662TiP - Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA Study

Abstract

BackgroundPreop CTRT is the standard of treatment of LARC and it results in significant tumor downstaging and local control with a complete pathological response (pCR) rate of about 15%. Immunotherapy can lead up to a 50% of response in metastatic colorectal cancer (mCRC) with deficient mismatch repair (MMR) status, but its activity is extremely low in MMR proficient mCRC. In this context, the role of RT in revert the tolerance to a low neoantigen-burden by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been widely elucidated. Furthermore, in LARC pts, preop CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. On the basis of such premises we are conducting the AVANA study to explore the role of Ave in combination with preop CTRT in LARC. Trial designThis is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features, cN+, cT4, high risk cT3, receive standard preop CTRT (external-beam RT 50.4 Gray in 28 fractions over 5.5 weeks + capecitabine 825mg/sqm/bid 5 days/week) plus 6 cycles of Ave 10mg/Kg every 2 weeks. Surgery with total mesorectal excision is performed at week 8-10 after the end of CTRT. Postop CT is recommended according to pathologic response. The primary end-point is pCR rate. Secondary end-points are R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-sided) and a power of 80%, a sample size of 101 pts is needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen will be considered for further studies if in at least 22 pts we observe a pCR. The enrollment is ongoing. Sponsored by GONO and partially supported by Merck. Clinical trial identification2017-003582-10. Legal entity responsible for the studyGONO. FundingMerck KGaA. DisclosureAll authors have declared no conflicts of interest.