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1.
J Clin Oncol ; 42(15): 1851-1860, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38452327

RESUMO

PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Aprovação de Drogas , Mutação , Nitrilas , Feniltioidantoína , Ftalazinas , Neoplasias de Próstata Resistentes à Castração , Reparo de DNA por Recombinação , United States Food and Drug Administration , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Benzamidas/uso terapêutico , Estados Unidos , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão
2.
J Clin Oncol ; 42(10): 1193-1201, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38381994

RESUMO

PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.


Assuntos
Neoplasias da Mama , Tetra-Hidronaftalenos , Adulto , Estados Unidos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , United States Food and Drug Administration , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
3.
Clin Cancer Res ; 24(13): 2999-3004, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29437768

RESUMO

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429-0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6-58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1-43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999-3004. ©2018 AACRSee related commentary by Spring and Bardia, p. 2981.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Aprovação de Drogas , Pós-Menopausa , Purinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Ensaios Clínicos como Assunto , Feminino , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/administração & dosagem , Purinas/efeitos adversos , Projetos de Pesquisa , Resultado do Tratamento
4.
Clin Cancer Res ; 22(20): 4968-4972, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27407089

RESUMO

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36-0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968-72. ©2016 AACR.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Aprovação de Drogas , Estradiol/análogos & derivados , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Estradiol/efeitos adversos , Estradiol/uso terapêutico , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
5.
Clin Cancer Res ; 21(21): 4760-6, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26324739

RESUMO

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Aprovação de Drogas , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , United States Food and Drug Administration , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Metástase Neoplásica , Seleção de Pacientes , Pós-Menopausa , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Projetos de Pesquisa , Resultado do Tratamento , Estados Unidos
6.
Clin Cancer Res ; 20(21): 5359-64, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25204553

RESUMO

On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab-docetaxel (TD), pertuzumab-trastuzumab-docetaxel (PTD), pertuzumab-trastuzumab, or pertuzumab-docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/genética , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Terapia Neoadjuvante/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug Administration
7.
Clin Cancer Res ; 19(24): 6650-6, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24150234

RESUMO

On December 10, 2012, the U.S. Food and Drug Administration granted full approval for a modified indication for abiraterone acetate (Zytiga tablets; Janssen Biotech, Inc.) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The approval was based on clinical trial COU-AA-302, which randomly allocated asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC and no visceral metastases to either abiraterone acetate plus prednisone (N = 546) or placebo plus prednisone (N = 542). The coprimary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). The median rPFS was 8.3 months in the placebo arm and had not yet been reached in the abiraterone acetate arm {HR, 0.43 [95% confidence interval (CI) 0.35-0.52]; P < 0.0001}. A prespecified interim analysis demonstrated an improvement in OS favoring the abiraterone acetate arm [HR, 0.79 (95% CI, 0.66-0.96)] but did not cross the O'Brien-Fleming boundary for statistical significance. Safety data confirmed the known adverse reaction profile of abiraterone acetate. Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in OS, and internal consistency across multiple secondary endpoints and exploratory patient-reported pain data. This is the first drug approval for mCRPC to use rPFS as the primary endpoint. Importantly, this approval was granted in the context of a prior statistically significant OS benefit that formed the basis of the original April 28, 2011, approval of abiraterone acetate for patients with mCRPC who had received prior chemotherapy containing docetaxel.


Assuntos
Androstadienos/administração & dosagem , Aprovação de Drogas , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona , Androstadienos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Humanos , Masculino , Prednisona/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/administração & dosagem , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
8.
Clin Cancer Res ; 19(18): 4911-6, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23801166

RESUMO

On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aprovação de Drogas , Metástase Neoplásica/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Docetaxel , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Taxoides/administração & dosagem , Trastuzumab , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
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