Roger von Moos1, Dieter Koeberle2, Sabina Schacher3, Stefanie Hayoz4, Ralph C Winterhalder5, Arnaud Roth6, György Bodoky7, Panagiotis Samaras8, Martin D Berger9, Daniel Rauch10, Piercarlo Saletti11, Ludwig Plasswilm12, Daniel Zwahlen13, Urs R Meier3, Pu Yan8, Paola Izzo14, Dirk Klingbiel4, Daniela Bärtschi4, Kathrin Zaugg8. 1. Kantonsspital Graubünden, Chur, Switzerland. Electronic address: roger.vonmoos@ksgr.com. 2. Kantonsspital St. Gallen, St. Gallen, Switzerland. 3. Kantonsspital Winterthur, Winterthur, Switzerland. 4. SAKK Coordinating Center, Bern, Switzerland. 5. Luzerner Kantonsspital, Luzern, Switzerland. 6. University Hospital Geneva, Geneva, Switzerland. 7. Szent László Teaching Hospital, Budapest, Hungary. 8. University Hospital Zürich, Zürich, Switzerland. 9. Inselspital Bern, Bern, Switzerland. 10. Regionalspital Thun, Thun, Switzerland. 11. IOSI, Bellinzona, Switzerland. 12. Kantonsspital St. Gallen, St. Gallen, Switzerland; Inselspital Bern, Bern, Switzerland. 13. Kantonsspital Graubünden, Chur, Switzerland. 14. Pathology CHUV, Lausanne, Switzerland.
Abstract
BACKGROUND: KRAS mutation occurs in ∼40% 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 end-points 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/m2 twice daily × 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.
BACKGROUND:KRAS mutation occurs in ∼40% 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 end-points 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/m2 twice daily × 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.
Authors: Rutika Mehta; Jessica Frakes; Jongphil Kim; Andrew Nixon; Yingmiao Liu; Lauren Howard; Maria E Martinez Jimenez; Estrella Carballido; Iman Imanirad; Julian Sanchez; Sophie Dessureault; Hao Xie; Seth Felder; Ibrahim Sahin; Sarah Hoffe; Mokenge Malafa; Richard Kim Journal: Oncologist Date: 2022-08-05 Impact factor: 5.837