Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08)

作者：von Moos Roger; Koeberle Dieter; Schacher Sabina; Hayoz Stefanie; Winterhalder Ralph C; Roth Arnaud; Bodoky Gyorgy; Samaras Panagiotis; Berger Martin D; Rauch Daniel; Saletti Piercarlo; Plasswilm Ludwig; Zwahlen Daniel; Meier Urs R; Yan Pu; Izzo Paola; Klingbiel Dirk; Bartschi Daniela; Zaugg Kathrin

来源：European Journal of Cancer, 2018, 89: 82-89.

DOI：10.1016/j.ejca.2017.11.005

• Dose escalation
• Chemoradiotherapy
• Efficacy Tyrosine kinase inhibitor
• Safety

Background: KRAS mutation occurs in w40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC.
Methods: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary endpoints were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4.
Results: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m(2) twice daily x 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%).
Conclusions: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www. clinicaltrials. gov: NCT00869570.

• 出版日期2018-1