GILBERTO DE CASTRO JUNIOR

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Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
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  • article 32 Citação(ões) na Scopus
    Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial(aEuro)
    (2016) CLEMENT, P. M.; GAULER, T.; MACHIELS, J. P.; HADDAD, R. I.; FAYETTE, J.; LICITRA, L. F.; TAHARA, M.; COHEN, E. E. W.; CUPISSOL, D.; GRAU, J. J.; GUIGAY, J.; CAPONIGRO, F.; CASTRO JR., G. de; VIANA, L. de Souza; KEILHOLZ, U.; CAMPO, J. M. del; CONG, X. J.; EHRNROOTH, E.; VERMORKEN, J. B.
    In the LUX-Head & Neck 1 study, older age (a parts per thousand yen65 years) did not adversely affect the benefit in patient-reported outcomes and antitumor activity observed with afatinib over methotrexate, which was consistent with findings from the overall population. Safety in older patients was also consistent with the overall population, favoring afatinib in terms of fewer dose reductions and discontinuations.In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged a parts per thousand yen65 and < 65 years. Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged a parts per thousand yen65 years (older) and 73% (239 afatinib; 116 methotrexate) < 65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. Advancing age (a parts per thousand yen65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. NCT01345682 (ClinicalTrials.gov).
  • article 30 Citação(ões) na Scopus
    Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial
    (2019) BURTNESS, Barbara; HADDAD, Robert; DINIS, Jose; TRIGO, Jose; YOKOTA, Tomoya; VIANA, Luciano de Souza; ROMANOV, Ilya; VERMORKEN, Jan; BOURHIS, Jean; TAHARA, Makoto; SEGALLA, Jose Getulio Martins; ESCOBAR, Yolanda; SORIA, Ainara; CHAVES, Mauel; JOHANSSON, Gun Wickart; FRIESLAND, Signe; TELL, Roger; NYMAN, Jan; ROTHSCHILD, Sacha; ZIPPELIUS, Alfred; ASARAWALA, Nirav; KARAVASILIS, Vasilios; RAUCH, Daniel; USLUOGLU, Nurguel; GOGUNSKA, Inna; ZABOLOTNIY, Dmytro; VINNYK, Yuriy; BURIAN, Oleksandr; HARRINGTON, Kevin; SYKES, Andrew; PEEL, David; LESTER, James; FOUNTZILAS, Georgios; NICOLAU, Ulisses Ribaldo; ROBINSON, Martin; SRINIVASAN, Devraj; FRAGKANDREA-NIXON, Ioanna; JUNOR, Elizabeth; GOLLINS, Simon; EVANS, Mererid; NEWBOLD, Kate; HWANG, David; SCHIPANI, Stefano; PSYRRI, Diamanto; RIZWANULLAH, Mohammed; RAUCH, Daniel; ATIQ, Omar; ARNAOUTAKIS, Konstantinos; BAUMAN, Jessica; BURTNESS, Barbara; MEHRA, Ranee; KANG, Hyunseok; CHUNG, Christine; DAVIS, Thomas; LANG, Istvan; HADDAD, Robert; JIMENO, Antonio; EVEN, Caroline; KERESZTES, Roger; NANGIA, Chaitali; IGNATIUS, Sai-Hong; SU, Yungpo Bernard; OVERTON, Lindsay Carol; GARRISON, Mitchell A.; JEONG, Woondong; BOER, Andras; WEHBE, Ahmad; ARGIRIS, Athanassios; CHIANG, Anne; WANG, Bushi; MORGENSZTERN, Daniel; HAIGENTZ JR., Missak; MARTINCIC, Danko; POROSNICU, Mercedes; GIBSON, Neil; EHRNROOTH, Eva; KOCSIS, Judit; HARRINGTON, Kevin; COHEN, Ezra E. W.; GIGLIO, Raul Eduardo; BLAJMAN, Cesar Raul; FREUE, Jose Mario; PILNIK, Norma Graciela; PALAZZO, Felipe Salvador; MCGRATH, Margaret; FUREDER, Thorsten; KORNEK, Gabriela; PAJKOS, Gabor; PICHLER, Angelika; BAUERNHOFER, Thomas; TINCHON, Christoph; GREIL, Richard; BURIAN, Martin; KIENZER, Heinz; SPECENIER, Pol; SAUTOIS, Brieuc; DEBRUYNE, Philip; GRAAS, Marie-Pascale; TAMAS, Laszlo; MAES, Annelies; LONCHAY, Christophe; DAISNE, Jean-Francois; FONTAINE, Christel; CASTRO JUNIOR, Gilberto; OLIVEIRA, Frias de; PEREIRA, Rodrigo Perez; MARCHI, Pedro Rafael Martins De; VIANA, Luciano de Souza; SEGALLA, Jose Getulio Martins; ANAND, A. L.; NICOLAU, Ulisses Ribaldo; LAZARETTI, Nicolas Silva; KULKARNI, Swati; ALAM, Yasmin; HO, Cheryl; SHENOUDA, George; SOULIERES, Denis; SULTANEM, Khalil; SINGH, Simron; MELLA, Pablo Gonzalez; SHARMA, Ajay; CAMPOS, Jose Antonio Solis; HOLECKOVA, Petra; PRAUSOVA, Jana; OBERMANNOVA, Radka; FRIBORG, Jeppe; SPECHT, Lena; ELSAID, Amr Abdelaziz; MINN, Heikki; MARTIN, Laurent; ROLLAND, Frederic; PSYRRI, Amanda; CERUSE, Philippe; CALAIS, Gilles; EVEN, Caroline; GUIGAY, Joe; FERTE, Charles; PEYRADE, Frederic; DUFFAUD, Florence; CHAMPEAUX-ORANGE, Elise; COUTTE, Alexandre; CLATOT, Florian; Sharma; FOURNEL, Pierre; MOAL, Laurence Bozec Le; DIETZ, Andreas; GRUENWALD, Viktor; GAULER, Thomas; GUNTINAS-LICHIUS, Orlando; HILDEBRANDT, Guido; KUHNT, Thomas; SCHMIDT, Horst-Juergen; HENKE, Michael; VOONA, Murali; RUECKERT, Anja; BRUGGER, Wolfram; ROTTER, Nicole; MAHLBERG, Rolf; PANDY, Ananda Selvakumar; KUMAR, Kirushna; NATHAN, Raj Kumar Poovna; SRINIVASAN, Venkatesan; ZADE, Bhooshan; JAIN, Minish; SRINIVASA, B. J.; NAIK, Radheshyam; VASILEVSKAYA, Irina; MOHANTY, B. K.; ASARAWALA, Nirav; CHARAS, Tomer; BILLAN, Salem; POPOVTZER, Aron; LICITRA, Lisa; FERRARI, Daris; FAO, Paolo; MERLANO, Marco; ROCCA, Maria Cossu; NANGIA, Chaitali Singh; HOMMA, Akihiro; FUJII, Hirofumi; TAHARA, Makoto; MINAMI, Syujiro; FUJII, Masato; YOKOTA, Tomoya; KADOWAKI, Shigenori; MURO, Kei; KIYOTA, Naomi; OKAMI, Kenji; CHAVES-CONDE, Manuel; YAGI, Toshinari; YOSHINO, Kunitoshi; MATSUMOTO, Koji; TAKAHASHI, Shunji; MATSUURA, Kazuto; AVITIA, Miguel Angel Alvarez; RIESTRA, Hector Jorge Gonzalez; MEERTEN, E. van; BUTER, J.; GELDERBLOM, A. J.; KIYOTA, Naomi; KAWECKI, Andrzej; GOLUSINSKI, Wojciech; DINIS, Jose; DINIS, Rui; RIBEIRO, Leonor; SILVA, Regina; MANSINHO, Helder; SELEZNEVA, Irina; BIAKHOV, Mikhail; GALIULIN, Rinat; HOMMA, Akihiro; IZMAILOV, Adel; ROMANOV, Ilya; VLADIMIROV, Vladimir; VINOGRADOV, Valery; MUFAZALOV, Fagim; VASILEVSKAYA, Irina; BASTE, Neus; CAMPO, Josep Ma del; NIN, Ricard Mesia; POUSA, Antonio Lopez; HOLECKOVA, Petra; CASTRO, Juan Jose Grau de; REIG, Oscar; VERA, Ruth; TRIGO, JoseManuel; IGLESIAS, Lara; TRUFERO, Javier Martinez; VAZQUEZ, Sergio; RUBIO, Belen; ALES, Jose Enrique; VILLAR, Esther; CAMPO, Josep Maria Del; RUBIO, Jordi
    ImportanceLocoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. ObjectiveTo assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. Design, Setting, and ParticipantsThis multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. InterventionsPatients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. Main Outcomes and MeasuresThe primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. ResultsA total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P=.48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). Conclusions and RelevanceThis study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. Trial RegistrationClinicalTrials.gov identifier: NCT01345669
  • article 1 Citação(ões) na Scopus
    EGFR Mutation Detection in Brazilian Patients With Non-Small-Cell Lung Cancer: Lessons From Real-World Data Scenario of Molecular Testing
    (2023) MONTELLA, Tatiane; ZALIS, Mariano; ZUKIN, Mauro; LIMA, Vladmir Claudio Cordeiro de; BALDOTTO, Clarissa; MARCHI, Pedro De; SALLES, Paulo; MATHIAS, Clarissa; BARRIOS, Carlos; KAWAMURA, Carolina; CALABRICH, Aknar; ARAUJO, Luiz Henrique; CASTRO, Gilberto; BUSTAMANTE, Carolina; MARIA, Andre Santa; REIS, Marcelo; FERREIRA, Carlos Gil
    PURPOSE There is a paucity of consistent data concerning genetic mutations in Brazilian patients with lung cancer. The aim of this study was to retrospectively analyze epidermal growth factor receptor (EGFR) mutations detected in a real-world scenario using a large cohort of Brazilian patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS This was a cross-sectional, observational, descriptive study on the basis of a database of EGFR molecular analysis from tumor samples of patients with a confirmatory histopathological diagnosis of primary lung cancer. Specimens were collected from 2013 to 2017 and were tested using cobas, next-generation sequencing, and Sanger sequencing platforms. RESULTS A total of 7,413 tumor specimens were tested. The patients were predominantly women with a median age of 67.0 years. Patients with at least one mutation represented 24.2% of the total sample. Among the positive patients, the majority had just one mutation, but two or more simultaneous mutations were observed in 1.52% of patients. Exon 19 deletion was the most prevalent alteration in the sample (12.8%), followed by exon 21 L858R (6.9%) and exon 20 insertion (1.6%). All others were considered uncommon mutations and were observed in 18.5% of all mutated patients and 4.0% of the total sample (2.3%18.7% depending on the sequencing method). CONCLUSION This study examined the prevalence of EGFR mutations in Brazilian patients with NSCLC using different technologies, suggesting that the type of method used, directed or nondirected against specific mutations, influences the analysis, particularly for uncommon mutations, which will be missed by mutation-specific approaches such as cobas testing. Our estimates are the largest in Latin America and are consistent with previous reports from other parts of the world. Besides the variability in methods described here as technology incorporation advances in a nonhomogeneous manner, it is probably like the real-world clinical setting Brazilian oncologists face in their daily practice.
  • article 81 Citação(ões) na Scopus
    Meta-Analysis of First-Line Therapies in Advanced Non-Small-Cell Lung Cancer Harboring EGFR-Activating Mutations
    (2014) HAALAND, Benjamin; TAN, Pui San; CASTRO JR., Gilberto de; LOPES, Gilberto
    Introduction: Tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib have been compared with chemotherapy as first-line therapies for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor-activating mutations. This meta-analysis compares gefitinib, erlotinib, afatinib, and chemotherapy. Methods: Literature search was performed using relevant keywords. Direct and indirect meta-estimates were generated using log-linear mixed-effects models, with random effects for study. Study-to-study heterogeneity was summarized using I-2 statistics and predictive intervals (PIs). Results: Literature search yielded eight randomized phase 3 clinical trials comparing gefitinib, erlotinib, or afatinib with chemotherapy as first-line therapy in patients with advanced non-small-cell lung cancer during the last 5 years. Hazard ratio meta-estimates for progression-free survival were for gefitinib versus chemotherapy 0.44 (95% confidence interval [CI] 0.31-0.63; 95% PI, 0.22-0.88), erlotinib versus chemotherapy 0.25 (95% CI, 0.15-0.42; 95% PI, 0.11-0.55), afatinib versus chemotherapy 0.44 (95% CI, 0.26-0.75; 95% PI, 0.20-0.98), erlotinib versus gefitinib 0.57 (95% CI, 0.30-1.08; 95% PI, 0.24-1.36), afatinib versus gefitinib 1.01 (95% CI, 0.53-1.92; 95% PI, 0.41-2.42), and erlotinib versus afatinib 0.56 (95% CI, 0.27-1.18; 95% PI, 0.22-1.46). Results for overall response rate and disease control rate were similar. There was no evidence that gefitinib, erlotinib, or afatinib improved overall survival compared with chemotherapy. Conclusion: Gefitinib, erlotinib, and afatinib out-performed chemotherapy in terms of progression-free survival, overall response rate, and disease control rate. Differences among gefitinib, erlotinib, and afatinib were not statistically significant.
  • article 11 Citação(ões) na Scopus
    A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma
    (2022) MUNHOZ, Rodrigo R.; NADER-MARTA, Guilherme; CAMARGO, Veridiana P. de; QUEIROZ, Marcello M.; CURY-MARTINS, Jade; RICCI, Herminia; MATTOS, Marcela R. de; MENEZES, Thiago A. F. de; MACHADO, Guilherme U. C.; BERTOLLI, Eduardo; BARROS, Milton; SOUZA, Carina E. de; FRANKE, Fabio; FERREIRA, Fabio O.; FEHER, Olavo; JR, Gilberto de Castro
    Background Cutaneous squamous-cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) with anti-programmed death receptor 1 (PD-1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti-PD-1 agent nivolumab in patients with advanced CSCC (aCSCC). Methods CA209-9JC was an open-label, single-arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment-naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Results Twenty-four patients with aCSCC were enrolled with a median age of 74 years (range, 48-93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow-up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment-related adverse events of any grade and grade >= 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities. Conclusions Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment-naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.
  • article 45 Citação(ões) na Scopus
    Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC
    (2019) BARLESI, Fabrice; GARON, Edward B.; KIM, Dong-Wan; FELIP, Enriqueta; HAN, Ji-Youn; KIM, Joo-Hang; AHN, Myung-Ju; FIDLER, Mary Jo; GUBENS, Matthew A.; CASTRO JR., Gilberto de; SURMONT, Veerle; LI, Qiao; DEITZ, Anne C.; LUBINIECKI, Gregory M.; HERBST, Roy S.
    Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had ""deteriorated"" status and more had ""improved"" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population.
  • article 64 Citação(ões) na Scopus
    Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study
    (2019) CHO, Byoung Chul; OBERMANNOVA, Radka; BEARZ, Alessandra; MCKEAGE, Mark; KIM, Dong-Wang; BATRA, Ullas; BORRA, Gloria; ORLOV, Sergey; KIM, Sang-We; GEATER, Sarayut L.; POSTMUS, Pieter E.; LAURIE, Scott A.; PARK, Keunchil; YANG, Cheng-Ta; ARDIZZONI, Andrea; BETTINI, Anna C.; CASTRO JR., Gilberto de; KIERTSMAN, Flavia; CHEN, Zhe; LAU, Yvonne Y.; VIRASWAMI-APPANNA, Kalyanee; PASSOS, Vanessa Q.; DZIADZIUSZKO, Rafal
    Introduction: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. Methods: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. Results: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). Conclusion: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity. (C) 2019 International Association for the Study of Lung Cancer.
  • article 734 Citação(ões) na Scopus
    11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial
    (2017) CAMERON, David; PICCART-GEBHART, Martine J.; GELBER, Richard D.; PROCTER, Marion; GOLDHIRSCH, Aron; AZAMBUJA, Evandro de; CASTRO JR., Gilberto; UNTCH, Michael; SMITH, Ian; GIANNI, Luca; BASELGA, Jose; AL-SAKAFF, Nedal; LAUER, Sabine; MCFADDEN, Eleanor; LEYLAND-JONES, Brian; BELL, Richard; DOWSETT, Mitch; JACKISCH, Christian
    Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1: 1: 1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10.09-11.53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0.76, 95% CI 0.68-0.86) and death (0.74, 0.64-0.86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1.02, 95% CI 0.89-1.17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7.3%) in the 2-years trastuzumab group, 74 (4.4%) in the 1-year trastuzumab group, and 15 (0.9%) in the observation group. Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.
  • article 83 Citação(ões) na Scopus
    Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score
    (2022) BURTNESS, Barbara; RISCHIN, Danny; GREIL, Richard; SOULIERES, Denis; TAHARA, Makoto; JR, Gilberto de Castro; PSYRRI, Amanda; BRANA, Irene; BASTE, Neus; NEUPANE, Prakash; BRATLAND, Ase; FUEREDER, Thorsten; HUGHES, Brett G. M.; MESIA, Ricard; NGAMPHAIBOON, Nuttapong; RORDORF, Tamara; ISHAK, Wan Zamaniah Wan; GE, Joy; SWABY, Ramona F.; GUMUSCU, Burak; HARRINGTON, Kevin
    PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) >= 1 and CPS >= 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS >= 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC. (c) 2022 by American Society of Clinical Oncology
  • article 27 Citação(ões) na Scopus
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