509O - Total neoadjuvant treatment (TNT) with non-operative management (NOM) for proficient mismatch repair locally advanced rectal cancer (pMMR LARC): First results of NO-CUT trial

Background

TNT followed by rectal surgery (ReSu) is standard of care in pMMR LARC. In patients achieving clinical complete response (cCR) after TNT, NOM consisting of intensive follow-up can be proposed as an alternative to ReSu. NO-CUT is a multicenter single arm phase II trial in patients with pMMR LARC (EudraCT 2017-003671-60) aimed at assessing if a) NOM jeopardizes distant relapse-free survival (DRFS); b) predictive biomarkers of cCR can be identified by multiomic analyses in tumor and blood samples.

Methods

Patients with cT3-4N0/cTxN1-2 lower/middle pMMR LARC in 4 cancer centres received TNT consisting of 4 CAPOX cycles followed by long-course chemoradiotherapy over 5 weeks. After TNT, patients were assigned to ReSu or NOM cohorts according to the protocol algorithm based on cCR parameters (Siena S. et al ASCO 2023). With 44 patients allocated to the NOM cohort, the study had an α = 0.1 and β = 0.2 to reject a 30-month DRFS (DRFS₃₀) of 75% (H₀), assuming a DRFS₃₀ of at least 87% (H₁) and a follow-up of 30 months. Assuming a 25% cCR rate after TNT, the study needed to enrol 180 patients. Multiomics correlative analyses comprised tissue transcriptomic signature (Isella C et al., Nature Genet, 2015) and tissue-agnostic circulating tumor DNA by Guardant Reveal (Nakamura Y. et al., JCO, 2024).

Results

From 2018 to 2024, 180 patients underwent TNT, 164 (91%) completed treatment per protocol, and 46 (25.5%) were assigned to NOM cohort. The DRFS30 was 96.9% in the NOM and 74% in the ReSU cohorts (median follow-up was 26 (18-36) and 10 (9-19) months, respectively). Local regrowth occurred in 15% of NOM and 9% of ReSu cohorts, respectively. As of April 1st 2024, 12 deaths (6.6%) were reported (1 adverse event-, 9 tumor-, and 2 other causes- related). Complete multiomics correlative analyses are in progress. Circulating tumor DNA by liquid biopsies in the first 77 patients correlated with cCR and DRFS.

Conclusions

The primary endpoint of NO-CUT trial was met, with the finding that this TNT approach led to a 25.5% NOM rate with a DRFS30 of 96.9%.Supported by grants from Fondazione AIRC ETS (grant IG 2017-20685) and Fondazione Oncologia Niguarda ETS (unrestricted NO-CUT Trial grant).

Clinical trial identification

EudraCT 2017-003671-60.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Fondazione AIRC ETS; Fondazione Oncologia Niguarda ETS.

Disclosure

A. Amatu: Financial Interests, Personal, Advisory Board: Amgen. F. Bergamo: Financial Interests, Personal, Invited Speaker: Lilly, BMS, MSD, Eisai, Bayer, Amgen; Financial Interests, Personal, Advisory Board: Servier, AAA; Other, Congress: Bayer, Ipsen, AAA. S. Mosconi: Financial Interests, Personal, Invited Speaker: RAY HC srl; Non-Financial Interests, Member of Board of Directors, Member of Expert Panel: AIOM; Non-Financial Interests, Member, Membership: AIOM; Non-Financial Interests, Membership: AIFET. A. Sartore Bianchi: Financial Interests, Personal, Invited Speaker: Amgen, Bayer, Pierre Fabre; Financial Interests, Personal, Advisory Board: Servier, Takeda. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi-Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics, Merck, MSD. All other authors have declared no conflicts of interest.