431P Neoadjuvant treatment with regorafenib and capecitabine combined with radiotherapy in locally advanced rectal cancer: A multicenter phase Ib trial (RECAP) SAKK 41/16

Abstract

Currently high risk locally advanced rectal cancer (LARC) patients (pts) are treated with intensified neoadjuvant chemotherapy and radiation (TNT). The previous study SAKK 41/08 showed that adding Sorafenib to long course chemoradiation (LcCRT) is highly active. This potential improvement in clinical outcome by adding a multi-TKI as Regorafenib (R) to LcCRT was investigated in the SAKK 41/16 trial. Pts with T3-4 and/or N+ M0 rectal cancer were included. Neoadjuvant LcRCT was given with Capecitabine 825mg/m2d1-d38 and 28 fractions of 1.8Gy (50.4Gy). R was added d1-14 and d22-35. The phase I part was done in a 3+3 dose escalation (DE) scheme for R. The recommended dose (RD) was used for the cohort expansion (CE). The primary endpoints included dose limiting toxicity (DLT) and pathological response (defined as near complete regression [npCR] or complete regression [pCR] according to Dworak) for the CE. 19 pts were required based on a one-sided type I error 20% and a power 80% for assuming a npCR/pCR rate of ≥ 40% for H1 compared to npCR/pCR rate of ≤ 20% for H0.. 25 pts were included. Two DLT occurred with R 120mg, ending in a RD of 80mg daily. 19 pts were treated with the RD, 8 pts (42.1%; one-sided 80% CI (lower bound): 30.7%; 95% CI: 20.3%-66.5%) reached the primary endpoint (5 pts [26.3%] had npCR and 3 pts [15.8%] had pCR). One additional patient received no surgery due to clinical CR. Downstaging of T and/or N was seen in 15 of 18 operated pts (83.3%). All pts had R0 resection and clear circumferential margin. Postoperative complications occurred in 6 pts (35.3%), one anastomotic leak grade G4, 3 pts with local infections. The most common treatment related adverse events ≥ G3 in the CE were diarrhea and rectal anastomotic leak in 2 pts each. Adding Regorafenib in RD 80 mg to LcCRT in LARC reached both primary endpoints and showed high activity. This regimen did not prolong the neoadjuvant treatment time in contrast to TNT. Toxicity was manageable, and postoperative complications were as expected. This regimen deserves further investigation especially in efficacy comparision to TNT regimens.