RESUMO
Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07-0.52) and progression-free survival (hazard ratios range: 0.30-0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Ensaios Clínicos como Assunto , Receptores ErbB/antagonistas & inibidores , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Estudos Observacionais como Assunto , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
PURPOSE: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). EXPERIMENTAL DESIGN: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m(2)) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m(2), twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. RESULTS: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. CONCLUSIONS: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity.
