Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Desenho de Fármacos , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Divisão Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fator de Crescimento Epidérmico , Receptores ErbB/imunologia , Receptores ErbB/fisiologia , Humanos , Infusões Intravenosas , Camundongos , Terapia de Alvo Molecular , Mutação , Transplante de Neoplasias , Panitumumabe , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genéticaRESUMO
OBJECTIVE: Mutation status of the KRAS gene in tumors has been shown to be a predictive biomarker of response to anti-epidermal growth factor receptor antibody therapy in patients with metastatic colorectal cancer. This retrospective analysis examined the association between efficacy and safety of the fully human anti-epidermal growth factor receptor antibody panitumumab and KRAS mutation status in Japanese metastatic colorectal cancer patients using data from two clinical trials with adherence to good clinical practices. METHODS: An exploratory, integrated analysis of data from KRAS evaluable patients enrolled in a Phase 1 study (Study 20040192) and a Phase 2 study (Study 20050216) was performed. Paraffin-embedded tumor samples were analyzed for KRAS status. Primary efficacy endpoint of this analysis was objective tumor response per modified response evaluation criteria in solid tumors; a key secondary endpoint was progression-free survival. Safety endpoints included incidence of adverse events. RESULTS: Tumor samples with known KRAS status were available from 8 of 13 (62%) metastatic colorectal cancer patients in the Phase 1 study and 16 of 53 patients (30%) in the Phase 2 study. Overall, 14 (58%) patients had wild-type KRAS tumors and 10 (42%) patients had mutated KRAS tumors. Four (17%) patients had a partial response; all responders had tumors with wild-type KRAS. Results of all secondary efficacy endpoints also favored patients with wild-type KRAS. Treatment-related adverse events were predominantly mild to moderate and skin related, and were similar between patients with tumors with wild-type and mutated KRAS in this small patient population. CONCLUSIONS: Mutated KRAS status in tumors of Japanese patients with metastatic colorectal cancer is associated with lack of response to panitumumab therapy.
Assuntos
Anticorpos Monoclonais/farmacologia , Povo Asiático/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Panitumumabe , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Análise de SobrevidaRESUMO
OBJECTIVE: Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), has antitumor activity and an acceptable safety profile in patients with metastatic colorectal cancer (mCRC). This Phase 2 study evaluated efficacy, pharmacokinetics and safety of panitumumab in Japanese patients with mCRC who developed progressive disease during or after fluoropyrimidine, irinotecan and oxaliplatin chemotherapy. METHODS: Eligible patients had histologically proven colorectal adenocarcinoma and EGFR tumor expression in > or =1% of tumor cells by immunohistochemistry. Patients received panitumumab 6 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (RECIST) by independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), pharmacokinetic parameters and incidence of adverse events. RESULTS: Fifty-two patients received at least one dose of panitumumab. Seven patients had partial responses for a confirmed ORR of 13.5% (95% CI: 5.6, 25.8). Median PFS was 8.0 weeks (95% CI: 7.4, 11.4) and median OS was 9.3 months (95% CI: 7.1, 12.8). Panitumumab pharmacokinetics were consistent with prior studies in Japanese and non-Japanese patients. The most common treatment-related adverse events (all, worst grade 3) were acne (81%, 2%), dry skin (62%, 0%), rash (46%, 2%), paronychia (33%, 2%), pruritus (33%, 0%) and hypomagnesemia (33%, 0%). No adverse event of infusion reaction was reported by the investigators. CONCLUSIONS: Panitumumab monotherapy was active in Japanese patients with chemotherapy-refractory mCRC, with pharmacokinetic and safety profiles similar to those seen in prior studies.