblatt L, Atkins MB, Regan MM, and McDermott DF
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Survival Analysis, Adult, Ipilimumab therapeutic use, Ipilimumab administration & dosage, Ipilimumab pharmacology, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell pathology, Sunitinib therapeutic use, Sunitinib administration & dosage, Sunitinib pharmacology, Nivolumab therapeutic use, Nivolumab administration & dosage, Nivolumab pharmacology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Kidney Neoplasms mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use
- Abstract
Background: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures., Methods: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method., Results: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs., Conclusions: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN., Trial Registration Number: NCT02231749., Competing Interests: Competing interests: CMM reports no conflicts of interest. OAJ reports no conflicts of interest. TP reports consulting or advisory roles with Bristol Myers Squibb (BMS), AstraZeneca, Ipsen, Pfizer, Novartis, Seagen, Roche, Exelixis, MSD, Merck Serono, Astellas Pharma, Johnson & Johnson, Eisai, MashupMD, Merck, and Incyte; travel, accommodations, expenses from Pfizer, MSD, AstraZeneca, Roche, and Ipsen; honoraria from AstraZeneca, Eisai, Merck, Novartis, Pfizer, Roche, Astellas Pharma, BMS GmbH & Co. KG, Exelixis, Incyte, Ipsen, Seagen, Merck Serono, Johnson & Johnson/Janssen, and MashupMD; and research funding from AstraZeneca, Roche, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai. RJM reports consulting or advisory roles with Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Pfizer, AstraZeneca, EMD Serono, Calithera Biosciences, and AVEO; travel, accommodations, and expenses from BMS; and research funding to institution from Pfizer, BMS, Eisai, Novartis, Genentech/Roche, Exelixis, Merck, and AVEO. NMT reports stock and other ownership interests with Amgen, Arcturus, Arcus Biosciences, BioCryst Pharmaceuticals, Corvus Pharmaceuticals, Johnson & Johnson/Janssen, Merck, Surface Oncology, Vanguard Health Care ETF, Xencor, First Trust Amex Biotech (FBT), Nuvation Bio, Revolution Medicines, and Spdr S&P Pharmaceuticals ETF; honoraria from BMS, Exelixis, Eisai Medical Research, Neoleukin Therapeutics, Merck Sharp & Dohme, Intellisphere, Oncorena, AstraZeneca/Merck, and Nektar Therapeutics; consulting or advisory roles with Oncorena, Merck Sharp & Dohme, BMS Foundation, and Nektar; and research funding to institution from Exelixis, BMS, Nektar, Arrowhead Pharmaceuticals, Novartis, and Calithera Biosciences. C-HL reports research funding to institution from BMS, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting or advisory roles with Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. YT reports consulting or advisory roles with Eisai, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; honoraria from Astellas Pharma, BMS Japan, Chugai Pharma, Ono Pharmaceutical, Takeda, Merck, Pfizer, and MSD; and research funding to institution from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Ono Pharmaceutical, Pfizer, and Takeda. MHV reports consulting or advisory roles with Novartis, GSK, Exelixis, Merck, Corvus, Calithera, and AVEO; travel, accommodations, and expenses from Takeda, Novartis; research funding with BMS and Roche/Genentech. ERP reports consulting or advisory roles with Seattle Genetics/Astellas, AstraZeneca, AVEO, BMS/Medarex, Calithera Biosciences, EMD Serono, Exelixis, IMV, Janssen, MEI Pharma, Merck, Signatera, Pfizer, and Regeneron; and research funding to institution from BMS, Merck Sharp & Dohme, Astellas, and Genentech/Roche. TKC reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from: Alkermes, Arcus Bio, AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. Institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA. Equity: Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium. Committees: NCCN, GU Steering Committee, ASCO (BOD 6-2024-, ESMO, ACCRU, KidneyCan. Medical writing and editorial assistance support may have been funded by Communications companies in part. No speaker’s bureau. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. BIR reports consulting or advisory roles with Pfizer, Merck, BMS, AVEO, Surface Oncology, Corvus Pharmaceuticals, Aravive, Arrowhead Pharmaceuticals, Eisai, Genentech, Alkermes, NiKang Therapeutics, EUSA Pharma, Athenex, Debiopharm Group, and HiberCell; leadership roles with MJH Life Sciences and MashupMD; travel, accommodations, and expenses from Pfizer, BMS, and Merck; stock and other ownership interests with PTC Therapeutics; and research funding to institution from Pfizer, Roche/ Genentech, BMS, Merck, AstraZeneca/MedImmune, Incyte, Arrowhead Pharmaceuticals, Seagen, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis, AVEO, Arcus Biosciences, HiberCell, Stata, ADC Therapeutics, Dracen, Janssen, Adela, Pionyr, VasGene Therapeutics, Gilead Sciences, Point Therapeutics, and Daiichi Sankyo/UCB Japan. HJH reports consulting or advisory roles with BMS, Pfizer, Exelixis, Bayer, Novartis, Merck, ARMO BioSciences, Corvus Pharmaceuticals, Surface Oncology, and Lilly; travel, accommodations, and expenses from BMS, Merck, Pfizer, Lilly, and Novartis; honoraria from BMS; and research funding to institution from BMS, Merck, Aravive, and Surface Oncology. BE reports consulting or advisory roles with Pfizer, BMS, Ipsen, AVEO, and Oncorena; travel, accommodations, and expenses from BMS, Ipsen, and MSD; honoraria from Pfizer, BMS, Ipsen, and Oncorena; and research funding to institution from BMS. LA reports consulting or advisory roles to institution with Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; non-financial interests with Pfizer, BMS, Ipsen, Roche, Exelixis, AVEO, AstraZeneca, MSD, ASCO, Kidney Foundation, and ESMO. LR reports employment with BMS and stock and other ownership interests with BMS. MBA reports consulting or advisory roles with Genentech, Novartis, BMS, Merck, Exelixis, Eisai, Agenus, Werewolf Pharma, Surface Oncology, Pyxis, Fathom Biotechnology, AVEO, Cota Healthcare, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Pfizer, Scholar Rock, Asher Biotherapeutics, Takeda, Sanofi, Simcha Therapeutics, GlaxoSmithKline, Oncorena, and Pliant; stock and other ownership interests with Werewolf Pharma and Pyxis; and research funding to institution from BMS and Merck. MMR reports consulting or advisory roles (institution) with Ipsen and Debiopharm; personal fees from BMS and Tolmar Pharmaceuticals; grants from Novartis, Pfizer, Ipsen, TerSera, Merck, Ferring, Pierre Fabre, Roche, AstraZeneca, Bayer, and BMS. DFM reports consulting or advisory roles with BMS, Merck, Genentech/Roche, Pfizer, Exelixis, Novartis, Array BioPharma, Peloton Therapeutics, EMD Serono, Jounce Therapeutics, Alkermes, Lilly, Eisai, Calithera Biosciences, Iovance Biotherapeutics, Werewolf Therapeutics, Synthekine, AVEO, Sanofi, and Xilio Therapeutics; other relationship with Beth Israel Deaconess Medical Center; research funding to institution from BMS, Merck, Genentech, Novartis, and Alkermes; and uncompensated relationships with X4 Pharma and AVEO., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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33. Mitral annular disjunction and mitral valve prolapse extrapolating adult data to an adolescent cohort?
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Cohen MI, Atkins MB, and Jordan CP
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- Humans, Adult, Adolescent, Death, Sudden, Cardiac etiology, Death, Sudden, Cardiac epidemiology, Risk Factors, Arrhythmias, Cardiac etiology, Mitral Valve Prolapse complications, Mitral Valve diagnostic imaging, Mitral Valve pathology
- Abstract
Purpose of Review: The aim of this study is to provide an update on mitral valve prolapse (MVP) and mitral annular disjunction (MAD) and who may be at risk for ventricular arrhythmias and sudden cardiac death., Recent Findings: MVP is generally considered a benign condition. However, a small subset of patients may be at risk for life-threatening ventricular arrhythmias. Among the risk factors identified in adults include patients with bileaflet mitral valves, myxomatous changes, myocardial fibrosis, and the presence of MAD. Advances in multimodal imaging have allowed for improved identification of fibrosis, anatomical valve derangements, and the amount of MAD. Recent guidelines have suggested that patients with MVP with or without MAD may be at risk for life-threatening arrhythmias if they have had prior ventricular arrhythmias, ventricular dysfunction, or unexplained syncope. Yet, extrapolation of adult data to a pediatric cohort with similar MVP and MAD at this juncture is challenging. There is, however, early evidence that some pediatric patients with significant myocardial fibrosis or abnormal tissue Doppler may be at risk for ventricular tachycardia., Summary: Mitral valve prolapse and mitral annular disjunction at times coexist and at other times can be seen as isolated entities. While the incidence of arrhythmic MVP is quite rare, there is increasing evidence that certain select adults with MVP may be at risk for ventricular tachycardia and sudden cardiac death. Future multicenter studies are needed to better understand the natural history of arrhythmic mitral valve disease and how early disease manifestation in children may impact findings now being reported in young adults., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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34. Clinical Outcomes of Immune Checkpoint Inhibitors in Unique Cohorts Underrepresented in Clinical Trials.
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Shah NJ, Della Pia A, Wu T, Williams A, Weber M, Sinclaire B, Gourna Paleoudis E, Alaoui A, Lev-Ari S, Adams S, Kaufman J, Parikh SB, Tonti E, Muller E, Serzan M, Cheruku D, Lee A, Sridhar A, Hee BTP, Ahn J, Pecora A, Ip A, and Atkins MB
- Abstract
Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m
2 , autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%-smokers, 30.4%-non-White, 22.8%-elderly, 20.8%-ECOG PS ≥ 2, 15.7%-history of AIDs, and 4.7%-history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs.- Published
- 2024
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35. Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).
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Atkins MB, Jegede OA, Haas NB, Mcdermott DF, Bilen MA, Stein M, Sosman J, Alter R, Plimack ER, Ornstein MC, Hurwitz M, Peace DJ, Einstein D, Catalano PJ, Hammers H, and Regan MM
- Subjects
- Humans, Nivolumab pharmacology, Nivolumab therapeutic use, Ipilimumab adverse effects, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Melanoma
- Abstract
Background: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration., Methods: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured., Results: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free., Conclusions: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population., Competing Interests: Competing interests: MBA has/had an advisory role for Bristol-Myers Squibb, Merck, Novartis, Eisai, Exelixis, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Simcha, Roche, SAB Bio, Pliant Therapeutics, Atreca, OncoRena, Sanofi and GSK and has served as a consultant: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, Agenus, Asher Bio, and AstraZeneca. He reports research support to his institution from Bristol-Myers Squibb and Merck. He holds stock/stock options in Pyxis Oncology, Werewolf and Elpis. OAJ—none. NBH is a paid consultant to BMS, Eisai, Exelixis, Merck and Roche Genentech. DFM has acted as a paid consultant for and/or as a member of the advisory boards of BMS, Pfizer, Merck, Alkermes, Inc, EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Technologies, Calithera Biosciences, Synthekine, Inc., Johnson served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. MH has served on Advisory Boards for Bristol Myers Squibb, CRISPR Therapeutics, Exelixis, Nektar Therapeutics, Janssen and has received research support to his institution from Alpine, Achilles Therapeutics, Apexigen, Arrowhead, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, CRISPR Therapeutics, Corvus, Eli Lilly, Endocyte, Fate Therapeutics, Genentech, Genmab, GSK, Innocrin, Iovance, KSQ, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi Aventis, SeaGen, Tmunity, Torque, Unum. He also reports Spouse salary from Gamida Cell, Arvinas. DJP holds stock in Bristol-Myers Squibb and Merck. DE reports research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, Mink Therapeutics, Novartis, Puma Biotechnology, and Sanofi, as well as discounted research sequencing from Foundation Medicine and honorarium from OncLive. PJC—none. HH has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, BMS, Pfizer, Merck, Corvus, Armo Biosciences, Eisai, Eli Lilly, Surface Oncology, Aveo and Novartis and has received grants to his institution from Merck, Bristol-Myers Squibb, Surface Oncology and Aravive for work performed as outside of the current study. MMR reports research funding to institution from AstraZeneca, Bayer, Biotheranostics, Bristol-Myers Squibb, DebioPharm, Ipsen, Novartis, Pfizer, Roche, TerSera Therapeutics, all outside of the current study, and a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, DebioPharm, Ipsen, TerSera Therapeutics, Tolmar Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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36. A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma.
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McKay RR, Leucht K, Xie W, Jegede O, Braun DA, Atkins MB, Grimm MO, and Choueiri TK
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- Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials, Phase II as Topic, Ipilimumab therapeutic use, Nivolumab therapeutic use, Progression-Free Survival, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Background: Nivolumab plus ipilimumab has demonstrated improved survival for treatment-naïve advanced clear cell renal cell carcinoma (RCC). A series of clinical trials evaluated the effect of salvage nivolumab plus ipilimumab in patients without an objective response to nivolumab. Given the size and heterogeneity of these studies, we performed a pooled analysis to better inform the activity of nivolumab plus ipilimumab after nivolumab., Patients and Methods: Eligible patients included those with advanced clear cell RCC having received no prior immunotherapy. The primary objective was confirmed objective response rate (ORR) by investigator-assessment. Secondary objectives included progression-free survival (PFS) and overall survival (OS)., Results: The analysis included 410 patients with clear cell RCC, of whom 340 (82.9%) had IMDC intermediate/poor risk disease, and 137 (33.4%) had prior treatment. The 16-18-week ORR to nivolumab prior to nivolumab plus ipilimumab was 22.7% (n = 93), and best ORR to nivolumab was 25.1% (n = 103). Two hundred and thirty (56.1%) patients treated with nivolumab received nivolumab plus ipilimumab at a median of 16 weeks (IQR 9-19) after initiation of nivolumab [27.0% (n = 62) with stable disease and 73.0% (n = 168) with progressive disease to nivolumab]. The ORR to nivolumab plus ipilimumab was 12.6% (n = 29). Six-month PFS on nivolumab plus ipilimumab was 37% (95% CI, 27-47). Median follow-up was 34.3 months and 3-year OS was 59% (95% CI, 53-64) from nivolumab start., Conclusion: A small subset of patients lacking a response to nivolumab derive benefit from salvage nivolumab plus ipilimumab. When possible, both drugs should be given in concomitantly, rather in an adaptive fashion., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2024
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37. Long-Term Survival in Patients With Relapsed/Refractory Advanced Renal Cell Carcinoma Treated With Tivozanib: Analysis of the Phase III TIVO-3 Trial.
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Beckermann KE, Asnis-Alibozek AG, Atkins MB, Escudier B, Hutson TE, Kasturi V, McDermott DF, Pal SK, Porta C, Rini BI, and Verzoni E
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- Humans, Phenylurea Compounds adverse effects, Protein Kinase Inhibitors adverse effects, Receptors, Vascular Endothelial Growth Factor therapeutic use, Sorafenib adverse effects, Vascular Endothelial Growth Factor A, Clinical Trials, Phase III as Topic, Randomized Controlled Trials as Topic, Antineoplastic Agents adverse effects, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology, Quinolines
- Abstract
Background: Tivozanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) with efficacy in advanced renal cell carcinoma (RCC). Long-term exploratory analyses from the TIVO-3 trial in relapsed/refractory (R/R) RCC including patients (26%) with prior immuno-oncology (IO) therapy are reported., Methods: Patients with R/R advanced RCC that progressed with 2 or 3 prior systemic therapies (≥1 VEGFR TKI) were randomized to tivozanib 1.5 mg QD or sorafenib 400 mg BID, stratified by IMDC risk and previous therapy. Safety, investigator-assessed long-term progression-free survival (LT-PFS), and serial overall survival (OS) were assessed., Results: Mean time on treatment was 11.0 months with tivozanib (n = 175) and 6.3 months with sorafenib (n = 175). Fewer grade ≥3 treatment-related adverse events occurred with tivozanib (46%) than sorafenib (55%). Dose modification rates were lower with tivozanib than sorafenib across age/prior IO subgroups; prior IO therapy did not impact dose reductions or discontinuations in either arm. Landmark LT-PFS rates were higher with tivozanib (3 years: 12.3% vs 2.4%; 4 years: 7.6% vs 0%). After 22.8 months mean follow-up, the OS HR was 0.89 (95% CI, 0.70-1.14); when conditioned on 12-month landmark PFS, tivozanib showed significant OS improvement over sorafenib (HR, 0.45; 95% CI, 0.22-0.91; 2-sided P = .0221)., Conclusions: Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 months. These post hoc exploratory analyses of LT-PFS and conditional OS support a clinically meaningful improvement with tivozanib versus sorafenib in this advanced RCC population., (© The Author(s) 2024. Published by Oxford University Press.)
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- 2024
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38. PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
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Denize T, Jegede OA, Matar S, El Ahmar N, West DJ, Walton E, Bagheri AS, Savla V, Nabil Laimon Y, Gupta S, Vemula SV, Braun DA, Burke KP, Catalano PJ, Freeman GJ, Motzer RJ, Atkins MB, McDermott DF, Sharpe AH, Choueiri TK, and Signoretti S
- Subjects
- Humans, Nivolumab therapeutic use, T-Lymphocytes, Regulatory metabolism, Hepatitis A Virus Cellular Receptor 2 metabolism, Everolimus therapeutic use, Programmed Cell Death 1 Receptor metabolism, Carcinoma, Renal Cell pathology
- Abstract
Purpose: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors., Experimental Design: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus., Conclusions: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value., (©2023 American Association for Cancer Research.)
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- 2024
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39. Corrigendum to "Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study" [Eur Urol 84(5) (2023) 449-454].
- Author
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Plimack ER, Powles T, Stus V, Gafanov R, Nosov D, Waddell T, Alekseev B, Pouliot F, Melichar B, Soulières D, Borchiellini D, McDermott RS, Vynnychenko I, Chang YH, Tamada S, Atkins MB, Li C, Perini R, Molife LR, Bedke J, and Rini BI
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- 2024
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40. Systemic Therapy for Melanoma: ASCO Guideline Update Q and A.
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Sondak VK, Atkins MB, Messersmith H, Provenzano A, Seth R, and Agarwala SS
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- Humans, Societies, Medical, Medical Oncology, Melanoma drug therapy
- Abstract
This Q&A answers questions regarding ASCO's recent Systemic Therapy for Melanoma guideline.
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- 2024
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41. The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.
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Walter AW, Lee JW, Streck JM, Gareen IF, Herman BA, Kircher SM, Carlos RC, Kumar SK, Mayer IA, Saba NF, Fenske TS, Neal JW, Atkins MB, Hodi FS, Kyriakopoulos CE, Tempany-Afdhal CM, Shanafelt TD, Wagner LI, Land SR, Ostroff JS, and Park ER
- Subjects
- Adult, Humans, Male, Middle Aged, Female, Socioeconomic Disparities in Health, Smoking adverse effects, Health Behavior, Smoking Cessation methods, Neoplasms epidemiology, Neoplasms therapy
- Abstract
Background: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer., Methods: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression., Results: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods., Conclusions: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2024
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42. Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases.
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In GK, Ribeiro JR, Yin J, Xiu J, Bustos MA, Ito F, Chow F, Zada G, Hwang L, Salama AKS, Park SJ, Moser JC, Darabi S, Domingo-Musibay E, Ascierto ML, Margolin K, Lutzky J, Gibney GT, Atkins MB, Izar B, Hoon DSB, and VanderWalde AM
- Abstract
Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset., (© 2023. The Author(s).)
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- 2023
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43. Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study.
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Plimack ER, Powles T, Stus V, Gafanov R, Nosov D, Waddell T, Alekseev B, Pouliot F, Melichar B, Soulières D, Borchiellini D, McDermott RS, Vynnychenko I, Chang YH, Tamada S, Atkins MB, Li C, Perini R, Molife LR, Bedke J, and Rini BI
- Subjects
- Humans, Axitinib adverse effects, Sunitinib therapeutic use, Follow-Up Studies, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology
- Abstract
Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma., (Copyright © 2023. Published by Elsevier B.V.)
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- 2023
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44. Corrigendum to "Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study" [Eur. Urol. (2023)].
- Author
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Plimack ER, Powles T, Stus V, Gafanov R, Nosov D, Waddell T, Alekseev B, Pouliot F, Melichar B, Soulières D, Borchiellini D, McDermott RS, Vynnychenko I, Chang YH, Tamada S, Atkins MB, Li C, Perini R, Rhoda Molife L, Bedke J, and Rini BI
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- 2023
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45. Cigarette and Alternative Tobacco Product Use among Adult Cancer Survivors Enrolled in 9 ECOG-ACRIN Clinical Trials.
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Streck JM, Lee JW, Walter AW, Rosen RL, Gareen IF, Kircher SM, Herman BA, Carlos RC, Kumar S, Mayer IA, Saba NF, Fenske TS, Neal JW, Atkins MB, Hodi FS, Kyriakopoulos CE, Tempany C, Shanafelt TD, Wagner LI, Land SR, Park ER, and Ostroff JS
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Adenosine Triphosphate, Azathioprine, Tobacco Use epidemiology, United States epidemiology, Clinical Trials as Topic, Cancer Survivors, Electronic Nicotine Delivery Systems, Neoplasms epidemiology, Tobacco Products, Tobacco, Smokeless
- Abstract
Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials., Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017-2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days., Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 < 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 < 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days., Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported., Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings., (©2023 American Association for Cancer Research.)
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- 2023
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46. Systemic Therapy for Melanoma: ASCO Guideline Update.
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Seth R, Agarwala SS, Messersmith H, Alluri KC, Ascierto PA, Atkins MB, Bollin K, Chacon M, Davis N, Faries MB, Funchain P, Gold JS, Guild S, Gyorki DE, Kaur V, Khushalani NI, Kirkwood JM, McQuade JL, Meyers MO, Provenzano A, Robert C, Santinami M, Sehdev A, Sondak VK, Spurrier G, Swami U, Truong TG, Tsai KK, van Akkooi A, and Weber J
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Ipilimumab therapeutic use, Nivolumab therapeutic use, Proto-Oncogene Proteins B-raf genetics, Melanoma, Cutaneous Malignant, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Oncolytic Virotherapy, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma., Methods: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature., Results: The updated review identified 21 additional randomized trials., Updated Recommendations: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF -mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.
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- 2023
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47. Re: Matthew S. Ernst, Vishal Navani, J. Connor Wells, et al. Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma. Eur Urol. 2023;84:109-116.
- Author
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Regan MM, Atkins MB, and McDermott DF
- Subjects
- Humans, Prognosis, Databases, Factual, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell secondary, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Published
- 2023
- Full Text
- View/download PDF
48. Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.
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Singh AK, McCausland FR, Claggett BL, Wanner C, Wiecek A, Atkins MB, Carroll K, Perkovic V, McMurray JJV, Wittes J, Snapinn S, Blackorby A, Meadowcroft A, Barker T, DiMino T, Mallett S, Cobitz AR, and Solomon SD
- Subjects
- Humans, Erythropoiesis, Renal Dialysis, Darbepoetin alfa adverse effects, Hemoglobins, Hematinics adverse effects, Erythropoietin adverse effects, Neoplasms complications, Neoplasms epidemiology, Neoplasms chemically induced, Renal Insufficiency, Chronic drug therapy
- Abstract
Background: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305)., Methods: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study)., Results: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined., Conclusions: Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat., Trial Registration: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
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- 2023
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49. The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.
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Lev-Ari S, Serzan M, Wu T, Ip A, Pascual L, Sinclaire B, Adams S, Marafelias M, Ayyagari L, Gill SK, Ma B, Zaemes JP, Della Pia A, Alaoui A, Madhavan S, Belouali A, Pecora A, Ahn J, Atkins MB, and Shah NJ
- Subjects
- Humans, Retrospective Studies, Immunosuppressive Agents therapeutic use, Proportional Hazards Models, Immune Checkpoint Inhibitors adverse effects, Melanoma drug therapy
- Abstract
Background: Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated., Methods: This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n = 370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models., Results: Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2 months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3 months; 95% CI, 6-20.1 months) (p < .001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p < .001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p = .01)., Conclusions: These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary., (© 2023 American Cancer Society.)
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- 2023
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50. Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma.
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Haanen JBAG, Larkin J, Choueiri TK, Albiges L, Rini BI, Atkins MB, Schmidinger M, Penkov K, Michelon E, Wang J, Mariani M, di Pietro A, and Motzer RJ
- Subjects
- Humans, Sunitinib pharmacology, Sunitinib therapeutic use, Axitinib pharmacology, Axitinib therapeutic use, Follow-Up Studies, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell secondary, Antineoplastic Agents therapeutic use, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Background: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial., Patients and Methods: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed., Results: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization., Conclusions: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing., Trial Registration: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
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