Short-Course Radiotherapy Based Total Neoadjuvant Therapy Combined with Toripalimab for Locally Advanced Rectal Cancer: Preliminary Findings from a Randomized, Prospective, Multicenter, Double-Arm, Phase II Trial (TORCH)

Abstract

<h3>Purpose/Objective(s)</h3> For patients with locally advanced rectal cancer (LARC), the standard treatment is neoadjuvant chemoradiotherapy combined with curative surgery. Total neoadjuvant therapy (TNT) has been used to increase rates of complete response and organ preservation, and achieve early control of distant metastasis. Recently, hypofractionated radiotherapy shows better synergistic effects in combination with PD-1/PD-L1 antibodies than conventional fractionated radiotherapy. Thus, the combination of short-course radiotherapy (SCRT) based TNT and immunotherapy is likely to further improve both tumor response and prognosis for LARC patients. <h3>Materials/Methods</h3> TORCH is a randomized, prospective, multicenter, double-arm, phase II trial. 130 LARC (T3-4/N+M0, distance from anus ≤10cm) patients will be treated with TNT approach and assigned to the consolidation arm (A) and induction arm (B). Arm A will receive SCRT (25 Gy/5Fx), followed by 6 cycles of Toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Arm B will first receive 2 cycles of ToriCAPOX, then receive SCRT, followed by 4 cycles of ToriCAPOX. Both groups will receive curative surgery or W&W strategy. The primary endpoint is the rate of complete response (CR, pCR plus cCR). The secondary endpoints include the grade 3-4 acute adverse effects (AE) rate, 3-year DFS rate, 3-year OS rate, etc. The "pick the winner" method is used to investigate the better regimen. <h3>Results</h3> Up to February 20, 2022, 81 patients have been recruited in the trial. A total of 16 patients (all MSS; arm A: 7, arm B: 9) have completed all neoadjuvant therapy. Most of them showed high risk factors of recurrence, including lower location (≤5cm, 14/16), deeper primary lesion invasion (cT4/MRF+, 7/16) and more positive lymph nodes (cN2, 9/16). Finally, 5 patients (arm A: 1, arm B: 4) achieved cCR and decided to adopt W&W strategy. 11 patients received surgery (Dixon: 6, Miles: 5) and the pathological results showed 8 cases of pCR (arm A: 4, arm B: 4), one near-pCR (arm A) and two non-pCR (arm A: 1, arm B: 1). Thus, the CR rate was amazingly high (CR rate: 81.25%, 13/16; pCR rate: 72.73%, 8/11). Even 6 patients who were evaluated as ycT3/N+/MRF+/EMVI+ before surgery was still demonstrated to be pCR after strict pathological examination. The only grade 3 AE was thrombocytopenia (37.50%, 6/16). And no grade 4 AE was observed. <h3>Conclusion</h3> SCRT base TNT combined with Toripalimab have achieved surprisingly excellent CR rate and good tolerance in LARC patients (in our cohort), which has the potential to improve organ preservation rate. In the future, this ongoing trial will demonstrate this efficacy and compare the two arms by larger sample size.