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1.
Eur Urol Oncol ; 7(4): 933-943, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38105142

RESUMEN

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC. METHODS: The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously). KEY FINDINGS AND LIMITATIONS: The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients. CONCLUSIONS AND CLINICAL IMPLICATIONS: Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied. PATIENT SUMMARY: In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Transicionales , Nivolumab , Humanos , Nivolumab/uso terapéutico , Anciano , Masculino , Femenino , Persona de Mediana Edad , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Adulto , Metástasis de la Neoplasia , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/mortalidad , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología
2.
J Thorac Oncol ; 18(7): 907-921, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36842467

RESUMEN

INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Anilidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Microambiente Tumoral
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