Nogova, Lucia, Mattonet, Christian, Scheffler, Matthias ORCID: 0000-0002-9031-1368, Taubert, Max ORCID: 0000-0001-8925-7782, Gardizi, Masyar, Sos, Martin L., Michels, Sebastian, Fischer, Rieke N., Limburg, Meike, Abdulla, Diana S. Y., Persigehl, Thorsten, Kobe, Carsten, Merkelbach-Bruse, Sabine, Franklin, Jeremy, Backes, Heiko, Schnell, Roland, Behringer, Dirk, Kaminsky, Britta, Eichstaedt, Martina, Stelzer, Christoph, Kinzig, Martina, Soergel, Fritz, Tian, Yingying, Junge, Lisa, Suleiman, Ahmed A., Frechen, Sebastian, Rokitta, Dennis, Ouyang, Dongsheng, Fuhr, Uwe, Buettner, Reinhard and Wolf, Juergen (2020). 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). S. 4991 - 5008. HOBOKEN: WILEY. ISSN 2045-7634

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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 degrees and pneumonia III degrees 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mattonet, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDorcid.org/0000-0002-9031-1368UNSPECIFIED
Taubert, MaxUNSPECIFIEDorcid.org/0000-0001-8925-7782UNSPECIFIED
Gardizi, MasyarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, Rieke N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Limburg, MeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdulla, Diana S. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobe, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franklin, JeremyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Backes, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnell, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behringer, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaminsky, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichstaedt, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stelzer, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kinzig, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soergel, FritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tian, YingyingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Junge, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suleiman, Ahmed A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frechen, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rokitta, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ouyang, DongshengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuhr, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-333155
DOI: 10.1002/cam4.3131
Journal or Publication Title: Cancer Med.
Volume: 9
Number: 14
Page Range: S. 4991 - 5008
Date: 2020
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 2045-7634
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; DOUBLE-BLIND; OPEN-LABEL; PROGRESSION-FREE; PLUS; SURVIVAL; THERAPY; EGFR; CHEMOTHERAPY; CRIZOTINIBMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33315

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