Search

Your search keyword '"Geczi L"' showing total 82 results
Start Over Author "Geczi L"
82 results on '"Geczi L"'

1. 1368P TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage response alterations (DDRm) – Exploration of tumor genetics associated with prolonged benefit

Author

de Bono, J.S., primary, Castro Marcos, E., additional, Laird, D.A., additional, Fizazi, K., additional, Dorff, T., additional, Zhao, S., additional, van Oort, I.M., additional, Gasparro, D., additional, Calabrò, F., additional, Pignata, S., additional, Geczi, L., additional, Barthelemy, P., additional, Kilari, D., additional, Hopkins, J.F., additional, Chen, H-C., additional, Healy, C.G., additional, Chelliserry, J., additional, Scagliotti, G.V., additional, and Mehra, N., additional

Published
2022
Full Text
View/download PDF

3. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Author

Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., Domchek S., Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., and Domchek S.

Abstract

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective(s): To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participant(s): Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Result(s): Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P <.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P <.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P <.001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P <.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P =.008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P =.001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P =.003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum w

Published
2021

4. LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361

Author

Alva, A., primary, Csőszi, T., additional, Ozguroglu, M., additional, Matsubara, N., additional, Geczi, L., additional, Cheng, S.Y-S., additional, Fradet, Y., additional, Oudard, S., additional, Vulsteke, C., additional, Morales Barrera, R., additional, Fléchon, A., additional, Gunduz, S., additional, Loriot, Y., additional, Rodriguez-Vida, A., additional, Mamtani, R., additional, Yu, E.Y., additional, Nam, K., additional, Imai, K., additional, Moreno, B.H., additional, and Powles, T.B., additional

Published
2020
Full Text
View/download PDF

5. Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carcinoma (UC): KEYNOTE-361

Author

Alva, Ajjai, Csoszi, T., Özgüroğlu, Mustafa, Matsubara, N., Geczi, L., Cheng, S. Y-S., Powles, T. B., and İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü

Abstract

ESMO Virtual Congress -- SEP 19-OCT 18, 2020 -- ELECTR NETWORK WOS:000573469102650 [No abstract available] European Soc Med Oncol Merck Sharp Dohme Corp.Merck & Company Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Published
2020

6. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author

Patel, V.L., Busch, E.L., Friebel, T.M., Cronin, A., Leslie, G., McGuffog, L., Adlard, J., Agata, S., Agnarsson, B.A., Ahmed, M., Aittomaki, K., Alducci, E., Andrulis, I.L., Arason, A., Arnold, N., Artioli, G., Arver, B., Auber, B., Azzollini, J., Balmana, J., Barkardottir, R.B., Barnes, D.R., Barroso, A., Barrowdale, D., Belotti, M., Benitez, J., Bertelsen, B., Blok, M.J., Bodrogi, I., Bonadona, V., Bonanni, B., Bondavalli, D., Boonen, S.E., Borde, J., Borg, A., Bradbury, A.R., Brady, A., Brewer, C., Brunet, J., Buecher, B., Buys, S.S., Cabezas-Camarero, S., Caldes, T., Caliebe, A., Caligo, M.A., Calvello, M., Campbell, I.G., Carnevali, I., Carrasco, E., Chan, T.L., Chu, A.T.W., Chung, W.K., Claes, K.B.M., Cook, J., Cortesi, L., Couch, F.J., Daly, M.B., Damante, G., Darder, E., Davidson, R., Hoya, M. de la, Puppa, L.D., Dennis, J., Diez, O., Ding, Y.C., Ditsch, N., Domchek, S.M., Donaldson, A., Dworniczak, B., Easton, D.F., Eccles, D.M., Eeles, R.A., Ehrencrona, H., Ejlertsen, B., Engel, C., Evans, D.G., Faivre, L., Faust, U., Feliubadalo, L., Foretova, L., Fostira, F., Fountzilas, G., Frost, D., Garcia-Barberan, V., Garre, P., Gauthier-Villars, M., Geczi, L., Gehrig, A., Gerdes, A.M., Gesta, P., Giannini, G., Glendon, G., Godwin, A.K., Goldgar, D.E., Greene, M.H., Gutierrez-Barrera, A.M., Hahnen, E., Hamann, U., Mensenkamp, A.R., Nielsen, H., Rebbeck, T.R., Patel, V.L., Busch, E.L., Friebel, T.M., Cronin, A., Leslie, G., McGuffog, L., Adlard, J., Agata, S., Agnarsson, B.A., Ahmed, M., Aittomaki, K., Alducci, E., Andrulis, I.L., Arason, A., Arnold, N., Artioli, G., Arver, B., Auber, B., Azzollini, J., Balmana, J., Barkardottir, R.B., Barnes, D.R., Barroso, A., Barrowdale, D., Belotti, M., Benitez, J., Bertelsen, B., Blok, M.J., Bodrogi, I., Bonadona, V., Bonanni, B., Bondavalli, D., Boonen, S.E., Borde, J., Borg, A., Bradbury, A.R., Brady, A., Brewer, C., Brunet, J., Buecher, B., Buys, S.S., Cabezas-Camarero, S., Caldes, T., Caliebe, A., Caligo, M.A., Calvello, M., Campbell, I.G., Carnevali, I., Carrasco, E., Chan, T.L., Chu, A.T.W., Chung, W.K., Claes, K.B.M., Cook, J., Cortesi, L., Couch, F.J., Daly, M.B., Damante, G., Darder, E., Davidson, R., Hoya, M. de la, Puppa, L.D., Dennis, J., Diez, O., Ding, Y.C., Ditsch, N., Domchek, S.M., Donaldson, A., Dworniczak, B., Easton, D.F., Eccles, D.M., Eeles, R.A., Ehrencrona, H., Ejlertsen, B., Engel, C., Evans, D.G., Faivre, L., Faust, U., Feliubadalo, L., Foretova, L., Fostira, F., Fountzilas, G., Frost, D., Garcia-Barberan, V., Garre, P., Gauthier-Villars, M., Geczi, L., Gehrig, A., Gerdes, A.M., Gesta, P., Giannini, G., Glendon, G., Godwin, A.K., Goldgar, D.E., Greene, M.H., Gutierrez-Barrera, A.M., Hahnen, E., Hamann, U., Mensenkamp, A.R., Nielsen, H., and Rebbeck, T.R.

Abstract

Contains fulltext : 218251.pdf (Publisher’s version ) (Closed access), Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020

7. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

Author

Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., Scarpitta R., Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., and Scarpitta R.

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR 1/4 1.78; 95% confidence interval (CI), 1.25-2.52; P 1/4 0.001], as well as elevated risk of Gleason 8 prostate cancer (HR 1/4 3.11; 95% CI, 1.63-5.95; P 1/4 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR 1/4 2.83; 95% CI, 1.71-4.68; P 1/4 0.00004) and elevated risk of Gleason 8 prostate cancer (HR 1/4 4.95; 95% CI, 2.12-11.54; P 1/4 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.Copyright © 2020 American Association for Cancer Research.

Published
2020

8. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author

Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020

9. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract

Author

Sternberg, C.N. Loriot, Y. James, N. Choy, E. Castellano, D. Lopez-Rios, F. Banna, G.L. De Giorgi, U. Masini, C. Bamias, A. Garcia del Muro, X. Duran, I. Powles, T. Gamulin, M. Zengerling, F. Geczi, L. Gedye, C. de Ducla, S. Fear, S. Merseburger, A.S.

Abstract

Background: Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective: To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants: Between November 2016 and March 2018 (median follow-up 12.7 mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS)2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations: The median treatment duration was 2.8 mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7 mo (95% confidence interval [CI]7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2 mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0 mo (95% CI 8.8–11.9)and 6-mo OS was 65% (95% CI 61–69%). Conclusions: SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary: In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients. © 2019 The Author(s) SAUL confirms the tolerability of atezolizumab in real-world patients with urinary tract carcinoma. Efficacy in the IMvigor211-like subgroup and the broader unselected population was consistent with previous anti-PD-L1/PD-1 pivotal trials, supporting the use of atezolizumab in these patients. © 2019 The Author(s)

Published
2019

10. Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate: A Randomized, Open-Label Phase 2 Study

Author

Attard, G., Merseburger, A. S., Arlt, W., Sternberg, C. N., Feyerabend, S., Berruti, A., Joniau, S., Geczi, L., Lefresne, F., Lahaye, M., Shelby, F. N., Pissart, G., Chua, S., Jones, R. J., Tombal, B., UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie

Abstract

IMPORTANCE: Abiraterone acetate is combined with prednisone, 5 mg, twice daily for metastatic castration-resistant prostate cancer (mCRPC) and with prednisone, 5 mg, once daily for newly diagnosed, high-risk, metastatic castration-sensitive prostate cancer. Understanding the physiological effects of these and other regimens is important. OBJECTIVE: To evaluate the safety of abiraterone acetate with 4 glucocorticoid regimens. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Analyses were conducted from August 2017 to June 2018. INTERVENTIONS: Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily (n = 41), 5 mg once daily (n = 41), 2.5 mg twice daily (n = 40), or dexamethasone, 0.5 mg, once daily (n = 42). MAIN OUTCOMES AND MEASURES: Primary end point was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. RESULTS: Of 164 men (median [range] age, 70 [50-90] years) randomized to receive abiraterone acetate, 1000 mg, daily with prednisone, 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24 (70.6%) of 34 patients (95% CI, 53.8%-83.2%), 14 (36.8%) of 38 patients (95% CI, 23.4%-52.7%), 21 (60.0%) of 35 patients (95% CI, 43.6%-74.4%), and 26 (70.3%) of 37 patients (95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess. Plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary end point, regardless of glucocorticoid regimen. Total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and homeostatic model assessment of insulin resistance, while total bone mineral density decreased. In the prednisone, 5 mg, twice daily, 5 mg once daily, 2.5 mg twice daily, and dexamethasone groups, median radiographic progression-free survival was 18.5, 15.3, 12.8, and 26.6 months, respectively. CONCLUSIONS AND RELEVANCE: Abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary end point (95% CI excluded 50% mineralocorticoid excess); abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be particularly active but may be associated with adverse metabolic consequences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01867710.

Published
2019

11. Results of the phase II TRAXAR study: A randomized phase II trial of axitinib and TRC105 (TRAX) versus axitinib (AX) alone in patients with advanced or metastatic renal cell carcinoma (mRCC)

Author

Choueiri, T.K., primary, Kocsis, J., additional, Pachynski, R.K., additional, Poprach, A., additional, Deshazo, M., additional, Zakharia, Y., additional, Lara, P.N., additional, Pal, S.K., additional, Geczi, L., additional, Ho, T.H., additional, Mangel, L., additional, Redman, B., additional, Ryan, C.W., additional, Olencki, T., additional, Simpson, B.E., additional, Adams, B., additional, Robertson, L., additional, Darif, M., additional, Theuer, C., additional, and Agarwal, N., additional

Published
2019
Full Text
View/download PDF

12. KEYNOTE-361: Phase 3 trial of pembrolizumab ± chemotherapy versus chemotherapy alone in advanced urothelial cancer

Author

Powles, T., primary, Loriot, Y., additional, Gschwend, J.E., additional, Bellmunt, J., additional, Geczi, L., additional, Vulsteke, C., additional, Abdelsalam, M., additional, Gafanov, R., additional, Kyun Bae, W., additional, Revesz, J., additional, Yamamoto, Y., additional, Anido, U., additional, Su, W., additional, Fleming, M., additional, Markus, M., additional, Feng, D., additional, Poehlein, C., additional, and Alva, A., additional

Published
2018
Full Text
View/download PDF

14. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Author

Petrylak, D.P. de Wit, R. Chi, K.N. Drakaki, A. Sternberg, C.N. Nishiyama, H. Castellano, D. Hussain, S. Fléchon, A. Bamias, A. Yu, E.Y. van der Heijden, M.S. Matsubara, N. Alekseev, B. Necchi, A. Géczi, L. Ou, Y.-C. Coskun, H.S. Su, W.-P. Hegemann, M. Percent, I.J. Lee, J.-L. Tucci, M. Semenov, A. Laestadius, F. Peer, A. Tortora, G. Safina, S. del Muro, X.G. Rodriguez-Vida, A. Cicin, I. Harputluoglu, H. Widau, R.C. Liepa, A.M. Walgren, R.A. Hamid, O. Zimmermann, A.H. Bell-McGuinn, K.M. Powles, T. Wong, S.-L.S. Tan, T.H. Hovey, E.J. Clay, T.D. Ng, S.S.W. Rutten, A. Machiels, J.-P. Dumez, H. Cheng, S.Y.-S. Ferrario, C. Sengeloev, L. Jensen, N.V. Thibault, C. Laguerre, B. Joly, F. Flechon, A. Culine, S. Becht, C. Niegisch, G. Stöckle, M. Grimm, M.-O. Gakis, G. Schultze-Seemann, W. Kalofonos, H. Mavroudis, D. Papandreou, C. Karavasilis, V. Révész, J. Geczi, L. Rosenbaum, E. Leibowitz-Amit, R. Kejzman, D. Sarid, D. Scagliotti, G.V. Bracarda, S. Massari, F. Osawa, T. Miyajima, N. Shinohara, N. Fukuta, F. Ohyama, C. Obara, W. Yamashita, S. Tomita, Y. Kawai, K. Fukasawa, S. Oyama, M. Yonese, J. Nagata, M. Uemura, M. Nishimura, K. Kawakita, M. Tsunemori, H. Hashine, K. Inokuchi, J. Yokomizo, A. Nagamori, S. Lee, H.J. Park, S.H. Rha, S.Y. Kim, Y.J. Lee, Y.-G. Cortés, L.V. Flores, C.L.U. Blaisse, R.J.B. Erdkamp, F.L.G. Aarts, M.J.B. Wojcik-Tomaszewska, J. Tomczak, P. Sikora-Kupis, B. Schenker, M. Herzal, A.A. Udrea, A.A. Karlov, P. Fomkin, R. Pulido, E.G. Mignorance, J.I.D. Gauna, D.C. Rodríguez-Vida, A. Su, Y.-L. Lin, C.-L. Lin, C.-C. Yeh, S.-P. Çiçin, I. Erman, M. Urun, Y. Golovko, Y. Bondarenko, I. Sinielnikov, I. Crabb, S. Syndikus, I. Huddart, R. Sundar, S. Chowdhury, S. Sarwar, N. Flaig, T. Pan, C.X. Schwarz, J. Cultrera, J. Hainsworth, J. Herms, B. Lawler, W. Lowe, T. Tagawa, S. Aragon-Ching, J. Vaishampayan, U.

Abstract

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd

Published
2017

15. Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m(2)) and the Currently Approved Dose (25 mg/m(2)) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA

Author

Eisenberger, M, Hardy-Bessard, AC, Kim, CS, Geczi, L, Ford, D, Mourey, L, Carles, J, Parente, P, Font, A, Kacso, G, Chadjaa, M, Zhang, WP, Bernard, J, and de Bono, J

Abstract

Purpose Cabazitaxel 25 mg/m(2) (C25) significantly improved overall survival (OS) versus mitoxantrone (P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study (ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m(2) (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20. (C) 2017 by American Society of Clinical Oncology

Published
2017

16. Pembrolizumab ± chemotherapy versus chemotherapy in advanced urothelial cancer: Phase 3 KEYNOTE-361 trial

Author

Powles, T., primary, Gschwend, J.E., additional, Loriot, Y., additional, Bellmunt, J., additional, Geczi, L., additional, Vulsteke, C., additional, Abdelsalam, M., additional, Gafanov, R., additional, Bae, W.K., additional, Revesz, J., additional, Yamamoto, Y., additional, Anido, U., additional, Su, W-P., additional, Fleming, M., additional, Markus, M., additional, Feng, D., additional, Poehlein, C., additional, and Alva, A., additional

Published
2017
Full Text
View/download PDF

18. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Author

Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, S, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Hegemann, M, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, Giampaolo, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Widau, Rc, Liepa, Am, Walgren, Ra, Hamid, O, Zimmermann, Ah, Bell-McGuinn, Km, Powles, T, Tortora, G (ORCID:0000-0002-1378-4962), Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, S, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Hegemann, M, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, Giampaolo, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Widau, Rc, Liepa, Am, Walgren, Ra, Hamid, O, Zimmermann, Ah, Bell-McGuinn, Km, Powles, T, and Tortora, G (ORCID:0000-0002-1378-4962)

Abstract

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m(2) plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125.Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4.07 months [95% CI 2.96-4.47] vs 2.76 months [2.60-2.96]; hazard ratio [HR] 0.757, 95% CI 0.607-0.943; p=0.0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24.5%, 95% CI 18.8-30.3) of 216 patients allocated ramucirumab and 31 (14.0%, 9.4-18.6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at g

Published
2017

19. 912PD - Results of the phase II TRAXAR study: A randomized phase II trial of axitinib and TRC105 (TRAX) versus axitinib (AX) alone in patients with advanced or metastatic renal cell carcinoma (mRCC)

Author

Choueiri, T.K., Kocsis, J., Pachynski, R.K., Poprach, A., Deshazo, M., Zakharia, Y., Lara, P.N., Pal, S.K., Geczi, L., Ho, T.H., Mangel, L., Redman, B., Ryan, C.W., Olencki, T., Simpson, B.E., Adams, B., Robertson, L., Darif, M., Theuer, C., and Agarwal, N.

Published
2019
Full Text
View/download PDF

24. The Y deletion gr/gr and susceptibility to testicular germ cell tumor

Author

Nathanson, KL, Kanetsky, PA, Hawes, R, Vaughn, DJ, Letrero, R, Tucker, K, Friedlander, M, Phillips, KA, Hogg, D, Jewett, MAS, Lohynska, R, Daugaard, G, Richard, S, Chompret, A, Bonati-Pellie, C, Heidenreich, A, Olah, E, Geczi, L, Bodrogi, I, Ormiston, WJ, Daly, PA, Oosterhuis, Wolter, Gillis, Ad, Looijenga, LHJ (Leendert), Guilford, P, Fossa, SD, Heimdal, K, Tjulandin, SA, Liubchenko, L, Stoll, H, Weber, W, Huddart, R, Crockford, GP, Forman, D, Oliver, DT, Einhorn, L, Weber, BL, Kramer, J (Judith), McMaster, M, Greene, MH, Pike, M, Cortessis, V, Chen, C (Christopher Li Hsian), Schwartz, SM, Bishop, DT, Easton, DF, Stratton, MR, Rapley, EA, Pathology, and Immunology

Published
2005

28. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II.

Author

Krege, S., Beyer, J., Souchon, R., Albers, P., Albrecht, W., Algaba, F., Bamberg, M., Bodrogi, I., Bokemeyer, C., Cavallin-Stahl, E., Classen, J., Clemm, C., Cohn-Cedermark, G., Culine, S., Daugaard, G., Mulder, P.H.M. de, Santis, M. de, Wit, M. de, Wit, R. de, Derigs, H.G., Dieckmann, K.P., Dieing, A., Droz, J.P., Fenner, M., Fizazi, K., Flechon, A., Fossa, S.D., Muro, X.G. del, Gauler, T., Geczi, L., Gerl, A., Germa-Lluch, J.R., Gillessen, S., Hartmann, J.T., Hartmann, M., Heidenreich, A., Hoeltl, W., Horwich, A., Huddart, R., Jewett, M., Joffe, J., Jones, W., Kisbenedek, L., Klepp, O., Kliesch, S., Koehrmann, K.U., Kollmannsberger, C., Kuczyk, M.A., Laguna, P.M., Galvis, O.L., Loy, V., Mason, M.D., Mead, G.M., Mueller, R., Nichols, C., Nicolai, N., Oliver, T., Ondrus, D., Oosterhof, G.O.N., Paz-Ares, L., Pizzocaro, G., Pont, J.J.H.H.M. de, Pottek, T., Powles, T., Rick, O., Rosti, G., Salvioni, R., Scheiderbauer, J., Schmelz, H.U., Schmidberger, H., Schmoll, H.J., Schrader, M., Sedlmayer, F., Skakkebaek, N.E., Sohaib, A., Tjulandin, S., Warde, P., Weinknecht, S., Weissbach, L., Wittekind, C., Winter, E., Wood, L., Maase, H. von der, Krege, S., Beyer, J., Souchon, R., Albers, P., Albrecht, W., Algaba, F., Bamberg, M., Bodrogi, I., Bokemeyer, C., Cavallin-Stahl, E., Classen, J., Clemm, C., Cohn-Cedermark, G., Culine, S., Daugaard, G., Mulder, P.H.M. de, Santis, M. de, Wit, M. de, Wit, R. de, Derigs, H.G., Dieckmann, K.P., Dieing, A., Droz, J.P., Fenner, M., Fizazi, K., Flechon, A., Fossa, S.D., Muro, X.G. del, Gauler, T., Geczi, L., Gerl, A., Germa-Lluch, J.R., Gillessen, S., Hartmann, J.T., Hartmann, M., Heidenreich, A., Hoeltl, W., Horwich, A., Huddart, R., Jewett, M., Joffe, J., Jones, W., Kisbenedek, L., Klepp, O., Kliesch, S., Koehrmann, K.U., Kollmannsberger, C., Kuczyk, M.A., Laguna, P.M., Galvis, O.L., Loy, V., Mason, M.D., Mead, G.M., Mueller, R., Nichols, C., Nicolai, N., Oliver, T., Ondrus, D., Oosterhof, G.O.N., Paz-Ares, L., Pizzocaro, G., Pont, J.J.H.H.M. de, Pottek, T., Powles, T., Rick, O., Rosti, G., Salvioni, R., Scheiderbauer, J., Schmelz, H.U., Schmidberger, H., Schmoll, H.J., Schrader, M., Sedlmayer, F., Skakkebaek, N.E., Sohaib, A., Tjulandin, S., Warde, P., Weinknecht, S., Weissbach, L., Wittekind, C., Winter, E., Wood, L., and Maase, H. von der

Abstract

Item does not contain fulltext, OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, The Netherlands. METHODS: Medical oncologists, urologic surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference and incorporated the new data into updated and revised guidelines. As for the first meeting the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The second part of the consensus paper includes the treatment of metastasised disease, residual tumour resection, salvage therapy, follow-up, and late toxicities. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early-stage as well as of advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Published
2008

29. Somatic mutations of KIT in familial testicular germ cell tumours

Author

Rapley, EA, Hockley, S, Warren, W, Johnson, L, Huddart, R, Crockford, G, Forman, D, Leahy, MG, Oliver, DT, Tucker, K, Friedlander, M, Phillips, KA, Hogg, D, Jewett, MAS, Lohynska, R, Daugaard, G, Richard, S, Heidenreich, A, Geczi, L, Bodrogi, I, Olah, E, Ormiston, WJ, Daly, PA, Looijenga, LHJ, Guilford, P, Aass, N, Fosså, SD, Heimdal, K, Tjulandin, SA, Liubchenko, L, Stoll, H, Weber, W, Einhorn, L, Weber, BL, McMaster, M, Greene, MH, Bishop, DT, Easton, D, Stratton, M, Rapley, EA, Hockley, S, Warren, W, Johnson, L, Huddart, R, Crockford, G, Forman, D, Leahy, MG, Oliver, DT, Tucker, K, Friedlander, M, Phillips, KA, Hogg, D, Jewett, MAS, Lohynska, R, Daugaard, G, Richard, S, Heidenreich, A, Geczi, L, Bodrogi, I, Olah, E, Ormiston, WJ, Daly, PA, Looijenga, LHJ, Guilford, P, Aass, N, Fosså, SD, Heimdal, K, Tjulandin, SA, Liubchenko, L, Stoll, H, Weber, W, Einhorn, L, Weber, BL, McMaster, M, Greene, MH, Bishop, DT, Easton, D, and Stratton, M

Abstract

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

Published
2004

32. Somatic mutations of KIT in familial testicular germ cell tumours

Author

Rapley, E A, primary, Hockley, S, additional, Warren, W, additional, Johnson, L, additional, Huddart, R, additional, Crockford, G, additional, Forman, D, additional, Leahy, M G, additional, Oliver, D T, additional, Tucker, K, additional, Friedlander, M, additional, Phillips, K-A, additional, Hogg, D, additional, Jewett, M A S, additional, Lohynska, R, additional, Daugaard, G, additional, Richard, S, additional, Heidenreich, A, additional, Geczi, L, additional, Bodrogi, I, additional, Olah, E, additional, Ormiston, W J, additional, Daly, P A, additional, Looijenga, L H J, additional, Guilford, P, additional, Aass, N, additional, Fosså, S D, additional, Heimdal, K, additional, Tjulandin, S A, additional, Liubchenko, L, additional, Stoll, H, additional, Weber, W, additional, Einhorn, L, additional, Weber, B L, additional, McMaster, M, additional, Greene, M H, additional, Bishop, D T, additional, Easton, D, additional, and Stratton, M R, additional

Published
2004
Full Text
View/download PDF

39. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial

Author

Koji Kawai, Satoshi Nagamori, Katherine M Bell-McGuinn, Cristiano Ferrario, Wen Pin Su, Isabel Syndikus, Aude Flechon, Georgios Gakis, Timothy Dudley Clay, Leticia Vazquez Cortés, Ronald de Wit, Florence Joly, Bozena Sikora-Kupis, Sergio Bracarda, Astra M. Liepa, Annemie Rutten, Daniel P. Petrylak, Su Peng Yeh, Annamaria Zimmermann, Sameera R. Wijayawardana, Mutsushi Kawakita, Siobhan Ng, Thean Hsiang Tan, Chikara Ohyama, Yu Jung Kim, Yuriy Golovko, Dimitrios Mavroudis, Jian Ri Li, Reinoud J. B. Blaisse, Mustafa Erman, Francesca Russo, Catherine Becht, Anghel Adrian Udrea, Robert Huddart, Syed A. Hussain, Fransiscus L.G. Erdkamp, Satoshi Fukasawa, Francesco Massari, Motohide Uemura, Boris Alekseev, Irfan Cicin, Se Hoon Park, Marcello Tucci, Lajos Géczi, Maureen J.B. Aarts, Yu Li Su, Fumimasa Fukuta, Hyo Jin Lee, Wolfgang Schultze-Seemann, Alexandra Drakaki, Hakan Harputluoglu, Xavier Garcia del Muro, Santhanam Sundar, Avivit Peer, Herlinde Dumez, William E. Lawler, Juan Ignacio Delgado Mignorance, Naveed Sarwar, Jeanny B. Aragon-Ching, Benjamin T. Herms, Fredrik Laestadius, Nobuaki Matsubara, Ivan Sinielnikov, Cora N. Sternberg, Hiroyuki Nishiyama, Piotr Tomczak, Brigitte Laguerre, Rebecca R. Hozak, Vasilis Karavasilis, Christina A. Schwentner, Hiroyuki Tsunemori, Masayoshi Nagata, Igor Bondarenko, Andrea Necchi, Yen Chuan Ou, Scott T. Tagawa, Constance Thibault, Richard A. Walgren, Akira Yokomizo, Evan Y. Yu, Alejo Rodriguez-Vida, Sufia Safina, Ulka N. Vaishampayan, János Révész, Aristotelis Bamias, Jae-Lyun Lee, Chien Liang Lin, Thomas W. Flaig, Roman Fomkin, Petr Alexandrovich Karlov, Joanna Wojcik-Tomaszewska, Junichi Inokuchi, Wataru Obara, Haralambos Kalofonos, John D. Hainsworth, Marc-Oliver Grimm, Thomas Eugene Lowe, Pablo Gajate Borau, Simon J. Crabb, Lisa Sengeloev, Junji Yonese, Simon Chowdhury, Elizabeth Jane Hovey, Daniel Castellano, Peter Istvan Acs, Chia-Chi Lin, Claudia Lorena Urzua Flores, Jean-Pascal Machiels, Kim N. Chi, Takahiro Osawa, Nobuo Shinohara, Daniel Kejzman, Günter Niegisch, David Sarid, Yuksel Urun, Yun Gyoo Lee, Oday Hamid, Alina Amalia Herzal, Michael Schenker, Eli Rosenbaum, Enrique Grande, Raya Leibowitz-Amit, Naoto Miyajima, Michiel S. van der Heijden, Shinichi Yamashita, Susanna Yee Shan Cheng, Kazuo Nishimura, Sun Young Rha, Thomas Powles, Hasan Şenol Coşkun, Jens Bedke, Ivor J. Percent, Christos Papandreou, James K. Schwarz, Masafumi Oyama, Giorgio V. Scagliotti, Chong-Xian Pan, Yoshihiko Tomita, Giampaolo Tortora, Stéphane Culine, Suet Lai Shirley Wong, Andrey Semenov, Jennifer L. Cultrera, Niels Viggo Jensen, Michael Stöckle, Katsuyoshi Hashine, Medical Oncology, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre du cancer, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, Sa, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Bedke, J, Gakis, G, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, G, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Tagawa, St, Vaishampayan, U, Aragon-Ching, Jb, Hamid, O, Liepa, Am, Wijayawardana, S, Russo, F, Walgren, Ra, Zimmermann, Ah, Hozak, Rr, Bell-McGuinn, Km, Powles, T, and Graduate School

Subjects
Male, 0301 basic medicine, MULTICENTER, Docetaxel, Gastroenterology, ANGIOGENESIS, VINFLUNINE, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Neoplasm Metastasis, education.field_of_study, CHEMOTHERAPY, Middle Aged, OPEN-LABEL, Prognosis, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Female, medicine.drug, EXPRESSION, Urologic Neoplasms, medicine.medical_specialty, BEVACIZUMAB, Population, BLADDER-CANCER, Neutropenia, Antibodies, Monoclonal, Humanized, Placebo, Ramucirumab, 03 medical and health sciences, Double-Blind Method, Internal medicine, medicine, Humans, Neoplasm Invasiveness, education, Survival rate, Aged, Platinum, Salvage Therapy, Carcinoma, Transitional Cell, business.industry, medicine.disease, ATEZOLIZUMAB, 030104 developmental biology, ENDOTHELIAL GROWTH-FACTOR, business, Febrile neutropenia, Follow-Up Studies
Abstract

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Published
2020
Full Text
View/download PDF

40. Docetaxel with or without Ramucirumab after Platinum-Based Chemotherapy and Checkpoint Inhibitors in Advanced Urothelial Carcinoma: A Pre-Specified Subgroup Analysis from the Phase 3 RANGE Trial

Author

Alexandra Drakaki, Simon Chowdhury, Chia-Chi Lin, Daniel Keizman, Michiel S. van der Heijden, Daniel P. Petrylak, Jae-Lyun Lee, Kim N. Chi, Sergio Bracarda, Daniel Castellano, Georgios Gakis, Andrea Necchi, Lajos Géczi, Ulka N. Vaishampayan, Annamaria Zimmermann, Thomas Powles, Conor J. Kirby, Katherine M Bell-McGuinn, Aude Flechon, Drakaki, A., Kirby, C. J., Van Der Heijden, M. S., Petrylak, D. P., Powles, T., Chi, K. N., Flechon, A., Necchi, A., Geczi, L., Lee, J. -L., Gakis, G., Bracarda, S., Chowdhury, S., Lin, C. -C., Keizman, D., Vaishampayan, U. N., Zimmermann, A. H., Bell-Mcguinn, K., Castellano, D., and Graduate School

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, ramucirumab, Urology, medicine.medical_treatment, Population, Subgroup analysis, Immune checkpoint inhibitor, Placebo, Ramucirumab, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, education, urothelial carcinoma, education.field_of_study, Chemotherapy, VEGFR inhibitor, Proportional hazards model, business.industry, Hazard ratio, platinum-refractory, 030104 developmental biology, Docetaxel, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

BACKGROUND: The phase 3 RANGE trial found ramucirumab/docetaxel improved progression-free survival (PFS) versus placebo/docetaxel (median 4.1 vs 2.8 months; hazard ratio [HR] = 0.757, p = 0.0118) for treatment of platinum-refractory metastatic urothelial carcinoma (UC). Some patients received an immune checkpoint inhibitor (ICI) prior to RANGE. In other studies, unselected patients with platinum-refractory UC exhibited an overall response rate (ORR) of 15–31% to ICIs. OBJECTIVE: Efficacy and safety data from the subgroup of patients treated with prior ICI were examined using prespecified analyses to compare outcomes between RANGE treatment arms. METHODS: Randomized, double-blind RANGE study (n = 530) took place July 2015-April 2017 in 23 countries. Forty-five patients (8.5%) received prior ICI. PFS was evaluated using the Kaplan-Meier method and unstratified Cox proportional hazards model. RESULTS: 17 ramucirumab/docetaxel arm, 28 placebo/docetaxel arm patients were treated with an ICI. The prior-ICI ramucirumab subgroup had worse Bellmunt scores at baseline versus placebo (score of 2-3 : 70.6% vs 25%, respectively). Most patients (84.4%) received the ICI immediately following platinum and immediately prior to RANGE. ORR to prior ICI was 6.7% Responses were achieved by 5/17 (29.4%) on ramucirumab/docetaxel, compared to 2/28 (7.1%) on placebo/docetaxel. Median PFS was 3.15 months on ramucirumab/docetaxel versus 2.73 months on placebo/docetaxel (HR = 0.786, 95% CI = 0.404–1.528, p = 0.4877). The frequency of grade≥3 adverse events was similar between arms. Limitations include sample size and treatment setting of the analyzed population. CONCLUSIONS: Ramucirumab/docetaxel may provide a clinical benefit with acceptable safety in the third-line setting for metastatic UC patients whose disease has progressed on both prior platinum chemotherapy and ICI therapy.

Published
2020

41. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

Author

Choueiri, T. K., Escudier, B., Powles, T., Mainwaring, P. N., Rini, B. l., Donskov, F., Hammers, H., Hutson, T. E., Lee, J.-L., Peltola, K., Roth, B. J., Bjamason, G. A., Geczi, L., Ream, B., Maroto, P., Heng, D. Y. C., Schmidinger, M., Kantoff, P. W., Borgman-Hagey, A., and Hessel, C.

Subjects
*AMIDES, *ANTINEOPLASTIC agents, *KIDNEY tumors, *PROGNOSIS, *PYRIDINE, *QUALITY of life, *RENAL cell carcinoma, *RESEARCH funding, *SURVIVAL analysis (Biometry), *RAPAMYCIN, *THERAPEUTICS
Abstract

Background: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.Methods: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.Results: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.Conclusions: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.). [ABSTRACT FROM AUTHOR]

Published
2015
Full Text
View/download PDF

42. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Author

Daniel P Petrylak, Ronald de Wit, Kim N Chi, Alexandra Drakaki, Cora N Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y Yu, Michiel S van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen-Chuan Ou, Hasan Senol Coskun, Wen-Pin Su, Miriam Hegemann, Ivor J Percent, Jae-Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Ryan C Widau, Astra M Liepa, Richard A Walgren, Oday Hamid, Annamaria H Zimmermann, Katherine M Bell-McGuinn, Thomas Powles, Suet-Lai Shirley Wong, Thean Hsiang Tan, Elizabeth Jane Hovey, Timothy Dudley Clay, Siobhan Su Wan Ng, Annemie Rutten, Jean-Pascal Machiels, Herlinde Dumez, Susanna Yee-Shan Cheng, Kim Nguyen Chi, Cristiano Ferrario, Lisa Sengeloev, Niels Viggo Jensen, Constance Thibault, Brigitte Laguerre, Florence Joly, Aude Flechon, Stéphane Culine, Catherine Becht, Günter Niegisch, Michael Stöckle, Marc-Oliver Grimm, Georgios Gakis, Wolfgang Schultze-Seemann, Haralambos Kalofonos, Dimitrios Mavroudis, Christos Papandreou, Vasilis Karavasilis, Janos Révész, Lajos Geczi, Eli Rosenbaum, Raya Leibowitz-Amit, Daniel Kejzman, David Sarid, Giorgio Vittorio Scagliotti, Sergio Bracarda, Francesco Massari, Takahiro Osawa, Naoto Miyajima, Nobuo Shinohara, Fumimasa Fukuta, Chikara Ohyama, Wataru Obara, Shinichi Yamashita, Yoshihiko Tomita, Koji Kawai, Satoshi Fukasawa, Masafumi Oyama, Junji Yonese, Masayoshi Nagata, Motohide Uemura, Kazuo Nishimura, Mutsushi Kawakita, Hiroyuki Tsunemori, Katsuyoshi Hashine, Junichi Inokuchi, Akira Yokomizo, Satoshi Nagamori, Hyo Jin Lee, Se Hoon Park, Sun Young Rha, Yu Jung Kim, Yun-Gyoo Lee, Leticia Vazquez Cortés, Claudia Lorena Urzua Flores, Reinoud J B Blaisse, Fransiscus L G Erdkamp, Maureen J B Aarts, Joanna Wojcik-Tomaszewska, Piotr Tomczak, Bozena Sikora-Kupis, Michael Schenker, Alina Amalia Herzal, Anghel Adrian Udrea, Petr Karlov, Sufia Z Safina, Roman Fomkin, Enrique Grande Pulido, F Xavier García Del Muro, Juan Ignacio Delgado Mignorance, Daniel Castellano Gauna, Alejo Rodríguez-Vida, Yu-Li Su, Chien-Liang Lin, Chia-Chi Lin, Su-Peng Yeh, Irfan Çiçin, Mustafa Erman, Yuksel Urun, Yurii Golovko, Igor Bondarenko, Ivan Sinielnikov, Simon Crabb, Isabel Syndikus, Robert Huddart, Santhanam Sundar, Simon Chowdhury, Naveed Sarwar, Thomas Flaig, Chong Xian Pan, Daniel Petrylak, James Schwarz, Ivor Percent, Jennifer Cultrera, John Hainsworth, Benjamin Herms, William Lawler, Thomas Lowe, Scott Tagawa, Jeanny Aragon-Ching, Ulka Vaishampayan, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service d'oncologie médicale, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Medische Oncologie (9), Petrylak, Dp, de Wit, R, Chi, Kn, Drakaki, A, Sternberg, Cn, Nishiyama, H, Castellano, D, Hussain, S, Flechon, A, Bamias, A, Yu, Ey, van der Heijden, M, Matsubara, N, Alekseev, B, Necchi, A, Geczi, L, Ou, Yc, Coskun, H, Su, Wp, Hegemann, M, Percent, Ij, Lee, Jl, Tucci, M, Semenov, A, Laestadius, F, Peer, A, Tortora, G, Safina, S, del Muro, Xg, Rodriguez-Vida, A, Cicin, I, Harputluoglu, H, Widau, Rc, Liepa, Am, Walgren, Ra, Hamid, O, Zimmermann, Ah, Bell-McGuinn, Km, Powles, T, and Medical Oncology

Subjects
0301 basic medicine, Male, Internationality, medicine.medical_treatment, Phases of clinical research, Docetaxel, Kaplan-Meier Estimate, Gastroenterology, 2ND-LINE THERAPY, 0302 clinical medicine, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Medicine, ramucirab, Medicine (all), Antibodies, Monoclonal, General Medicine, Middle Aged, OPEN-LABEL, Prognosis, Neoadjuvant Therapy, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Taxoids, medicine.drug, Adult, medicine.medical_specialty, Metastatic Urothelial Carcinoma, Urology, Locally advanced, BLADDER-CANCER, Placebo, Antibodies, Monoclonal, Humanized, Risk Assessment, Ramucirumab, Antibodies, Disease-Free Survival, Double blind, II TRIAL, 03 medical and health sciences, LUNG-CANCER, Aged, Carcinoma, Transitional Cell, Double-Blind Method, Humans, Neoplasm Invasiveness, Neoplasm Staging, Proportional Hazards Models, Survival Analysis, Urinary Bladder Neoplasms, Internal medicine, BREAST-CANCER, In patient, Adverse effect, Platinum, Chemotherapy, FACTOR RECEPTOR-2, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Carcinoma, TRANSITIONAL-CELL-CARCINOMA, Surgery, Discontinuation, Regimen, Ramucirumab, docetaxel, 030104 developmental biology, ENDOTHELIAL GROWTH-FACTOR, Transitional Cell, business, FOLLOW-UP
Abstract

Summary Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m 2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company.

Published
2017

43. Cisplatin- or Carboplatin-Based Chemotherapy Plus Pembrolizumab in Advanced Urothelial Cancer: Exploratory Analysis From the Phase 3 KEYNOTE-361 Study.

Author

Powles T, Csőszi T, Loriot Y, Matsubara N, Geczi L, Cheng SY, Fradet Y, Alva A, Oudard S, Vulsteke C, Morales-Barrera R, Fléchon A, Gunduz S, Liu CC, Moreno BH, Bavle A, and Özgüroğlu M

Subjects
Humans, Male, Female, Aged, Middle Aged, Urologic Neoplasms drug therapy, Urologic Neoplasms pathology, Urologic Neoplasms mortality, Gemcitabine, Aged, 80 and over, Adult, Deoxycytidine analogs & derivatives, Deoxycytidine administration & dosage, Deoxycytidine therapeutic use, Carcinoma, Transitional Cell drug therapy, Treatment Outcome, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms pathology, Progression-Free Survival, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized therapeutic use, Carboplatin administration & dosage, Cisplatin administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols administration & dosage
Abstract

Introduction: KEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported., Patients and Methods: Eligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361., Results: Of 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI, 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI, 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent antiprogrammed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported., Conclusion: Results suggest trends toward OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2025
Full Text
View/download PDF

44. Final Results from SAUL, a Single-arm International Study of Atezolizumab in Unselected Patients with Pretreated Locally Advanced/Metastatic Urinary Tract Carcinoma.

Author

Sternberg CN, Loriot Y, Choy E, Castellano D, Lopez-Rios F, Banna GL, Zengerling F, De Giorgi U, Gedye C, Masini C, Bamias A, Garcia Del Muro X, Duran I, Powles T, Retz M, Gamulin M, Geczi L, Huddart RA, Calabrò F, Kandula G, Skamnioti P, and Merseburger AS

Abstract

Background and Objective: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data., Methods: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS)., Key Findings and Limitations: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest., Conclusions and Clinical Implications: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities., Patient Summary: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Published
2024
Full Text
View/download PDF

45. Single-course bleomycin, etoposide, and cisplatin (1xBEP) as adjuvant treatment in testicular nonseminoma clinical stage 1: outcome, safety, and risk factors for relapse in a population-based study.

Author

Dieckmann KP, Pokrivcak T, Geczi L, Niehaus D, Dralle-Filiz I, Matthies C, Dienes T, Zschäbitz S, Paffenholz P, Gschliesser T, Pichler R, Mego M, Bader P, Zengerling F, Heinzelbecker J, Krausewitz P, Krege S, Aurilio G, Aksoy C, Hentrich M, Seidel C, Törzsök P, Nestler T, Majewski M, Hiester A, Buchler T, Vallet S, Studentova H, Schönburg S, Niedersüß-Beke D, Ring J, Trenti E, Heidenreich A, Wülfing C, Isbarn H, Pichlmeier U, and Pichler M

Abstract

Introduction: Clinical stage 1 (CS1) nonseminomatous (NS) germ cell tumors involve a 30% probability of relapse upon surveillance. Adjuvant chemotherapy with one course of bleomycin, etoposide, and cisplatin (1xBEP) can reduce this risk to <5%. However, 1xBEP results are based solely on five controlled trials from high-volume centers. We analyzed the outcome in a real-life population., Patients and Methods: In a multicentric international study, 423 NS CS1 patients receiving 1xBEP were retrospectively evaluated. Median follow-up was 37 (range, 6-89) months. Primary end points were relapse-free and overall survival evaluated after 5 years. We also looked at associations of relapse with clinico-pathological factors using stratified Kaplan-Meier methods and Cox regression models. Treatment modality and outcome of recurrences were analyzed descriptively., Results: The 5-year relapse-free survival rate was 96.2%. Thirteen patients (3.1%; 95% confidence interval, 1.65-5.04%) relapsed after a median time of 13 months, of which 10 were salvaged (77%). Relapses were mostly confined to retroperitoneal nodes. Three patients succumbed, two to disease progression and one to toxicity of chemotherapy. Pathological stage >pT2 was significantly associated with relapse rate., Conclusion: The relapse rate of 3.1% found in this population of NS CS1 patients treated with 1xBEP at the routine care level was not inferior to the median rate of 2.3% reported from a meta-analysis of controlled trials. Also, the cure rate of relapses of 77% is consistent with the previously reported rate of 80%. This study clearly shows that the 1xBEP regimen represents a safe treatment for NS CS1 patients., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Published
2022
Full Text
View/download PDF

46. Clinical Results and Biomarker Analyses of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or Metastatic Renal Cell Carcinoma (TRAXAR).

Author

Choueiri TK, Zakharia Y, Pal S, Kocsis J, Pachynski R, Poprach A, Nixon AB, Liu Y, Starr M, Lyu J, Owzar K, deShazo M, Lara P, Geczi L, Ho TH, Walsh M, Adams B, Robertson L, Darif M, Theuer C, and Agarwal N

Subjects
Antibodies, Monoclonal, Axitinib, Humans, Vascular Endothelial Growth Factor A, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy
Abstract

Lessons Learned: The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels., Background: Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors., Methods: TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels., Conclusion: The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Published
2021
Full Text
View/download PDF

47. Real-world safety and efficacy of nivolumab for ≥ 2nd line treatment of metastatic renal cell carcinoma: A retrospective cohort study in Croatia, Hungary, and Malta.

Author

Vrdoljak E, Magri C, Gamulin M, Bošković L, Omrčen T, Bajić Ž, Dienes T, and Geczi L

Subjects
Aged, Croatia, Female, Humans, Hungary, Male, Malta, Middle Aged, Neoplasm Metastasis, Retrospective Studies, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Nivolumab adverse effects, Nivolumab therapeutic use
Abstract

The objective of our study was to assess the real-world safety and efficacy of nivolumab in the second- or later-line treatment of metastatic renal cell carcinoma (mRCC). We conducted a multicenter, retrospective, observational study of real-world data from patients who were treated with nivolumab under a patient expanded access program from 2015 to 2017 in Croatia, Hungary, and Malta. The primary safety endpoint was the discontinuation of therapy because of adverse events. The primary efficacy endpoint was overall survival (OS). We collected data from 87 patients with a median (interquartile range (IQR)) age of 63 (57-68) years, and 21% were females. The median (IQR) follow-up was 11 (5-31) months. Treatment was discontinued because of toxicity in 4 (5%) patients. Four (5%) patients experienced treatment-related adverse events of grade 3 or 4. The OS was 18.0 (95% CI: 11.0 to 28.6) months, and the PFS was 8.5 (95% CI: 4.9 to 12.1) months. Our study indicated a good safety and efficacy profile of nivolumab in the second- or later-line treatment of mRCC patients in a real-world clinical practice environment, which is comparable with the findings of the registrational trial.

Published
2021
Full Text
View/download PDF

48. Real-World Safety and Efficacy of Nivolumab in Advanced Squamous and Nonsquamous Non-Small-Cell Lung Cancer: A Retrospective Cohort Study in Croatia, Hungary, and Malta.

Author

Vrdoljak E, Jakopović M, Geczi L, Bogos K, Bošković L, Magri C, Bitar L, Bajić Ž, and Samaržija M

Abstract

Background: There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) especially in South East Europe, a region with particularly high incidence and an unfavorable mortality-to-incidence ratio for lung cancer., Objectives: To evaluate the real-world safety and efficacy of nivolumab in patients with previously treated advanced squamous and nonsquamous NSCLC in South East Europe., Methods: This is a multicenter, retrospective cohort study on patients with stage IIIB or IV disease with at least one previous systemic treatment who received nivolumab through an expanded-access program between 2015 and 2017 in Croatia, Malta, and Hungary. The primary endpoint was the proportion of patients whose therapy was discontinued because of toxicity. Secondary endpoints were the incidence of adverse events (AEs), objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS)., Results: We analyzed data on 239 patients with a median (IQR) age of 62 (57-68), and 33% of them were women. Treatment was discontinued because of toxicity in 11.6% (95% CI 7.8% to 16.5%) of patients. The PFS was 6.4 (95% CI 5.2 to 8.6) months, and the median OS was 14.1 (10.6 to 18.0) months., Conclusions: The safety and efficacy of nivolumab in previously treated patients with advanced NSCLC in the real-world South East Europe clinical settings were consistent with the results of randomized clinical trials and comparable to the results from other countries., Competing Interests: Eduard Vrdoljak received support for clinical trials and scientific projects from Pfizer, Roche, BMS, and AZ; speaker fees and consulting from Amgen, Astellas, Astra Zeneca, Boehringer Ingelheim, Johnson & Johnson, Novartis, Pharmaswiss, Pfizer, Roche, Sanofi, MSD, and Merck. Marko Jakopović received speaker fees and traveler grants from Roche, MSD, Boehringer Ingelheim, Astra Zeneca, BMS, Pfizer, Novartis, and Eli Lilly and advisory boards of Roche, MSD, Boehringer Ingelheim, Astra Zeneca, BMS, and Pfizer. Lajos Geczi declares no conflicts of interest. Krisztina Bogos received speaker and travel fees from Astra Zeneca, MSD, BMS, Pfizer, and Boehringer Ingelheim. Lidija Bošković received speaker fees and consulting from Amgen, Boehringer Ingelheim, MSD, Astra Zeneca, Roche, Novartis, Merck, and Sanofi. Claude Magri received financial support for conferences/symposia from BMS, Lilly, MSD, Pfizer, Sanofi, and Servier. Lela Bitar declares no conflicts of interest. Žarko Bajić has been giving workshops in clinical trials' critical appraisals and has done study designs, data analysis, and marketing research for Abbott, Abbvie, AstraZeneca, Bayer, Biogen, Boehringer Ingelheim, Eli Lilly, Fresenius Kabi, GlaxoSmithKline, Janssen Cilag, Merck, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Reckitt Benckiser, Roche, Sanofi, Servier, Takeda, and Teva. Miroslav Samaržija received speaker fees and traveler grants from Roche, MSD, Boehringer Ingelheim, Astra Zeneca, BMS, Pfizer, Novartis, and Eli Lilly and advisory boards of Roche, MSD, Boehringer Ingelheim, Astra Zeneca, BMS, and Pfizer., (Copyright © 2020 Eduard Vrdoljak et al.)

Published
2020
Full Text
View/download PDF

49. Primary Results from SAUL, a Multinational Single-arm Safety Study of Atezolizumab Therapy for Locally Advanced or Metastatic Urothelial or Nonurothelial Carcinoma of the Urinary Tract.

Author

Sternberg CN, Loriot Y, James N, Choy E, Castellano D, Lopez-Rios F, Banna GL, De Giorgi U, Masini C, Bamias A, Garcia Del Muro X, Duran I, Powles T, Gamulin M, Zengerling F, Geczi L, Gedye C, de Ducla S, Fear S, and Merseburger AS

Subjects
Aged, Anemia chemically induced, Anorexia chemically induced, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Asthenia chemically induced, Carcinoma, Transitional Cell secondary, Colitis chemically induced, Disease Progression, Fatigue chemically induced, Female, Humans, Hypertension chemically induced, Male, Middle Aged, Progression-Free Survival, Retreatment, Survival Rate, Urinary Tract Infections chemically induced, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Transitional Cell drug therapy, Urologic Neoplasms drug therapy, Urologic Neoplasms pathology
Abstract

Background: Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab., Objective: To determine the safety and efficacy of atezolizumab in an international real-world setting., Design, Setting, and Participants: Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406)., Intervention: Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity., Outcome Measurements and Statistical Analysis: The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results and Limitations: The median treatment duration was 2.8mo (range 0-19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8-9.9). The 6-mo OS rate was 60% (95% CI 57-63%), median PFS was 2.2mo (95% CI 2.1-2.4), and the ORR was 13% (95% CI 11-16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8-11.9) and 6-mo OS was 65% (95% CI 61-69%)., Conclusions: SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options., Patient Summary: In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2019
Full Text
View/download PDF

50. Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study.

Author

Dieckmann KP, Radtke A, Geczi L, Matthies C, Anheuser P, Eckardt U, Sommer J, Zengerling F, Trenti E, Pichler R, Belz H, Zastrow S, Winter A, Melchior S, Hammel J, Kranz J, Bolten M, Krege S, Haben B, Loidl W, Ruf CG, Heinzelbecker J, Heidenreich A, Cremers JF, Oing C, Hermanns T, Fankhauser CD, Gillessen S, Reichegger H, Cathomas R, Pichler M, Hentrich M, Eredics K, Lorch A, Wülfing C, Peine S, Wosniok W, Bokemeyer C, and Belge G

Subjects
Adolescent, Adult, Aged, Biomarkers, Tumor genetics, Case-Control Studies, Chorionic Gonadotropin, beta Subunit, Human blood, Circulating MicroRNA genetics, Europe, Humans, L-Lactate Dehydrogenase blood, Male, MicroRNAs genetics, Middle Aged, Neoplasms, Germ Cell and Embryonal genetics, Neoplasms, Germ Cell and Embryonal pathology, Neoplasms, Germ Cell and Embryonal surgery, Orchiectomy, Predictive Value of Tests, Prospective Studies, Seminoma genetics, Seminoma pathology, Seminoma surgery, Testicular Neoplasms genetics, Testicular Neoplasms pathology, Testicular Neoplasms surgery, Treatment Outcome, Young Adult, alpha-Fetoproteins metabolism, Biomarkers, Tumor blood, Circulating MicroRNA blood, MicroRNAs blood, Neoplasms, Germ Cell and Embryonal blood, Seminoma blood, Testicular Neoplasms blood
Abstract

Purpose: Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT., Patients and Methods: In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase., Results: For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p., Conclusion: The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

Published
2019
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results