Phase II study of short-course radiotherapy (SCRT) followed by consolidation chemotherapy with FOLFOXIRI as total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) patients (pts): The ShorTrip study.

3592 Background: TNT is a recognised option for the treatment of LARC. The efficacy of both FOLFIRINOX followed by long-course CTRT and SCRT followed by FOLFOX or CAPOX was demonstrated in two phase III trials. No data are available regarding the feasibility and activity of SCRT followed by the triplet as TNT in LARC. Methods: ShorTrip is an Italian, prospective, multicentre, single-arm phase II trial (NCT05253846). Pts ≤70 years with medium-high (5-10 cm from the anal verge) LARC with at least one of the following features: cT4, cN2, involved mesorectal fascia (MRF+) or cT3N+, received SCRT followed by 8 cycles of FOLFOXIRI and surgery. The primary endpoint was the pCR rate. According to the Fleming single stage design, hypothesizing p0 = 0.25 and p1 = 0.40, setting 90% power with an α error of 0.10 (one-sided), the experimental regimen would have been considered promising if at least 21 pCRs were observed out of 63 enrolled pts. After the first 11 pts starting consolidation treatment, a higher than expected occurrence of severe neutropenia after the 1 st cycle of FOLFOXIRI (N = 7, 64%) was observed and the protocol was amended to administer one cycle of FOLFOX after SCRT followed by 7 cycles of FOLFOXIRI. Results: From January 2022 to February 2024, 64 pts were enrolled in 9 centres with the following characteristics: median age 62 years (IQR 55-66), male 66%, ECOG PS = 0 89%, medium/high rectum 76%/24%, cT2/cT3/cT4 5%/76%/19%, cN0/cN1/cN2 2%/35%/63%, MRF+ 42%, lateral nodes 35%, EMVI+ 41%. The 52 tumors tested for MMR were pMMR. One patient withdrew consent after the 1 st cycle of chemotherapy and was not evaluated for pathological response. 21 (33%) and 43 (67%) pts achieved pCR and major pathological response (MPR), respectively. Almost all pCRs (N = 20, 95%) and MPRs (N = 42, 98%) were observed in pts receiving at least 5 cycles of FOLFOXIRI (N = 56). Among 63 resected pts, 62 (98%) and 1 (2%) achieved R0 and R1 resections, respectively. All pts completed SCRT and the only grade 3/4 acute toxicity was diarrhoea in 7 (11%) pts. 49 (77%) pts received 8 cycles of consolidation treatment as planned. Irinotecan was never administered in 5 (8%) pts. Main grade 3/4 toxicity during consolidation are listed in the Table. Early post-surgical complications were reported in 8 (13%) pts. Conclusions: SCRT followed by one cycle of FOLFOX and 7 cycles of FOLFOXIRI showed a promising activity and a feasible safety profile and is therefore worth of further studies especially in the NOM scenario. Clinical trial information: NCT05253846 . Main G3/4 Adverse Events during consolidation CT Overall populationN=64n (%) Pre-amendmentN=11n (%) Post-amendmentN=53n (%) Any event 40 (62) 9 (82) 31 (58) Neutropenia 33 (52) 8 (72) 25 (47) Febrile Neutropenia 3 (5) 1 (9) 2 (4) Anaemia 5 (8) 1 (9) 4 (8) Diarrhoea 6 (9) 2 (18) 4 (8) Stomatitis 5 (8) 1 (9) 4 (8) Neurotoxicity 1 (2) 1 (9) - Asthenia 4 (6) 2 (18) 2 (4)