Updated 5-year survival outcomes of short-course radiation followed by mFOLFOX-6 plus avelumab in locally advanced microsatellite-stable rectal adenocarcinoma: The Averectal phase II study.

3643 Background: Total neoadjuvant therapy (TNT) for microsatellite-stable (MSS) locally advanced rectal cancer consists of induction or consolidation chemotherapy combined with either long-course chemoradiation (LCCRT) or short-course radiation therapy (SCRT). While TNT has yielded variable outcomes across studies, it has consistently improved pathologic complete response (pCR) rates and paved the way for non-operative management strategies. However, the use of SCRT within TNT has been associated with higher rates of local recurrence. The integration of immunotherapy into total neoadjuvant therapy (TNT) improves outcomes in LARC, particularly pathologic complete response (pCR), which may translate into improvements in disease-free survival (DFS) and overall survival (OS), in addition to improvement in local recurrence rate (LRR) especially when used with SCRT, potentially through synergistic effects with radiotherapy. Methods: The Averectal trial is an investigator-initiated, open-label, single-arm, multicenter, phase II study including 44 patients. 40 patients with LARC completed treatment with SCRT (5 Gy x5 fractions) followed by 6 cycles of mFOLFOX-6 plus avelumab every 2 weeks, followed by TME. The primary outcome was pCR vs. historical control. Secondary outcomes were 3-year DFS, LRR and the association of the ImmunoScore (IS) with outcomes including pCR. Results: 15/40 (37.5 %) patients achieved pCR compared to 16 % in the historical control group with statistically significant p = 0.025, and 27/40 (67.5 %) had a major pathologic response. Patients who achieved pCR had a higher mean IS compared with those who did not (68 vs. 52, p = 0.049). With a median follow up of 72.8 months (range 15.4-97.1), the median OS and DFS were not reached. The mean OS and DFS were 85.3 months and 79 months respectively, and the 5-year OS and DFS were 81.9% and 74.6%. Only 2/40 patients had local recurrence, accounting for a LRR of 5%. In patients with high versus low IS, median OS was not reached in either group (p = 0.9), with mean OS of 79.3 months versus 84.7 months, respectively. Similarly, median DFS was not reached, although there was a trend towards improved DFS in the high IS group (p = 0.175), with mean DFS of 77.6 months versus 70.7 months for high and low IS, respectively. Conclusions: The addition of avelumab to TNT in patients with MSS LARC resulted in a statistically significant increase in pCR, notably among those with high IS, and was associated with continued improvement in survival outcomes at 5 years. Clinical trial information: NCT03503630 .