Phase II trial of anti PD-1 monoclonal antibody and FOLFOXIRI combined with long-course radiotherapy as the total neoadjuvant treatment for proficient mismatch repair, locally advanced, low rectal cancer (PANFORTE).

e15621 Background: The current standard treatment for locally advanced low rectal cancer (LALRC) achieves a complete response (CR) rate of only 20–30%. Consequently, radical surgery frequently results in the loss of anal organs, severely affecting patients’ quality of life. Therefore, there is an urgent clinical need to identify novel strategies that can maximize tumor regression and preserve anal function. Recent trials has demonstrated radiotherapy showed a distinctive synergistic anti-tumor effect with immune checkpoint inhibitors. Therefore, this study aim to assess the efficacy and safety of an immunotherapy-based total neoadjuvant therapy (TNT) in patients with proficient mismatch repair (pMMR) LALRC. Methods: In this ongoing single-arm study, we plan to enroll 53 patients with pMMR LALRC. Inclusion criteria include ECOG performance status ≤ 1 and an inferior tumor margin distance from the anal verge (DAV) ≤ 5 cm. Eligible patients receive 4 cycles of FOLFOXIRI plus serplulimab (200 mg) . Subsequently, they undergo long-course radiotherapy combination with capecitabine and 2 cycles of serplulimab (200 mg), followed by another 4 cycles of FOLFOXIRI and serplulimab (200 mg) . The primary endpoint is CR rate with the sum of clinical complete response (cCR) and pathological complete response (pCR). Secondary endpoints include sphincter preservation rate and safety. Single-cell RNA (scRNA) sequencing was utilized to investigate the molecular characterization. Results: Between November 2023 and June 2024, 22 patients were enrolled with male percentage of 50%, median age of 59 years (IQR, 54–66) and median DAV of 4 cm (IQR, 3–5). 86.3% (19/22) patients completed the full TNT regimen. Among the 20 patients eligible for endpoint assessments, the overall CR rate was 75% (15/20), and the sphincter preservation rate was 95% (19/20). 11 (55%) patients achieving cCR opted for a watch-and-wait approach, whereas 9 patients underwent radical surgery. 20% (4/20) achieved pCR and 25% (5/20) had a tumor regression grade (TRG) of 2. The most common severe toxicity was neutropenia (grade 3, 27.3% [6/22]; grade 4, 36.4% [8/22]). One (4.6%, 1/22) patient experienced grade 4 hyperammonemia encephalopathy. Other grade 3 toxicities included decreased hemoglobin (13.6%, 3/22), diarrhea, myocarditis, myasthenia gravis, and thrombocytopenia (each 4.6%, 1/22). The scRNA sequencing indicated that non-CR patients exhibited lower T cell infiltration and weaker MHC-I/II signaling. Conclusions: Our study indicates that this TNT regimen significantly enhances CR rates and anal preservation in pMMR LALRC compared to historical benchmarks, with an acceptable safety profile. These findings suggest that this new approach may be an alternative treatment option for LALRC patients who strongly desire anal preservation. Clinical trial information: NCT06099951 .