Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.
Cancer Med
; 9(14): 4991-5007, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32436621
ABSTRACT
BACKGROUND:
Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR.METHODS:
Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination.RESULTS:
Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively.CONCLUSIONS:
Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
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Proteínas Proto-Oncogênicas p21(ras)
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Carcinoma Pulmonar de Células não Pequenas
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Fluordesoxiglucose F18
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Tomografia por Emissão de Pósitrons
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Everolimo
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Sorafenibe
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Neoplasias Pulmonares
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cancer Med
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha