Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced microsatellite stable rectal adenocarcinoma: The Averectal study.

Background: Total neoadjuvant therapy(TNT) has improved complete pathologic response (pCR) rate and disease-free survival (DFS) in locally advanced rectal cancer (LARC), though an increased local recurrence rate (LRR) with short-course radiotherapy (SCRT) is concerning. Synergism between immunotherapy and radiotherapy may improve outcomes in LARC, even where microsatellite stable (MSS) tumours exist. The Averectal trial evaluated SCRT, followed by chemotherapy and immunotherapy with avelumab and total mesorectal excision (TME) in these patients.

Methods: Patients with LARC received SCRT (5 Gy x5 fractions), 6 cycles of mFOLFOX-6 plus avelumab every 2 weeks, followed by TME in an investigator-initiated, open-label, single-arm, multicentre, phase II study. The primary outcome was pCR vs. historical control. Secondary outcomes were 3-year DFS, local recurrence rate (LR) and the association of the ImmunoScore (IS) with outcomes including pCR, safety, and quality of life (QoL).

Results: Out Of 44 MSS patients enrolled from 3 centres (July 2018 -October 2020), 40 completed treatment and analysed (65 % male, median age 58.5 [31.0, 74.0] years). Median follow-up was 44 months (11.4, 51.4). Fifteen patients (37.5 %) achieved pCR; and 67.5 % had a major pathologic response. Mean DFS was 42 months (37.9, 46.1). Mean OS was 46.3 months (44.4, 48.2). Median DFS and OS were not reached. Three-year DFS was 85 %. LRR was 2.5 %. Patients with vs. without pCR had higher mean IS (68 vs. 52, p = 0.036). Serious adverse events occurred in 23.5 % (one was related to avelumab). Three patients died (7.5 %), due to disease progression. QOL was similar between baseline and last follow-up.

Conclusion: Adding avelumab to neoadjuvant chemotherapy mFOLFOX6 after SCRT, followed by TME, improved pCR without increasing LRR, with acceptable toxicity and QOL.