RESUMO
BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Neoplasias da Mama , Letrozol , Feminino , Humanos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Letrozol/administração & dosagem , Letrozol/efeitos adversos , Letrozol/uso terapêutico , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/uso terapêutico , Receptor ErbB-2/metabolismo , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Receptores de Estrogênio , Receptores de Progesterona , Gosserrelina/administração & dosagem , Gosserrelina/efeitos adversos , Gosserrelina/uso terapêutico , Antineoplásicos Hormonais , MasculinoRESUMO
BACKGROUND: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. METHODS: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. CONCLUSIONS: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).
Assuntos
Anticorpos Monoclonais Humanizados , Inibidores de Checkpoint Imunológico , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Indazóis , Neoplasias Renais , Pirimidinas , Sulfonamidas , Sunitinibe , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Sunitinibe/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Idoso , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , OximasRESUMO
BACKGROUND: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. METHODS: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. FINDINGS: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). INTERPRETATION: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Adulto JovemRESUMO
BACKGROUND: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing. FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group. INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Avaliação de Resultados em Cuidados de Saúde , Placebos/administração & dosagem , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/secundárioRESUMO
BACKGROUND: A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. METHODS: In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. RESULTS: The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. CONCLUSIONS: Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Nitrilas/efeitos adversos , Piperazinas/efeitos adversos , Pós-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Receptores de Estrogênio/análise , Triazóis/efeitos adversosRESUMO
AIM: This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1). PATIENTS & METHODS: Women (≥18 years) were randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin. RESULTS: For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26). CONCLUSION: LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.
Assuntos
Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/prevenção & controle , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Filgrastim , Humanos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Polietilenoglicóis , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. METHODS: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. FINDINGS: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). INTERPRETATION: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. FUNDING: Eli Lilly and Company.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Indução de Remissão/métodos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalos de Confiança , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento , RamucirumabRESUMO
BACKGROUND: In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. METHODS: In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816. FINDINGS: Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2-12·1] vs 6·5 months [4·7-8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56-1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. INTERPRETATION: Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. FUNDING: Pfizer Inc.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Axitinibe , Carcinoma de Células Renais/patologia , Fatores de Confusão Epidemiológicos , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , América do Norte , Razão de Chances , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Projetos de Pesquisa , Índice de Gravidade de Doença , Sorafenibe , Resultado do TratamentoRESUMO
BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.PALOMA-2 demonstrated statistically and clinically significant improvement in progression-free survival with palbociclib plus letrozole versus placebo plus letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC). Here, we report results for the secondary end point overall survival (OS). Postmenopausal women (N = 666) with ER+/HER2- ABC without previous systemic therapy for ABC were randomly assigned 2:1 to palbociclib plus letrozole or placebo plus letrozole. After a median follow-up of 90.1 months, 405 deaths were observed and 155 patients were known to be alive. The median OS was 53.9 months (95% CI, 49.8 to 60.8) with palbociclib plus letrozole versus 51.2 months (95% CI, 43.7 to 58.9) with placebo plus letrozole (hazard ratio [HR], 0.96 [95% CI, 0.78 to 1.18]; stratified one-sided P = .34). An imbalance in the number of patients with unknown survival outcome between the treatment arms (13.3% v 21.2%, respectively) limited interpretation of OS results. With recovered survival data, the median OS was 53.8 (95% CI, 49.8 to 59.2) versus 49.8 months (95% CI, 42.3 to 56.4), respectively (HR, 0.92 [95% CI, 0.76 to 1.12]; one-sided P = .21). OS was not significantly improved with palbociclib plus letrozole compared with placebo plus letrozole.
Assuntos
Neoplasias da Mama , Piperazinas , Piridinas , Humanos , Feminino , Letrozol , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD-L1) expression, as quantified by combined positive score (CPS; PD-L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple-negative breast cancer (mTNBC) in the phase 3 KEYNOTE-119 study. This exploratory analysis was conducted to determine whether the expression of PD-L1 on tumour cells contributes to the predictive value of PD-L1 CPS in mTNBC. PD-L1 expression in tumour samples was assessed using PD-L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD-L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58-0.80) for CPS, 0.55 (95% CI = 0.46-0.64) for TPS, and 0.67 (95% CI = 0.56-0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression-free survival, and overall survival. Data from this exploratory analysis suggest that, although PD-L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD-L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD-L1 expression) may improve prediction. PD-L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.
Assuntos
Antígeno B7-H1 , Neoplasias de Mama Triplo Negativas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Intervalo Livre de Progressão , Biomarcadores Tumorais/metabolismoRESUMO
BACKGROUND: In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119. METHODS: Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline. RESULTS: HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, -1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points. CONCLUSIONS: HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10.
Assuntos
Qualidade de Vida , Neoplasias de Mama Triplo Negativas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1 , Náusea , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , VômitoRESUMO
BACKGROUND: In KEYNOTE-355 (NCT02819518), addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer (TNBC) with tumor PD-L1 combined positive score (CPS) ≥10. We report patient-reported outcomes (PROs) from KEYNOTE-355. METHODS: Patients were randomized 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). QLQ-C30, QLQ-BR23, and EQ-5D visual analogue scale (VAS) were prespecified. PROs were analyzed for patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. Change in PRO scores from baseline were assessed at week 15 (latest time point at which completion/compliance rates were ≥60%/≥80%). Time to deterioration (TTD) in PROs was defined as time to first onset of ≥ 10-point worsening in score from baseline. RESULTS: PRO analyses included 317 patients with tumor PD-L1 CPS ≥10 (pembrolizumab plus chemotherapy; n = 217; placebo plus chemotherapy, n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (GHS/QoL; least-squares mean difference, -1.81 [95% CI, -6.92 to 3.30]), emotional functioning (-1.43 [-7.03 to 4.16]), physical functioning (-1.05 [-6.59 to 4.50]), or EQ-5D VAS (0.18 [-5.04 to 5.39]), and no between-group difference in TTD in QLQ-C30 GHS/QoL, emotional functioning, or physical functioning. CONCLUSIONS: Together with the efficacy and safety findings, PRO results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced TNBC with tumor PD-L1 (CPS ≥10).
RESUMO
BACKGROUND: PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated. OBJECTIVE: The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened. PATIENTS AND METHODS: Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses. RESULTS: Of 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656-1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups. CONCLUSION: Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).
Assuntos
Medicamentos Biossimilares , Neoplasias da Mama , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Receptor ErbB-2 , Trastuzumab/efeitos adversosRESUMO
This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab (R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: [-8.77% to 10.17%]) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Medicamentos Biossimilares/administração & dosagem , Ciclofosfamida/administração & dosagem , Método Duplo-Cego , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). METHODS: Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. FINDINGS: Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade ≥3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. INTERPRETATION: This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: In a randomized phase III trial in treatment-naive patients with metastatic renal cell carcinoma (RCC), axitinib versus sorafenib yielded numerically longer progression-free survival (median, 10.1 vs. 6.5 months; hazard ratio [HR], 0.77; 1-sided P = .038) and significantly higher objective response rate (32% vs. 15%; 1-sided P = .0006). In this article, we report overall survival (OS) and updated safety results. PATIENTS AND METHODS: Previously untreated patients with metastatic RCC (n = 288), stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1), were randomized 2:1 to receive axitinib 5 mg twice per day (b.i.d.; n = 192) or sorafenib 400 mg b.i.d. (n = 96). RESULTS: Median OS (95% confidence interval [CI]) was 21.7 months (18.0-31.7) with axitinib versus 23.3 months (18.1-33.2) with sorafenib (stratified HR, 0.995; 95% CI, 0.731-1.356; 1-sided P = .4883). Among patients with ECOG PS of 0, median OS was numerically longer with axitinib than with sorafenib (41.2 vs. 31.9 months; HR, 0.811, 1-sided P = .1748), whereas among patients with ECOG PS 1, median OS was shorter with axitinib than with sorafenib (14.2 vs. 19.8 months; HR, 1.203; 1-sided; P = .7973). Incidence and severity of common adverse events were consistent with previous reports. CONCLUSION: OS was similar between axitinib and sorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Axitinibe , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. PATIENTS AND METHODS: In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. RESULTS: Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. CONCLUSION: Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Intervalo Livre de Doença , Docetaxel , Método Duplo-Cego , Esquema de Medicação , Fadiga/induzido quimicamente , Neutropenia Febril/induzido quimicamente , Feminino , Síndrome Mão-Pé/etiologia , Humanos , Hipertensão/induzido quimicamente , Imunoglobulina G , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estomatite/induzido quimicamente , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do Tratamento , RamucirumabRESUMO
PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ≥ 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.